When I look into the eyes of a patient losing the battle with cancer, I say to myself, “It doesn’t have to be this way.”

— Andrew C. von Eschenbach, M.D. Director, National Cancer Institute, physician, cancer survivor

The Nation’s Investment in Cancer Research

A Plan and Budget Proposal for Fiscal Year 2004

Prepared by the Director National Cancer Institute

NATIONAL INSTITUTES OF HEALTH U.S. Department of Health and Human Services The National Cancer Institute

. . . working to achieve a future when all cancers are controlled or eliminated.

Through studies of the cell, we: ■ Explore how specific cancer-causing mutations and protein errors disrupt normal cellular communication and lead to uncontrolled growth and loss of normal function. ■ Learn which genes and proteins play a key role in cancer invasion and spread. ■ Develop molecular agents that will interact with malfunctioning proteins to prevent cancerous growth.

With studies of cancer in the context of the person, we: ■ Identify the integral ways that surrounding cells and tissues contribute to tumor growth — and the means of manipulating this microenvironment to defeat the cancer. ■ Apply new technologies and informatics to detect cancer and monitor therapy. ■ Learn how to prevent and treat cancer with agents and technologies that attack the cancer, but leave the person unharmed.

With population studies, we: ■ Investigate gene-environment interactions that increase people’s risk of developing cancer and their need for enhancing prevention and early detection measures. ■ Identify specific ways to reduce cancer risk by changing behavior and eliminating harmful environmental exposures. ■ Develop effective communication and delivery strategies to ensure that all people benefit from cancer prevention, early detection, and treatment.

“Without research, there is no hope.” — The Honorable Paul G. Rogers, Sponsor, National Cancer Act of 1971

Front cover graphic: Scanning electron micrograph of metastatic lung cancer cells in culture, courtesy of Jeffrey Wyckoff, Jeffrey E. Segall, and John Condeelis at the Albert Einstein College of Medicine and the Analytical Imaging Facility at the Albert Einstein College of Medicine, an Albert Einstein Comprehensive Cancer Center shared resource. Director’s Message knowledge gainedaboutthegenetic,molecular, andcellularbasisofcancerintothe and delivered We opportunities, threethemeswilldominateNCI’s planninganddecisionmaking: in ourunderstandingofcancerandabilitytocontroleliminateit.To takefulladvantageofthese the fruitsofmanyyearsinvestigationwillyield,overnexttwodecades,unimaginedleapsforward interventions todetect,diagnose,treat,andpreventcancer;ensurethattheseare We We that influencecancer. of thebehavioral,social,andenvironmentalfactors of thebody, andthewholepersonincontext “microenvironment” andthebroaderenvironment the tumorincontextofbothitsimmediate the proteinalongwithgenethatproducesit, of thehumansystem.Thatis,wemustconsider cancer developsandprogresseswithinthecontext the disparatepiecesofknowledgethatrevealhow logical researchtocomprehensivelyweavetogether advantage oftheexplosionintechnologyandbio- tothestudyofcancer systems approach Our intramural researchprogramwillset anew into clinicalpracticeandpublic healthprograms. more effective cancercareandcontrol interventions interventions intoclinicaltrials andtointegrate potential preventive,diagnostic, andtherapeutic greater emphasisontranslational researchtomove and theinterfaceofagingcancer. We alsoplace the tumormicroenvironment,cancersurvivorship, budget proposalnewinitiatives For FiscalYear 2004, weare the-art science. clinical practiceandpublichealthwithstate-of- comprehensive CancerCenters,toinformboth our researchresults,withspecialemphasison I amcommittingNCItorigorouslydisseminate against cancer. Whileadheringto our NCImandate, development-delivery forlife sary delays,alongthe agencies andprivategroupstoeliminateunneces- edge tocancercare

must need to as anationstandatthatdefiningmoment delivery ensure theapplicationofourresearchknowl- oeorefrstwr nintegrated hone oureffortstowardan to allwhoneedthem. . Ourchallengewillbetocontinueacceleratetheengineof . NCIwillcollaboratewithother pathway ofdiscovery- adding toourplanand to betterunderstand saving interventions . We musttake We We and otheradvocates. October 2002 National CancerInstitute Director Andrew C.vonEschenbach,M.D. comprehensive science. evaluated toward thegoalsdescribedinfollowingpagesis and Iam support ofthePresident’s ManagementAgenda, against thecriteriarecentlyestablishedin We diverse populationgroups. disparities intheincidenceofcanceramong and reducebiologic,socioeconomic,cultural and treatment.Andwewillstrivetounderstand and timelycancerprevention,screening,diagnosis, income, andgender, hasaccesstohighquality ensuring thateveryAmerican,regardlessofrace, of scientists,physicians, through partnershipswithourNation’s community of theNationalInstitutesHealth,especially to collaborateaggressively We standard forexemplarytranslationalresearch. in historywhenasurgeofnewtechnologiesand

will alsoaskthatourprogramsbeexamined are will redoubleoureffortstoeliminatedisparities working tofindnewandmoreeffectiveways against theobjectivesofsoundand committed tomakingsurethatprogress A Planand BudgetProposal forFiscalYear 2004 discovery both insideandoutside nurses, discovery development cancer survivors, ; totranslate , development by of ,

1 DIRECTOR’S MESSAGE Table of Contents

1 Director’s Message

3 Executive Summary

8 Highlights of Progress

14 Our Role in Cancer Research

18 National Agendas for Disease-Specific Research

24 Planning and Priority Setting for Cancer Research Fiscal Year 2004 Budget Request

26 Building the Nation’s Cancer Research Capacity 27 Enhancing Investigator-Initiated Research 32 Expanding the Capacity of Centers, Networks, and Consortia 36 National Clinical Trials Program in Treatment and Prevention 42 Developing Bioinformatics for Cancer Research

46 The Interface of Aging and Cancer

48 Advancing Discovery and Its Application 49 Genes and the Environment 55 Signatures of the Cancer Cell and Its Microenvironment 60 Molecular Targets of Prevention and Treatment 65 Cancer Imaging and Molecular Sensing 72 Cancer Communications

77 Addressing Areas of Public Health Emphasis 78 Improving the Quality of Cancer Care 84 Reducing Cancer-Related Health Disparities 88 Cancer Survivorship: Improving Treatment Outcomes and Quality of Life 94 Research on Tobacco and Tobacco-Related Cancers

Progress Reports 31 Increased Investment Strengthens Research Training and Career Development 83 Sustained Investment in Studying Cancer Trends Improves Knowledge and Understanding of Cancer

Spotlights on Research 41 Drug Discovery and Development: A Life Saving Investment 54 Genes and Proteins: Profiles of Hope

Story of Discovery 70 Harnessing Apoptosis to Destroy Cancer Cells

People’s Stories 23 Esophageal Cancer 93 Adult Survivors of Childhood Cancers

2 The Nation’s Investment in Cancer Research health programs. translational research,andtoensurethe nary collaborations,toacceleratethe to thecancercommunityaswestrivemorefullyintegrate eliminated, by The goaloftheNationalCancerInstitute Executive Summary primarily through advicefromexpertsin Progress Disease-Specific Research program todevelop that framework,NCIalsocarries outanextensive and careforpatientswithall vent, control,detectand research anddevelopmentourabilitytopre- priorities thatarebroadlyapplicabletocancer The frameworkfortheNCIbudgetisbuilton services mustbeoptimized. access tosupportive,palliative,andgeneralmedical enrollment, research,andsurveillance.Inaddition, treatment andmedicalcare,clinicaltrialdesign prevention andearlydetection,socialsupport, will requireaggressivestrategiesforcancer the nextseveraldecades.Ourchangingagestructure in theUnitedStatestoincreasesubstantiallyover older persons,researchersexpectthecancerburden size ofthepopulationandgrowingproportion related healthdisparities.Becauseoftheincreasing redouble ourefforts toeliminatepersistentcancer- tially bycancersite,sex,andrace,wemust T as wellbreastandlungcancerinwomen. melanoma, cancersoftheliverandesophagus, rise. Theseincludenon-Hodgkin’s lymphoma, reduce ratesofsomecancersthatarestillonthe and toincreasephysicalactivity. We alsoneedto reduce tobaccouse,weightgain,andsunexposure But westillneedtoemploygreaterefforts to ers areadoptingstate-of-the-artcancertreatments. cervical, andcolorectalcancers,morepractition- frame. Morepeoplearegettingscreenedforbreast, cancer incidencestabilizedoverasimilartime- rates decreasedfrom1993to1999,whileof Recent reportsindicatethatoverallcancerdeath rends invariouspopulationgroupsdiffer substan- stimulating andsupportingresearchitsapplication.We providevisionandleadership National Agendasfor quickly types ofcancer , chartingthecourse diagnose, treat, development delivery . Within is toachieveafuturewhenallcancersarecontrolledor of theseinterventionsthroughclinicalandpublic of interventionsandnewtechnologythrough these continuetobeprioritiesforNCI. Development orforStudyingEmerging Trends, for CancerResearchTraining andCareer While wearenotrequestingincreasesinfunding Addressing AreasofPublicHealthEmphasis and $210,350,000willfundresearchfor Advancing DiscoveryandItsApplication Capacity Building theNation’s CancerResearch An additional$577,517,000willbeusedfor NCI commitmentsinto2004(CoreBudget). $294,014,000 willbeprovidedtocontinue 2003 President’s Budget.Ofthisincrease, increase of$1,348,131,000overtheFiscalYear Request is$5,986,000,000.Thisrepresentsan Our totalproposedFiscalYear 2004Budget part ofmanyNCIinitiatives. Funding fordisease-specificresearchisanintegral Mouse ModelsofHumanCancersConsortium. Molecular AnalysisTechnologies Program,andthe Early DetectionResearchNetwork,theInnovative Specialized ProgramsofResearchExcellence,the cancer throughbroad-basedinitiativessuchasthe NCI supportsresearchfocusedonspecifictypesof and developingnewinitiativeswhenneeded. to applyfordisease-specificresearchfunding, existing researchprograms,encouragingscientists mendations bymodifyingandsupplementing Review Groups(PRGs).We addressPRGrecom- B Research Capacity Building theNation’s Cancer tures, andcollaborations thatenableus to pursue ing thestrongresearchmechanisms, supportstruc- American peopledepends onbuildingandsustain- ringing thebenefitsofcancer researchtothe discovery , $266,250,000willsupport activities throughinterdiscipli- A Planand BudgetProposal for FiscalYear 2004 , .

3 EXECUTIVE SUMMARY rapidly evolving discoveries. NCI must provide to the newest trials and state-of-the-art care through the vision, creative environment, and diverse partnerships with NCI-designated Cancer Centers, resources needed to ensure a fast paced and syner- Minority-Serving Institutions, and NCI Special gistic flow of innovative thinking among scientists Populations Networks. in disparate scientific disciplines. We must also leverage our collaborations with other government NCI’s National Clinical Trials Program in agencies, academia, and industry, focused on steer- Treatment and Prevention provides a versatile ing major breakthroughs toward the delivery of system to safely move emerging cancer interven- effective cancer interventions. tions into health care delivery. NCI’s challenge is to provide the leadership demanded by the emerg- Investigator-Initiated Research has always been ing paradigm of molecular targeted therapy in the driving force behind advances in biomedical cancer treatment and prevention. With adequate research. Access to powerful new tools, special funding in 2004, NCI will be poised to identify resources, and scientific collaborations are increas- the most important questions that can be addressed ingly important to an investigator’s ability to devel- through clinical trials; create the flexible mecha- op the independent concepts that lead to discovery nisms and support that will bring together basic and translate results to targeted drugs and treat- scientists and clinicians to find the answers; fund ment. NCI aims to balance the flow of resources to tissue and specimen banks; help develop surrogate ensure that the best ideas are promoted through endpoints for use in small translational trials; move flexible funding options such as cooperative agree- the most promising interventions into large and ments, seed funds, and supplemental funds for easily accessible trials; and simplify administration unanticipated opportunities. Compelling proposals activities while increasing patient accrual, to sub- are supported with exceptions funding, particularly stantially increase the number of new treatments those suggesting novel approaches. Expert NCI and other interventions being evaluated. With advisory panels and Progress Review Groups con- sufficient funding, we can make state-of-the-art tinue to identify priority research and recommend clinical trials and the ensuing discoveries available funding. With increased resources in 2004, we will be to all who can benefit from them. able to fund the top 35 percent of competing grant applications using flexible criteria and continue to Bioinformatics for Cancer Research will help allocate the first 80 to 90 percent of available funds us harness the growing flood of scientific informa- for research project grants through conventional tion using NCI’s systems for resource sharing and selection processes, while ensuring that proposals for translating pioneering research into better med- from new investigators are also funded. icine. Virtual experiments will use data from multi- ple sources. We will generate hypotheses and NCI-supported Centers, Networks, and create and manage more knowledge faster with Consortia encourage the interdisciplinary collabo- systems that standardize, support, and integrate rations needed to address the “big picture” prob- information from our diverse research. caCORE, a lems in cancer research and integrate clinical obser- standards-based cancer knowledge resource, makes vations with research investigation. The rapid pace possible “in silico” experiments with the Cancer of scientific and technological discovery requires Models Database, Cancer Genome Anatomy that scientists of diverse backgrounds work togeth- Projects, and the Cancer Therapy Evaluation er to share information and resources. In 2004, NCI Program. For example, participants in the Cancer will use new funding to increase the number and Molecular Analysis Project locate and assess possi- geographic distribution of Cancer Centers, provid- ble molecular targets, find therapeutic agents, ing service to regional communities in addition to screen for toxicity, and identify clinical trials. expanding crosscutting research capacity. Cancer Bioinformatics holds impressive potential for facili- Centers will serve as platforms to support new tating cancer diagnosis, as demonstrated in the technology development, improve informatics recent marriage of proteomics and artificial intelli- capabilities, and conduct more clinical and popula- gence that resulted in a promising ovarian cancer- tion research. Specialized Programs of Research screening test. In 2004, NCI will use new funds to Excellence will be expanded based on needs for expand our own informatics infrastructure and the disease-specific translational research. Underserved informatics capacity of the research community. and minority populations will have improved access

4 The Nation’s Investment in Cancer Research progress inthese areas.Newfundingin 2004will large initiativesarealreadymakingimportant selectively target molecularsignatures. Several molecular profiles,andtodevise treatmentsthat to diagnoseandclassifytumors accordingtotheir information todetectcancers attheirearlieststage, ing cancer-associated signaturesandusingthis growth. With newtechnologies,scientistsareread- interact withcancercellstoencouragetumor cells inthesurroundingmicroenvironmentthat signatures ofbothcancercellsand“co-conspirator” Its Microenvironment Research on becomes asignalofthepresencecancer. nant, itssignaturechangesandthischange tion inthebody. Asanormalcellbecomesmalig- identifiable characteristicsrelatedtoacell’s func- All cellshave“molecularsignatures”–unique, with cancersusceptibility. clinical, behavioral,andsocietalissuesassociated them; andsupportcollaborativestudiesofthe other genesandenvironmentalfactorsmodify genes inhigh-riskfamiliesandinvestigatehow their interactionsincancercausation;identify factors andsusceptibilitygenesdetermine funding toidentifyadditionalenvironmentalrisk high riskforcancer. In2004,NCI willusenew tion ofpredisposinggenesfoundinfamiliesat Registries provideresourcesforthecharacteriza- for large population studies.NCICancerFamily investigators togethertopooldataandresources bringing epidemiologists,genomicists,andother collaborations, suchastheCohortConsortium,by NCI isinvestinginthisareathroughlarge-scale cer prevention,earlydetection,andtreatment. development ofmoreeffective approachestocan- cer andenvironmentalriskfactors,enablingthe between individualinheritedsusceptibilitytocan- increases ourunderstandingoftheinterplay The studyof benefit allpeopleaffected byoratriskforcancer. results intheclinicandpublichealthprograms,to needs allowsustofacilitateapplicationofresearch ery. Betterunderstandingouraudiencesandtheir activities allowustoacceleratethepaceofdiscov- beyond thesizeandscopeofourcurrentresearch nities andemergent fieldsofresearchthatlie Increased investmentinbroadscientificopportu- Its Application Advancing Discoveryand Signatures oftheCancerCelland Genes andtheEnvironment focuses onidentifyingthe methods into therapeuticclinicaltrials; advance Screening Trial; integratefunctional imaging of imagingtechnologies,such astheNationalLung imaging agentsanddevices; increaseclinicaltrials NCI willbeabletoexpand developmentofnovel ment toclinicaluse.With newfundingin2004, ing imagingadvancesfromdiscoveryanddevelop- public-private partnerships,wearemovingpromis- biosensor research.Throughclinicaltrialsand techniques foranimalresearch,andsupporting digital imagingdatabases,buildingmicro-imaging functional imaging,developingmolecularand patient monitoring.Accordingly, NCIisimproving use fewerinvasiveinterventions,andimprove accurate cancerdiagnoses,individualizetherapies, and biosensortechnologiestoensureearlier, more patient care.NCI’s challengeistoimproveimaging the bloodstreampromiseevenmoreoptionsfor molecule-size biosensorsthatcanbeinjectedinto tion, diagnosis,andtreatment.Experimental, Sensing Investment in characteristics ofeachpatient’s tumor. against cancer, basedontheunique molecular This workwillspeeddevelopmentofinterventions develop thenextgenerationofcancervaccines. radiation therapywithmoleculartherapeutics;and them intoclinicaluse;investigatecombinationsof date drugsdevelopedtohitthetargets andmove targets; support basicandclinicalresearchtovali- use newfundingin2004tocharacterizepotential ment”) fromsupportingcancergrowth.NCIwill vent surroundingtissues(the“tumormicroenviron- the immunesystemtocombatcancerorpre- ing itself,orself-destruct.Otherstrategiesharness ger thecancercelltorevertnormal,stopreplicat- multi-disciplinary approachtodiscoverwaystrig- targets, thatcausetumorgrowth.NCIisusinga efficacy agentsagainstthemolecularfeatures,or directing anewgenerationoflowtoxicity, high Prevention andTreatment. research aswehoneinon cer haslaunchedanexcitingnewerainbiomedical Our abilitytodecipherthemolecularbasisofcan- interventions basedonthisnewknowledge. or promotestumorgrowth;andtocreatetargeted cells, surroundingandimmunecellscontrols gression; todefinehowcommunicationamongcancer at variouspointsduringcancerinitiationandpro- signatures ofcellsinthecancermicroenvironment be usedtodefineandcharacterizethemolecular has dramaticallyimprovedcancerdetec- Cancer ImagingandMolecular A Planand BudgetProposal for FiscalYear 2004 Molecular Targets of Researchers are

5 EXECUTIVE SUMMARY image-guided interventions; and stimulate research increases in 2004, NCI will engage in activities to on biosensors. Significant advances in these areas improve methodology and measurement of patient will increasingly save and improve lives. outcomes; support innovative research on the dif- fusion, quality, and outcomes of cancer interven- Cancer Communications empowers people to tions and its translation to best practices in patient make informed cancer-related decisions and adopt care; enhance quality-of-care research within the behaviors to improve their health. NCI is working NCI clinical trials program; strengthen cancer to optimize the use of communications tools to communications; and inform science-based meet the information needs of all groups while Federal decision making. building strategies to enhance the important inter- action between patients and their doctors and Effectively Reducing Cancer-Related Health nurses. Lives are saved through communication Disparities requires new understanding to explain interventions that decrease or prevent smoking, social, cultural, environmental, biological, and influence good nutritional choices, and increase behavioral determinants of cancer, the interactions the number of people who are screened to detect among them, and the mechanisms by which they cancer early. Enhanced NCI databases and Web contribute to disparities in cancer care and preven- sites include user friendly topical formats and clin- tion. NCI continues to address disparities among ical trials information. In 2004, NCI plans to estab- all population groups through numerous initiatives lish new data collection and analysis strategies, such as the establishment of new centers focused including the first national health communications on disparities research, the Cancer Prevention survey of U.S. populations; accelerate the pace of Fellowship Program, and the implementation of research and development of communications a landmark study to determine factors that con- interventions; increase access to and use of cancer tribute to cancer among groups hardest hit by the information; and improve our understanding of disease. In 2004, we will use funding increases to and ability to effectively move research results into expand our research on the causes of health dispar- clinical practice and public health programs. ities in cancer; define and monitor disparities; develop and implement new policy, community, and clinical interventions, and evaluate their Addressing Areas of impact; and expand minority investigator competi- Public Health Emphasis tion for, and minority population involvement in, health disparities research and clinical trials. Progress against cancer takes place not only in the laboratory and the physician’s office, but also with- Through statistics on Cancer Survivorship, we in broad public health programs. NCI has identi- are beginning to see the fruits of the “War on fied four areas to more fully address cancer care Cancer” launched in 1971. Once almost uniformly and its consequences and translate research into fatal, cancer has become a chronic illness for many full application for people affected by cancer. and, for growing numbers of people, a curable dis- ease. Fewer deaths from other diseases and the Improving the Quality of Cancer Care is a aging of the population also contribute to the ris- major national concern. Barriers to high quality ing number of cancer survivors. However, we have care include system and financial limitations, many questions about the health status and quality proximity of healthcare facilities, available of life for most patients in their post-treatment education and information, and physician and years. What is clear is that most of our current patient biases. To address these concerns, NCI is treatments will produce some measure of adversi- helping to ensure that the best available scientific ty. NCI is initiating a focused effort in 2004 to evidence guides cancer care decision making. NCI understand the mechanisms that affect a cancer is supporting the Cancer Care Outcomes Research patient’s response to disease, treatment, and recov- and Surveillance Consortium and other studies to ery; develop tools to assess quality of life following strengthen the science base for understanding treatment; track outcomes for cancer survivors; palliative care and symptom management disseminate clinical guidelines; and expand the and end-of-life distress as well as examining scientific base for understanding the adverse late depression in cancer patients. With funding effects of current and new cancer treatments.

6 The Nation’s Investment in Cancer Research iclYa 03PeietsBde $4,637,869 Discovery andApplicationIncrease Capacity BuildingIncrease Increase toCore Budget Fiscal Year 2003President's Budget (dollars inthousands) NCI's BudgetRequestforFiscalYear 2004 T Public HealthEmphasisIncrease related cancers. research tobetterunderstandandtreattobacco- tobacco useandaddiction;applycuttingedge support investigationstounderstandandtreat needed toconductavigorousresearchprogram; use newfundsin2004toexpandtheinfrastructure needs ofcurrentandformersmokers.NCIwill NCI-supported researchistargeting the health identify morepotentagentsforcancerprevention, Study aswellpreclinicalandclinicalstudiesto initiatives, includingtheLungCancerScreening persistence, andrelapse.Throughseveralnew environmental factorsinsmokinginitiation, carcinogenesis, includingtheroleofgeneticand understanding oftobacco-relatedaddictionand bined. NCIresearchisfocusedonimproving United States)thandoalldrugsofabusecom- death (approximately430,000peryearinthe of cancer. Tobacco usecausesmorepremature tobacco useandexposureontheincidence Cancers Research onTobacco andTobacco-Related tlF 04Bde eus $5,986,000 otal FY2004 BudgetRequest eeoigBonomtc o acrRsac 88,000 69,887 340,100 79,530 Developing BioinformaticsforCancerResearch National ClinicalTrials Program inTreatment andPrevention Expanding theCapacityofCenters,Networks,andConsortia Enhancing Investigator-Initiated Research acrIaigadMlclrSnig 78,700 54,800 41,200 Cancer Communications Cancer ImagingandMolecularSensing Molecular Targets ofPrevention andTreatment Signatures oftheCancerCellandItsMicroenvironment Genes andtheEnvironment mrvn h ult fCne ae 27,000 61,350 76,000 Research onTobacco andTobacco-Related Cancers Cancer Survivorship Reducing Cancer-Related HealthDisparities Improving theQualityofCancerCare is drivenbythedevastatingimpactof uttlCpct ulig577,517 Subtotal CapacityBuilding uttlDsoeyadApiain266,250 Subtotal DiscoveryandApplication uttlPbi elhEpai 210,350 Subtotal PublicHealthEmphasis tributed tothisdocument. edgments listofpeopleandorganizationswhocon- or eliminateallcancers.Seepage100forourack new heights,andbringsusclosertoourgoalcontrol captures theopportunities,challengescommunityto in helpingusdevelopaplanforFiscalYear 2004that ument. Allofthesecontributionshavebeeninvaluable responded toourrequestforinputadraftofthisdoc- mer of2002,asimilarnumberpeopleoutsideNCI priority areas(ExtraordinaryOpportunities).Inthesum- cancer communityforsuggestionsaboutnewscientific side NCIrespondedtooursweepingsolicitationthe some 40individualsandorganizationsinsideout- mation, andidentifynewareastoexplore.In2001, people atNCIreviewdrafts,providebackgroundinfor- Budget andFinancialManagement.Numerousother for thevariouspriorityareasandwithOfficeof the coregroupofNCIleaderswhoserveasChampions conceptualization toproduction.Theyworkalongside leadership andguidanceforplandevelopmentfrom the OfficeofSciencePlanningandAssessmentprovide ise forthedevelopmentofthisdocument.Members country providetheirinsights,perspectives,andexpert- professional, andadvocacyorganizationsaroundthe boards, inothergovernmentagencies,andresearch, Each year, countlesspeopleatNCI,onouradvisory Community Planning atNCIIncludestheLargerCancer A Planand BudgetProposal for FiscalYear 2004 294,014 39,750 51,800 46,000 nowl-

7 EXECUTIVE SUMMARY Highlights of Progress

Every year thousands of NCI-supported research projects move us closer to a time when cancer can be controlled or eliminated. The recent doubling of NCI’s budget has been instrumental in funding numerous studies across the cancer continuum and from fundamental laboratory research to patient care. These highlights of recent progress provide a snapshot of the breadth of our research advances.

Trends in Research and Care fered substantially — e.g. by cancer site, sex, and race. Most notably, because of increasing population NCI Releases the Cancer Progress Report. and the growing proportion of older persons, To build on areas of greatest success and pinpoint researchers expect the cancer burden in the United areas of greatest need, NCI is working with many States to increase substantially over the next several partners to stay abreast of progress in cancer decades. Our changing age structure will require research and care in the United States. NCI’s aggressive strategies for cancer prevention and early Cancer Progress Report,1 first published in detection, social support, treatment and medical December 2001, describes the Nation’s progress in care, clinical trial design and enrollment, research, reducing the cancer burden, encompassing the con- and surveillance. In addition, access to supportive, tinuum from prevention to deaths from specific palliative, and general medical services must be cancers. Also reflected are declines in certain optimized. behaviors that cause cancer, especially cigarette smoking by adults. More people are getting Prevention and Control screened for breast, cervical, and colorectal cancers, and more practitioners are adopting state-of-the-art Smoking Cessation Drug May Help Address cancer treatments. At the same time, work needs to Smoking-Related Health Disparities. In a recent be done to reduce rates of some cancers that are landmark study, investigators found that bupropion, still on the rise. These include non-Hodgkin’s a promising smoking cessation drug previously lymphoma, melanoma, cancers of the liver and studied mostly in White populations, is effective esophagus, as well as breast and lung cancer in in helping African Americans quit smoking. women. Greater efforts also are needed to reduce Bupropion also seemed to curb both weight gain tobacco use, weight gain, and sun exposure and to and feelings of depression among study partici- increase physical activity. We must also redouble pants, key indicators of whether a person will return our efforts to eliminate persistent cancer-related to smoking. The success of this treatment is espe- health disparities among population groups. cially significant given that smoking rates are higher for African Americans than for the overall popula- Changing Age Structure of the United States tion of the United States. For example, close to half Will Help Guide the Future of Cancer of African Americans who live in inner cities smoke Research and Care. The Annual Report to the compared to about one quarter of the general Nation on the Status of Cancer, 1973-1999, population. Smoking is the leading cause of lung Featuring Implications of Age and Aging on the U.S. cancer and a major risk factor for other cancers as Cancer Burden,2 was released in May of 2002. The well as heart disease, respiratory disorders, and report is encouraging. Overall cancer death rates other diseases prevalent in African American groups. decreased from 1993 to 1999, while rates of cancer Researchers hope that a successful smoking incidence stabilized over a similar timeframe. cessation program, aided by bupropion, may help However, trends in various populations groups dif- reduce smoking-related health disparities experi-

1 progressreport.cancer.gov 2 Prepared by the National Cancer Institute, the Centers for Disease Control and Prevention, the National Center for Health Statistics, the American Cancer Society, and the North American Association of Central Cancer Registries. seer.cancer.gov/reportcard

8 The Nation’s Investment in Cancer Research in thisdocument: Other cancerpreventionandcontrolhighlights ing years. the ovariesshouldberemovedbeforechildbear- The researchersfoundnoevidencetosuggestthat ture menopausearemanageablebymedication. about 50percent.Sideeffects broughtonbyprema- 96 percentandbreastcancerriskwasreducedby study, ovariancancerriskwasreducedbyastriking practice toreducecancerrisk.InanNCI-supported Recently completedlarge studieshavevalidatedthis ovaries), oncetheyhavefinishedhavingchildren. undergo prophylactic oophorectomy(removalofthe recommending thatwomenwiththesemutations of anumbersmallstudies,physicianshavebeen than thegeneralpopulation.Basedonfindings breast and/orovariancancer, andatayoungerage genes W ■ ■ Cancer RiskinWomen with Oophorectomy afterChildbearingYears Lowers fulness ofcalciumforcancerprevention. can becommunicatedtothepublicaboutuse- cancer. Furtherstudyisneededbefore clearadvice the complexityofinteractionbetweendietand cancer whileincreasingtheriskofanotherillustrates The findingthatcalciumcanreducetheriskofone provided someprotectionagainstprostatecancer. cancer, whilelycopene,acomponentoftomatoes, products substantiallyincreasetheriskforprostate study showedthathighlevelsofcalciumanddairy consuming highlevelsofcalciumdaily. Asimilar their riskofdevelopingcancerthedistalcolonby discovered thatbothmenandwomencouldreduce with tensofthousandsparticipants,investigators clarify someofthesefindings.Inonerecentstudy, results pointtotheneedforlarge, carefulstudiesto of developingcancer. Thesometimesconflicting examined howwhatweeatordrinkaffects ourrisk Is Complex. Potential ofDietaryAidsforCancerPrevention cancer burdencausedbytobaccouse. enced byAfricanAmericansaswelltheoverall 5 4 3 Specialized ProgramsofResearchExcellence. Fordescriptionseepage32. For moreinformationonproteinprofiling, seepage54. other. Thisisknownas“allelic imbalance.” comprise whatwecall “chromosome8.”Sometimeserrorsoccur thatmakeonechromosomeofapair substantiallydifferent fromth Chromosomes come inpairsthataretypicallynearlyidentical inmakeup.Forexamplechromosome 8pandchromosome8qtogether omen whowerebornwithcertainmutationstothe cancer, page21 Genetic signaturesandriskfactorsforpancreatic Risk factorsforesophageal cancer, page23 BRCA1 Over theyears,manystudieshave and BRCA2 , aremorelikelytodevelop BRCA Mutations. profiling researchers usedtheemerging technologyofprotein to ruleoutcancer. To addressthisconcern, ease aresubjectedtobiopsy, andassociatedanxiety, down sideisthatanumberofmenwithoutthedis- by detectingtheircancerinitsearlieststages.The positive. ThePSAtestisquitehelpfultomanymen low-up biopsymustbeperformedifthePSAtestis times elevatedevenintheabsenceofcancer, afol- with prostatecancer. However, sincePSAissome- gen (PSA),whichisconsistentlyelevatedinmen the levelsofaproteincalledprostate-specificanti- cancer, doctorscurrentlyuseabloodtesttomeasure SPORE positives andunnecessarybiopsies. cancer ataveryearlystage,withfewerfalse accurate meanstodetectanddiagnoseprostate development, thisnewtestmayleadtoamore could behopedforwiththePSAtest.With further classified farfewermenwithoutthediseasethan identified mostmenwithprostatecancerandmis- the blood.Inpreliminarystudy, thistestcorrectly the dynamicpatternsofnineseparateproteinsin uses computer-based artificialintelligence tostudy Cancer LooksPromising. New BloodTest forEarlyDetectionofProstate Prognosis Detection, Diagnosis,and ■ ■ ■ ■ ance scientists discoveredthatpatientswithallelicimbal- develop amorereliableprognostictool.Previously, such assuspiciousabnormalitiesintumorDNA,to Many scientistsarelookingformolecularmarkers, scope. Thisiscalledhistopathologicalstaging. ine smallamountsoftumortissueunderthemicro- recur aftersurgery, healthprofessionalsmustexam- To Useful forPrognosisofColorectalCancer. imbalance intumortissue. Now, investigators have has beenverydifficult toaccuratelymeasureallelic have apoorerprognosis.Until recently, however, it

Key factorsinadolescentcigaretteuse,page95 bupropion, pages94-95 Genetic signatureandeffectiveness of Aspirin forpreventingcoloncancer, page40 page 36 Arthritis drugandpreventionofcolonpolyps, estimate thechancethatcolorectalcancermight 5 in certainchromosomesofthetumortendto 3 4 to fashionanewbloodtest.Thetest Study SuggestsNewMolecularTest A Planand BudgetProposal for FiscalYear 2004 To e

screen forprostate

9 HIGHLIGHTS OF PROGRESS developed a highly sensitive test using a technique ■ Blood test of protein patterns and called “digital SNP analysis.” This new test early detection of ovarian cancer, pages 45, measures the allelic imbalance in two colon cancer- 54, and 59 associated chromosomes, 8 and 18. They found ■ Gene expression array for prognosis of diffuse that, after five years of follow up, cancer recurred in large-B cell lymphoma, page 54 42 percent of patients with allelic imbalance in both ■ Signatures of lung cancer sub-classes, page 59 chromosomes and in 26 percent of those with one chromosome affected. In contrast, all patients with Treatment no detectable allelic imbalance in chromosomes 8 or 18 remained disease free after five years. Since New Approach to Immunotherapy for routine histopathological staging would have mis- Advanced Melanoma Results in Dramatic takenly predicted recurrence in at least some of Tumor Regression. In a recent study of these disease-free patients, this new test appears to melanoma7 patients, researchers discovered a way to provide an improved prognostic indicator of col- enhance the immune system’s natural, but weak, orectal cancer. Further research must be done to ability to attack cancer cells. Investigators began by show whether this technique will work as well for collecting a small number of white blood cells from other cancer sites. the tumors of each of 13 patients. From these, they isolated the cells that were most adept at attacking Ovarian Cancer patients with BRCA Mutation melanoma — those that could best recognize an Have Better Survival than Non-Carriers. antigen8 abundantly expressed on melanoma cells Women who inherit mutations to the BRCA1 or and to a lesser extent on normal melanocytes. They BRCA2 gene, have a greater risk of developing grew large quantities of these white blood cells and ovarian cancer. However, until recently, researchers injected them back into each patient along with an could not predict whether women with these muta- immune-boosting protein. To prevent the patient’s tions would fare better, the same, or worse than naturally occurring white blood cells from crowding other women with ovarian cancer. To examine this out the melanoma-attacking cells, investigators issue, researchers studied the medical records of temporarily depleted the patient’s immune system almost 900 newly diagnosed ovarian cancer patients with chemotherapy prior to injection. With this with inherited BRCA mutations and followed their treatment regimen, six patients experienced dra- progress for five years.6 Investigators compared the matic regression of metastatic tumors. Surgeons progress of these women to that of patients who removed the traces of tumors from two of these had no BRCA mutation. On average, the patients patients who have remained cancer free, one for with BRCA mutations survived for about 53.4 over two years. In some patients, the melanoma- months, almost 20 months longer than women killing cells also attacked normal melanocytes, without the mutations. This survival advantage was resulting in patches of skin without pigmentation not due to earlier detection, but seems to reflect a (a non-threatening condition known as vitiligo). difference in the pattern of the disease in women Other side effects were treatable. This pioneering with and without BRCA mutations. The mechanism study establishes two landmark principles of cancer of this phenomenon is not known. Further follow research. First, this unique approach to harnessing up in this continuing study should reveal whether the immune system can be an effective treatment the better survival of BRCA mutation carriers is for patients with metastatic cancer. Secondly, natu- long-term or limited to the first few years of the rally occurring antigens that are over-expressed on disease. cancer cells may provide useful immunotherapy tar- gets for cancers such as prostate, breast, ovarian, Other detection, diagnosis, and prognosis and thyroid, since the organ function is either not highlights in this document: necessary for survival or can readily be replaced. ■ Genetic signatures and diagnosis of acute lymphoblastic leukemia, pages 44 and 54

6 The study was performed in Israel where more women have the mutations, making it easier to conduct a large study. 7 Melanoma is cancer of the melanocytes, the pigment producing cells of the skin. It is almost always fatal once it spreads beyond the initial site. 8 An antigen is a protein or protein fragment located on the outside of a cell.

10 The Nation’s Investment in Cancer Research bevacizumab asacancertreatment, includingPhase clinical trialsarecurrentlyunderwaytoevaluate esis willworkinpatients.Morethan20additional advances inattackingcancerbythwartingangiogen- toward showingthatrecentexcitinglaboratory for growth.Thisstudyisanimportantfirststep vessels (angiogenesis)tobringoxygenandnutrients VEGF, neededbythetumortogenerate newblood placebo. Bevacizumabtargets aprotein, called as comparedtotwomonthsinpatientstakinga no measurabletumorgrowthforaboutfivemonths, treatment options.Patientsgiventhisdrugshowed in patientswithadvanceddiseaseandnoknown cantly slowedthegrowthofmetastaticrenalcancer recent clinicaltrial,thedrugbevacizumabsignifi- Growth inPatientswithKidneyCancer. Molecularly Targeted DrugSlowsTumor both diagnosticandtherapeuticinterventions. and AIB1mayopenhighlypromisingavenuesfor scientists anticipatethatfurtherresearchonHER-2 tamoxifen-resistant, ER-positivebreastcancers,and recently approvedfluvestrantfortreatmentof The UnitedStatesFoodandDrugAdministration ing new, moreeffective treatmentapproaches. on themechanismsoftamoxifenresistanceisyield- were tumorsresistanttotamoxifen.Thisresearch a secondprotein,AIB1,aresimultaneouslyelevated, with tamoxifen.OnlyinwomenwhereHER-2and covered thatHER-2,byitself,doesnotinterfere don’t respondtotamoxifen.Investigatorsalsodis- another drug,fluvestrant,worksagainsttumorsthat studying theseproblems,researchersfoundthat resistant totamoxifen,butonlyinsomewomen.In certain protein,HER-2,seemtomaketumorsmore works onlyforalimitedtime.Also,highlevelsof drug andwhyinthosewhoarehelped,itoften puzzle ofwhysomewomenneverrespondtothis body. However, scientistshavebeenfacedwiththe breast cancerbyloweringestrogenlevelsinthe The drugtamoxifenworkswellagainstER-positive more aggressivelywhenexposedtoestrogen. “estrogen receptorpositive”(ER-positive)grows Tr Resistance toTamoxifen forBreastCancer SPORE ScientistsFindWays toOvercome molecularly targeted Researchers haveidentifiedanotherpromising 11 10 9 FOLFOX4 regimen: 5-fluorouracil/leucovorin/oxaliplatinSaltz regimen:irinotecan/5-fluorouracil/leucovorin without harminghealthy tissues. Molecularly targeted drugsaredesignedtointeractwithanddisruptcertainmolecular featuresthatarecriticaltothesurviv See alsopage22. eatment. A subclassofbreastcancerknownas 10 cancer treatmentdrug.Ina 9 Other treatmenthighlightsinthisdocument: ment forcolorectalcancer. for possibleuseofthisdrugasasecond-linetreat- the UnitedStatesFoodandDrugAdministration the manufacturerofoxaliplatinissubmittingdatato United States.Asfurthertestsarebeingconducted, is thesecondleadingcauseofcancerdeathin men. Theseresultsareimpressiveforadiseasethat compared to58percentofthoseontheSaltzregi- patients onFOLFOX4werelivingafteroneyear, cantly feweroverall.Furthermore,71percentof the Saltzregimen,severesideeffects weresignifi- patients developedaneurotoxicitynotseenwith and tumorswereslowertoprogress.Althoughmany FOLFOX4 respondedbettertotheirmedication ■ ■ ■ ■ ■ therapy, the“Saltzregimen.” months longerthanpatientsreceivingstandard experimental drugoxaliplatin),livedaboutfour the “FOLFOX4regimen”(whichincludes advanced colorectalcancerwhoweretreatedwith survival ofcolorectalcancerpatients.Patientswith bination withcurrentdrugs,appearstoimprovethe discovered anewchemotherapydrugthat,incom- Researchers conductingalarge clinicaltrialhave Patients withAdvancedColorectalCancer. Experimental DrugImprovesSurvivalof and severaltypesofleukemia. ian, pancreatic,andlungcancers,mesothelioma, II trialsforprostate,breast,colorectal,cervical,ovar- III trialsforbreastandcolorectalcancersPhase Immunotoxin andhairycellleukemia,page64 Gleevec (imatinib)andGIST, page37 leukemia, page37 Gleevec (imatinib)andchronicmyelogenous leukemia survival,page37 Methotrexate andT-cell acutelymphoblastic breast cancerpatients,page37 T amoxifen followingchemotherapyand A Planand BudgetProposal for FiscalYear 2004 al ofthecancercell, 11 Patients treatedwith

11 HIGHLIGHTS OF PROGRESS Understanding the Gene-Environment Interactions Are Causes of Cancer Identified for Non-Hodgkin’s Lymphoma. Despite much research, the relationship between SPORE Scientists Say Inherited BRCA2 exposures experienced by farm workers and non- Mutations May Increase Risk for Pancreatic Hodgkin’s lymphoma (NHL) is unclear. However, Cancer.12 Scientists believe that 10 percent of all past studies did not consider gene-environment cases of pancreatic cancer are hereditary. However, interactions that might occur in some genetic sub- although mutations have been found in the tumors types of this disease. Because of the way statistical of patients with non-hereditary pancreatic cancers, analysis works, when the genetic subtypes of NHL the major gene(s) responsible for inherited cases are not studied individually, real associations have yet to be discovered. Uncovering the causal between farming exposures and NHL might remain mutations would provide a way to identify people hidden. Investigators recently reviewed the exposure who might benefit from special surveillance data and studied NHL biopsies from about 200 because of an increased genetic risk of developing patients who had participated in a prior study. this disease. In a recent study, investigators These researchers were able to identify a searched for suspicious mutations in the BRCA2 particular genetic subtype of NHL that appears to gene of pancreatic patients who had at least three be susceptible to the effects of pesticides. Larger relatives with this disease. They discovered muta- studies are needed to clarify the mechanisms tions likely to be involved in tumor development in behind this gene-environment interaction and to 5 out of 29 (or 17 percent) of patients in the study. discover ways to intervene to prevent NHL. Further research is needed to better define the risk of pancreatic, and other cancers, in patients with Survivorship these mutations. Additional genetic as well as envi- ronmental factors may influence this risk. African American Cancer Survivors Report Poorer Functional Health than Whites. SPORE Study of Tumor Microenvironments Older and minority patients have been under- Yields New Insights into Cancer. Unique molec- represented in research of post-cancer treatment ular interactions occur between cancer cells and issues. Investigators interviewed 180 African their surrounding tissues, the “tumor microenviron- American and White long-term breast, colorectal, ment.” For example, when healthy tissues of the and prostate cancer survivors to identify differences body are invaded with cancer cells, they become in reported health problems, illness symptoms, inflamed and form fibrous, scar-like tissue — known functional difficulties, health worries and concerns, as “desmoplastic tissue.” In certain tumors that and overall perceptions of health. Although African penetrate into surrounding tissues as they grow Americans did not report significantly more symp- (known as infiltrating tumors), this desmoplastic tis- toms resulting from their cancer or its treatment, sue comprises the bulk of the tumor, outpacing the they did report a greater decrease in physical func- actual cancer cells. Recently, a team of scientists tioning, perhaps related to treatment. Older African characterized the patterns of genes expressed in Americans also reported less concern about devel- the cancerous growth and the microenvironment of opment of second cancers, suggesting a need for two types of infiltrating cancer — pancreatic and targeted education about the importance of follow- infiltrating breast cancer. They discovered a highly up care and screening. Continued research is need- ordered, coordinated process of tumor invasion, ed to understand post-cancer treatment issues involving four distinct kinds of tissue and struc- among older and minority patients. tured molecular interactions between the cancer and its surrounding tissues. This kind of insight Adult Survivors of Childhood Cancer Lack into how cancers interact with their microenviron- Detailed Knowledge of Their Past Illness. ment may lead to previously unimagined strategies Childhood cancer cure rates have risen dramatically for imaging, diagnosis by blood test, and drug over the past few decades, creating a growing body development and delivery for pancreatic, infiltrative of adult survivors who face long-term health risks breast, and numerous other cancers.13 related to their cancer and treatment. Researchers interviewed 635 adult survivors of childhood cancer to find out how much they knew about their

12 See also page 21. 13 See also Signatures of the Cancer Cell and Its Microenvironment, pages 55-59.

12 The Nation’s Investment in Cancer Research portionate burden ofinvasivecancersand cancer ethnic minoritiesintheUnited Statesbearadispro- Appropriate CancerTreatment. Racial andEthnicMinorities ReceiveLess Quality ofCancerCare ■ ■ ■ ■ ■ Other survivorshiphighlightsinthisdocument: mote quittinginthishigh-riskpopulation. needed interventionstopreventsmokingandpro- information gainedbythisresearchwillhelpcraft education, andthosewhohadbrainradiation.The years oldwhenbeginningtosmoke,thosewithless to continuesmoking:thosewhowereatleastthirteen vivors whodidstartsmoking,someweremorelikely brain radiationwerelesslikelytosmoke.Amongsur- ing hadeitherpulmonaryrelatedcancertreatmentor less education.AfricanAmericansandsurvivorshav- well asthosewithalowerhouseholdincomeand/or later childhoodweremorelikelytostartsmoking,as Survivors whohadbeendiagnosedwithcancerin smokers, and11percentwereformersmokers. than thegeneralpopulation,17percentwerecurrent although thesesurvivorswerelesslikelytosmoke adult survivorsofchildhoodcancershowedthat, health problems.Arecentsurveyofalmost10,000 survivors, whoareathighriskfortobacco-related acterize smokingpatternsamongchildhoodcancer Cancer Survivors. Smoking RatesCharacterizedamongChildhood past illnessandhowitwastreated. for educatingchildhoodcancersurvivorsabouttheir care andsurveillance.Thisstudyhighlightsaneed from understandingtheirneedforspecialfollow-up Such missinginformationcouldpreventsurvivors could causeserioushealthproblemsinthefuture. of thoseinterviewedrealizedthatpasttreatments site orsitesofradiationtreatment.Only35percent they receivedcertainchemotherapydrugs,andthe disease, includingthenameoftheircancer, whether vivors wereabletogiveadetailedsummaryoftheir previous illnessandtreatment.Noneofthesur- page 92 Social interventionsforbreastcancersurvivors, following treatmentforleukemia,page92 Growth hormonereplacementforchildren Lung cancersurvivorqualityoflife,page92 heart failure,page92 Chemotherapy dosageandcongestive cancer treatment,page92 T ool usedforstudiesontheconsequencesof Researchers areworkingtochar- Racial and ■ ■ ■ highlights inthisdocument: Other qualityofcare prostatecancer. for of suffering amongpatientswhoundergo surgery theburden scrutiny ofadverseoutcomestoreduce The researcherspointoutaneedformorecareful postoperative andlateurinarycomplications. volume ofthissurgery, experiencedfewer at hospitalsandbysurgeons whoperformedahigh those menwhounderwentremovaloftheprostate cations, incontinence).Investigatorsdiscoveredthat affect postoperative morbidity(e.g.urinarycompli- whether thechoiceofhospitalsorsurgeons might survival ishighoverall,researcherswondered patients receivingprostatecancersurgery, forwhich of thisoperation.Althoughisnottruefor and/or bysurgeons thatperformthehighestvolume is betterwhenthesurgery isconductedathospitals For manycancersrequiringsurgery, patientsurvival Decreases withNumberPerformed. Rate ofComplicationsfromProstateSurgery ences anddecisionsalsoplayedapart. location, andinsurancecoverage.Patientprefer- surgeries performed bythesurgeon, geographic where surgery isperformed,thenumberofprevious hospital image, ageatdiagnosis,thesizeof aboutbody socioeconomic status,patientconcerns explained inpartbynon-clinicalfactors,suchas likely torelapseanddie.Thesedisparitiescouldbe Those receivinginferiortherapywerealsomore (such asbreastconserving),andadjuvanttherapies. conservative receives thebestavailableprimary, confirmed thatracialdifferences areevidentinwho or useofspecificcancertreatments.Theirreview whether anyofthesedisparitiesstemfromaccessto reviewed publishedscientificstudiestofindout cancer. Agroupofinvestigatorsextensively cer, andAsian/PacificIslanderstodevelopstomach Hispanics aremorelikelytodevelopcervicalcan- percent morelikelythanWhitestodieofcancer. likely todevelopanumberofcancersandare33 deaths. AfricanAmericans,forexample,aremore prostate cancer, page85 African Americanmenand riskforadvanced page 85 within theChinese-American population, Educational interventionsand cervicalscreening cell lungcancer, page85 American patientswithadvancednon-small Social factorsandsurvivalamongAfrican A Planand BudgetProposal for FiscalYear 2004

13 HIGHLIGHTS OF PROGRESS Our Role in Cancer Research

The National Cancer Institute’s goal is to achieve a future when all cancers are controlled or eliminated by stimulating and supporting scientific discovery and its application. As the leader of the National Cancer Program, we provide vision and leadership to the cancer community. We work to: ■ More fully integrate discovery activities through interdisciplinary collaborations. ■ Accelerate development of interventions and new technology through translational research. ■ Ensure the delivery of these interventions for application in the clinic and public health programs.

organizations. Proposals submitted by extramural Integrate Accelerate investigators are selected for funding by peer DISCOVERY DEVELOPMENT Interdisciplinary Translational review, a rigorous process by which scientific Science Research experts evaluate new proposals and recommend the most scientifically meritorious for funding. Partnerships & Collaborations Some studies involve basic laboratory research on genomics, proteomics, and molecular interactions.

Ensure Others help us gain understanding of cancer in spe- DELIVERY cific populations, such as former smokers, to better Application in the Clinic & understand cancer risks related to environmental Public Health Programs and lifestyle factors.

In addition to direct research funding, NCI offers Scientific Discovery the Nation’s cancer scientists a variety of useful research services and tools. NCI-supported NCI supports a broad range of research to expand Cancer Centers and Centers of Research scientific discovery at the molecular and cellular Excellence such as the In Vivo Cellular and level, within a cell’s microenvironment, and in rela- Molecular Imaging Centers and the Centers of tion to human and environmental factors that influ- Excellence in Cancer Communications Research ence cancer development and progression, and the provide the kind of interdisciplinary environments patient experience. These insights provide the plat- required for special projects. The Transdisciplinary forms on which to accomplish improvements in pre- Tobacco Use Research Centers are supporting a vention, control, early detection and diagnosis, broad array of studies on nicotine addiction and treatment, and post-treatment care. genetic and environmental factors related to smok- ing. Resources such as tissue samples, statistics on Each year, almost 5,000 principal investigators cancer incidence and mortality, databases of genetic lead research projects that result in better ways to information, imaging databases, and software for combat cancer. These scientists conduct studies at analyzing statistical and genetic data1 are made NCI and at nearly 650 universities, hospitals, and available at little or no cost. Consortia like the other sites in nearly every state in the Nation and in Mouse Models of Human Cancers Consortium more than 20 foreign countries. Intramural research allow scientists from around the world to share activities serve as hubs for new development their expertise and resources in creating strains through cutting edge basic, clinical, and epidemio- of mice that develop cancers similar to those seen logical research. Extramural program experts in humans, making widely available an invaluable provide guidance and oversight for research con- tool for cancer researchers. ducted at universities, teaching hospitals, and other

1 For a directory, go to cancer.gov/resources.

14 The Nation’s Investment in Cancer Research 2 See pages36-40ormore informationabouttheNCINational ClinicalTrials Program. ■ ■ ■ ■ ■ works andconsortiaprovide opportunitiesforresearch thatcannotbeconductedbyinvestigatorsatsingleinstitutions. Specialized Programs ofResearch Excellence(SPOREs),otherCentersofResearch Excellence,andNCI-supportnet- Networks, andConsortia Ongoing ResearchShowsValue ofCentersResearch Excellence, making itpossibletomonitor treatmentoutcomes tating moreaccurateimage-guided therapies,and faster, more accuratedetectionanddiagnosis,facili- and biosensingtechnologies areopeningdoorsto and diagnosis.Likewise,new molecularimaging large amountsofinformationforcancerscreening accelerating theratewithwhichwecanprocess genomics andproteomicsresearcharedramatically matics andtherelatedexplosionoftechnologyfor treat it.Forexample,recentadvancesinbioinfor- and thenmaybeadvancedfurtherstilltohelpus improved anddistributedtohelpusdiagnoseit, helps ustounderstandcancermayeventuallybe that wehavebeenusing.Thus,anewtoolfirst developing newtechnologiesortransformingthose research intointerventionsalmostinevitablymeans intervention development tive platformsfortranslationalresearchand today’s cancerscientists,NCIalsouses interdisciplinary environmentrequiredtosupport In additiontopromotingintegrationandthe Intervention Development established collaborationswithindustrysponsors. and biologicalanalysesinclinicaltrialsofnovelagentsaimedatspecificmoleculartargets. Bothconsortiahave have successfullyevaluatedtheefficacy andpharmacokineticsofNCI-sponsored agentsandincorporatedmolecular gliomas andare considered theprimaryfocusnationallyformostnewagenttrialsinadultbraintumors.Theseconsortia American BrainTumor Consortium, T to conductclinicaltrialsofpromising newagents. institutions are engagedinsixresearch projects. Fiveare laboratory basedandthesixthisamulticenterprogram r together thenation’s topscientistsfrom different disciplinestoconductanintegratedprogram ofbasicandclinical The Chronic Lymphocytic Leukemia(CLL)Research Consortium studies onspecialpopulationsincludingAfricanAmericans,Hispanics,andAsianAmericans. biomarkers fordiagnosis,prognosis, andtreatment. Additionally, theprostate SPOREsare developingmicroarrays for for prostate cancerusinghighthroughput analysisandtechnologiesthatwillultimatelybringintoclinicalpracticenew Prostate CancerSPOREs high riskforovariancancer. Thetrialisbeingconductedthrough collaborationwiththeCancerGeneticsNetwork. to determineifthisscreening method,alongwithtransvaginalultrasounds,iseffective forearlydetectioninwomenat Ovarian CancerSPOREs r physicians tomakemore confidentdecisionstousethetherapyaswellhelpidentifypatientswhoare likelyto term response tochemotherapybefore breast cancersurgery. Thesekindsoftechniquesmayallowpatientsandtheir Breast CancerSPOREs esearch focusedonasingledisease.CLListhemostcommon,andcurrently incurable,adultleukemia.Nine elapse andmaywishtoconsiderotheroptions. wo adultbraintumorconsortia,the are testingtheuseofimagingandgenearrayassessmentstofindmarkersthatpredict long- are participatinginascreening trialtotesttheefficacy ofobtainingperiodicCA125valuesand have workedtogethertodevelopthenecessaryinfrastructure tovalidaterelevant biomarkers . Translating basic New Approaches toBrainTumor TherapyCNSConsortium have greatly expanded theclinicalresearch agendafortherapyinadultswith collabora- patients. clinical trialsayearinvolvingmorethan200,000 Oncology programs,NCIsupportsover1,300 Cooperative GroupandCommunityClinical private practicephysiciansinNCI’s ClinicalTrials tion ofmorethan10,000medicalschooland possible toallwhocanbenefit.With the participa- preventing cancerandprovidingaccessasearly treatments, diagnostictools,andinterventionsfor our largest such researchactivitysupportedbyNCIis late scientificunderstandingtotheclinic.The advantage, NCIpromotescollaborationsthattrans- To diagnosing, treating,andmonitoringcancer. further expandtheoptionsforpreciselydetecting, in realtime.Similarly, nanotechnologypromisesto expansion oftheProgramto improvethequality Centers Program running partnershipsbyestablishing the In theearly1960s,webegan oneofourlongest

ensure thatweusepublicfundstogreatest Clinical Trials Program , amulti-institutionalresearch program, brings 2 A Planand BudgetProposal for FiscalYear 2004 . Congressencouragedthe for testingcancer and the Cancer North

15 OUR ROLE IN CANCER RESEARCH NCI Team Includes Advisory Groups Scientists, medical experts, and advocates work together to help shape NCI’s policies and programs through a number of standing and ad hoc advisory groups. The National Cancer Advisory Board provides overall guidance for NCI and a final assessment of the research proposals selected for funding through peer review. The Board of Scientific Counselors evaluates the progress, performance, and productivity of the Institute’s intramural research programs and scientists through regular site visits to NCI. The Board of Scientific Advisors plays a similar role for NCI’s extramural program, reviewing the progress of ongoing pro- grams and providing feedback on proposed new research activities. NCI convenes Progress Review Groups of scientific and medical experts and advocates to examine the research needs and opportunities for specif- ic types of cancer. NCI is also strongly influenced by the President’s Cancer Panel. This and other advisory groups provide seasoned assessment of progress and problems in the Nation’s effort to reduce the burden of cancer.

In addition to their membership on other NCI advisory groups, advocates advise the NCI Director on broad program and research priorities through the Director’s Consumer Liaison Group. Members of this all-con- sumer advisory committee have provided assistance to the Institute in other ways as well, including gather- ing suggestions from the advocacy community on survivorship issues, disseminating and promoting cancer trials training, and assisting with various strategic planning efforts. NCI also solicits the advice of patients and their family members through the recently created Consumer Advocates in Research and Related Activities (CARRA) program. Through this program, approximately 200 individuals are available to participate in a wide range of NCI activities. For example, they participate in advisory groups to help assess needs for specific cancers, provide advice on the design of clinical trials, and review education materials.

Go to deainfo.nci.nih.gov/advisory/boards.htm for more information on NCI Advisory groups.

of cancer care by bringing cancer scientists and in the lives of people. The results of NCI-supported oncologists together in the same setting with research consistently provide cancer patients and patients and their families. Today, two-thirds of those who care for them with information, tools, and the 60 Centers funded by NCI are comprehensive tests that can be used for improved cancer inter- Cancer Centers, so designated because of the ventions and can help people make better health breadth and depth of the research conducted by choices and physicians select treatment options that their investigators and their role in public education are more targeted and less invasive and result in and outreach. fewer adverse side effects. Evidence-based cancer control interventions influence the nature of public NCI Centers of Excellence are smaller in scale health programs to more effectively reduce cancer than NCI Cancer Centers and generally focus on risk and promote better health practices. For exam- one or a few types of cancer or scientific areas. ple, once its effectiveness was confirmed in clinical More than 40 Specialized Programs of Research trials, oncologists were quick to adopt the use of Excellence bring together groups of cancer scien- tamoxifen in the care of breast cancer patients. tists with specialized expertise to focus on transla- Likewise, since studies established the link between tional research for disease-specific cancers. NCI diet and cancer risk, more and more of us strive to also brings investigators together for translational include five servings of fruits and vegetables in our research through networks like the Early daily diets. Detection Research Network, which assembles groups of scientists to identify markers and NCI programs to reduce the disparities in the develop tests to detect early signs of cancer. occurrence of cancer, its treatment, and outcomes among various racial and ethnic groups include Intervention Delivery and research into the causes of health disparities and Communication measures to translate research results into better health for groups at high risk for cancer. For While delivery of most interventions is ultimately example, NCI-supported investigators are using the responsibility of healthcare and public health insurance data to examine the extent to which African organizations, NCI’s role is to ensure that our American, Hispanic, and Caucasian patients are research findings reach the community and are receiving recommended treatments for colon cancer. translated into practices that will make a difference Researchers are also seeking the causes of disparities

16 The Nation’s Investment in Cancer Research 3 Also calledSTI571orGleevec.™ medical communityandthepublicthrough While majorscientificadvancestypicallyreachthe its long-termeffects. approved anti-canceragentimatinib, leukemia patientstreatedwiththerecently that investigatorsarefollowingchronicmyelogenous between NCIandamajorpharmaceuticalcompany Agreements. Itisthroughsuchanagreement Cooperative ResearchandDevelopment with industrythrougharrangementsknownas NCI intramuralinvestigatorscanalsocollaborate licensing thediscoveriestoindustry. Inaddition, sities andNCItopursuecommercializationby or diagnostictests that mayleadto When NCI-supportedresearchresultsindiscoveries populations acrosstheUnitedStates. screening andtreatmentamonglowerincome among veteransandtheelderlycervicalcancer efforts toraisetheratesofcoloncancerscreening at improvingthequalityofcancercare agencies toworkonanumberof NCI haspartneredwithotherstateandFederal specific racialandethnicgroups. weight controlprogramstargeted totheneedsof is supportingfieldtestsofsmokingcessationand among otherunderservedgroups.Inaddition,NCI vaccine mixturethatareknown tostimulatepartsoftheimmunesystem. produce proteinsthataresimilartoorthesameas targetonthecancercell,andaddingmoleculesto genetically engineeredtumorcellstostimulatetheimmune system,addinggenestothevaccinemixture Consortium researchersarealsoimprovingtheeffectiveness ofnewandexistingvaccinesbyvaccinatingwith in clinicalcare. and pharmaceuticalindustries.Severalvaccinesdeveloped byconsortiummembersarecurrentlybeingused expertise inoncology, vaccinology, and translationalresearchalongwithrepresentativesofthebiotechnology Cancer ResearchhasestablishedaVaccine Initiativetobringtogetheraconsortiumofscientistswith lymphoma. To speed thedevelopmentofvaccinesandtheirtranslationtopatientcare,NCI’s Centerfor had efficacyinearlytrialspatientswithadvancedcolorectal cancer, renal cellcarcinoma,melanoma,and stimulate theimmunesystemtoattackcancercellswhile eliminatingorlimitingtoxicity. Theapproachhas appear wellsuitedtoavaccineapproach,andclinicaltrialshavedemonstratedthatthesevaccinescan Recent advancesingenomicsandproteomicshaveenabledthediscoveryofnovelmoleculartargetsthat Consortium FocusesonDevelopingCancerVaccines new drugs,noveltechnologies, , Federallawsencourageuniver- projects aimed 3 to determine , suchas discovery, development,anddelivery. are abletomovedrugsthroughthepipelineof companies areacceleratingthepacewithwhichwe Food andDrugAdministrationpharmaceutical ronmental factors.Likewise,partnershipswiththe hypotheses relatingcancersusceptibilityandenvi- tions aswellinformingourfundamentalresearch mation iscriticaltotargeting publichealthinterven- Prevention, andstatecancerregistries.Thisinfor- efforts ofNCI, theCentersforDiseaseControland collected andanalyzedthroughthecombined preponderance ofdataoncancertrendshavebeen improving theNation’s health.Forexample,the and stateagencies ventions through We to participateinclinicaltrials. research findingsandinformationonopportunities who needtolearnaboutcancer, withnewsofrecent work tocreatethebestmethodsforreachingall advocacy organizations. NCI-supportedresearchers directly toconsumersandthroughphysicians brochures andeducationalpackagesdistributed service inallregionsofthecountry, andprinted on cancerandclinicaltrials,toll-freetelephone For example,NCIprovidesWeb-based information range ofother nates informationonnewinterventionsthrougha journals andnewsreports,NCIproactivelydissemi-

also fostercollaborationsleadingtonewinter- cancer communicationsactivities partnerships withotherFederal charged withstrategicrolesin A Planand BudgetProposal for FiscalYear 2004 .

17 OUR ROLE IN CANCER RESEARCH People don’t get “cancer.” They develop cancer of the breast, the prostate, the lung, or any of over 100 other types of the disease. The recommendations of Progress Review Groups are central to sustaining the best possible science and making the fastest advances against specific cancers.— Andrew C. von Eschenbach, M.D.

National Agendas for Disease-Specific Research

Unlike the common belief of 30 or 40 years ago, we know today that there are more than 100 dis- tinct types of cancer. We are also learning that many diseases have subtypes with unique molecular char- acteristics that influence how they develop and progress and how they can be effectively prevented, detected, and treated. For these reasons, NCI carries out an ambitious program of research on specific types of cancer. These efforts along with the broad-based programs described in this document provide the framework for national agendas for disease-specific research.

NCI leads the development and pursuit of disease- selected to assess the state of the science and specific research by assessing the current under- recommend future research-related priorities for standing of specific cancers, the funded research, one type of cancer or a group of closely related can- our ability to prevent and treat the disease, and the cers. The deliberations of each PRG are informed extent of our success. We chart the course primarily by a larger group of more than 100 leaders from through advice from expert Progress Review diverse disciplines and the advocacy community Groups (PRGs) who work with us to evaluate the who assemble for a Roundtable Meeting to discuss state of the science for specific types of cancer or their understanding of the disease, barriers to groups of related cancers, identify research gaps and progress, and key research and resource priorities resource needs, and develop recommendations for for the next five years. PRGs use the input from future priorities. NCI’s planning and evaluation these Roundtable groups to develop comprehensive process for disease-specific research involves three and widely distributed reports and recommenda- distinct phases: developing recommendations tions for national research agendas.1 through the PRGs, planning for and implementing those recommendations with advice from internal For example, recently assembled PRGs have identi- implementation working groups, and reporting on fied some specific initiatives they believe are need- progress. This comprehensive and integrated ed to speed research progress. approach to planning helps us demonstrate our ■ The Gynecologic Cancers PRG has identified progress and the wise use of resources to the scien- a need to develop a virtual shared specimen tific community and the public. Through these and resource that will improve timely access to high other crosscutting efforts, NCI establishes a frame- quality tissue and body fluid samples and enable work for accountability that is in keeping with the gynecologic cancer researchers to exploit emerg- President’s Management Agenda and the ing genomics, proteomics, and informatics tech- Congressionally mandated Government nologies. This critical tool would support the dis- Performance and Results Act. covery of new and urgently needed early detec- tion methods and new prevention and treatment Developing Recommendations targets. ■ The Lung Cancer PRG believes faster progress Progress Review Groups (PRGs) are panels of 20 against the difficult problem of lung cancer will to 30 prominent members of the scientific, medical, be achieved with scientifically integrated, inter- private sector, and advocacy communities who are disciplinary, multi-institutional consortia organized

1 prg.cancer.gov

18 The Nation’s Investment in Cancer Research ■ The ProgressReviewGroup(PRG)Process Planning NationalAgendasforDisease-SpecificResearch: 2 Status oftheProcessforEstablishedPRGsas September2002 Stomach &EsophagealCancers In therecommendation phase: See pages55-59forNCI’s futureplansforresearchonthetumormicroenvironment. Recommendation ■ ■ ■ ■ ■ ■ The cancer development. injury, inflammation,andinfectiononlung need tobetterelucidatethecontributionsof biobehavioral aspectsoftobaccocontrolandthe continued researchonthegenetic,social,and tions, thisPRGhasunderscoredtheneedfor disciplines. Amongitsothertoprecommenda- around thedisease,ratherthanscientific tions betweenthecancercellanditsimmediate scope ofresearchtoincludeanalysisinterac- characteristics ofthecancercells.Expanding Most studiestodatehaveexaminedonlythe ment andgrowthinbladderkidneycancers. likely playsanimportantroleintumordevelop- understand thetumormicroenvironment,which this groupfocusesattentiononourneedtobetter next fiveyears.Onepriorityareaidentifiedby advance progressagainstthesecancersoverthe intervention development,anddeliverythatwill across thefullspectrumoffundamentalresearch, identified andprioritizedresearchquestions PRG co-chairs. NCI leadershipappoints Committee totheDirector. ommendations toAdvisory PRG co-chairspresentrec- recommendations. prepare report& PRG members develops recommendations. Roundtable meets& table. membersplanround- PRG invite PRGmembers. PRG co-chairsidentify& Kidney andBladderCancersPRG Kidney &Bladder Cancers Gynecologic Cancers Lung Cancer Leukemia, Lymphoma, & Pancreatic Cancer Brain Tumors Colorectal Cancers In theimplementationphase: ■ ■ ■ ■ ■ Implementation Myeloma plan. disease-specific strategic NCI prepares&promotes meeting. NCI andPRGholdresponse recommendations. proposed responseto NCI prepares recommendations. projects toPRG NCI mapsitsinitiatives& Group ofinternalexperts. NCI establishesWorking has ■ of andaccesstoresearchresources. supporting researchcollaborationsordevelopment building initiativesdescribedonpages26-45for recommendation andarecloselytiedtothecapacity following wereemphasizedinmorethanonePRG tives identifiedinthisdocument.Forexample,the PRG recommendationsthatparallelpriorityinitia- A numberofcommonthemeshaveemerged across on disease-specificresearch Excellence (SPOREs)andconsortiafocused tional SpecializedProgramsofResearch Cross-disciplinary collaborationssuchasaddi- promotes tumorgrowth. cell anditsmicroenvironmentenableseven explore howtheinteractionbetweencancer ommendation alignswithNCI’s newthrustto tumor developmentandmaintenance.Thisrec- understand theroleofcellularcommunicationin tumor microenvironmentwillhelpresearchersto surroundings andcancer-associated changesinthe A Planand BudgetProposal for FiscalYear 2004 ■ ■ ■ ■ Reporting Prostate Cancer Breast Cancer In thereporting phase: plan. disease-specific strategic NCI revises&promotes progress. NCI &PRGdiscuss report. NCI developsaprogress NCI collectsprogressdata. 2

19 NATIONAL AGENDAS FOR DISEASE-SPECIFIC RESEARCH ■ Enhanced bioinformatics to enable better ■ Definition of molecular pathways and cellular researcher access to data and analytic tools interactions involved in cancer initiation, ■ Training on emerging technical developments progression, and metastasis and career development opportunities related to ■ Molecular profiling for the detection of specific types of cancer, to attract new precancerous conditions and early cancers and investigators for monitoring treatment response ■ More extensive and fully documented tissue ■ Development and testing of molecular targeted resources therapy ■ Preclinical models that more faithfully reflect ■ Improved imaging for early detection, guided the behavior of specific tumors in humans therapy, and real time monitoring of treatment response Other recommendations may be addressed through ■ Treatment side effect and quality of life out- our priority initiatives described on pages 48-92 for comes studies, including establishing registries supporting research on genes and the environment, and cohorts for study signatures of the cancer cell and its microenviron- ■ Education of medical providers and patients ment, molecular targets, cancer imaging, survivor- about cancer risk, prevention, detection, ship, and cancer communications. treatment, follow-up, and end-of-life care ■ Discovery of genetic and environmental factors and interactions that lead to cancer

NCI Programs Support Disease-Specific Research A number of NCI’s existing programs support research focused on specific types of cancer. ■ Specialized Programs of Research Excellence (SPOREs) have proven to be highly effective chan- nels for disease-specific translational research. The scope of the SPOREs is expanding to establish research hubs for additional cancers so that by the end of Fiscal Year 2002, 40 disease-specific SPOREs will be supported, with further expansions planned. Much of this expansion has been in response to PRG recommendations. Increasingly, SPOREs are partnering with Cancer Centers and NCI-sponsored research networks and consortia to build synergism and share resources to speed progress against specific cancers. Current SPOREs exist for brain, breast, gastrointestinal, genitourinary, head and neck, lung, ovarian, pancreatic, prostate, and skin cancer sites as well as for lymphoma. Future SPOREs will be established for gynecological, leukemia, and myeloma can- cers. (See pages 8, 10, 11, and 30 to learn about specific research activities taking place at SPOREs).3 ■ Early Detection Research Network (EDRN) participants develop, evaluate, and validate markers for earlier cancer detection and risk assessment. The Network includes academic and private collabo- rations and resources for basic, translational, and clinical research. EDRN collaborative groups include those focused on breast, gynecologic, gastrointestinal, lung and upper aerodigestive tract, prostate, and urologic cancers.4 ■ NCI’s Innovative Molecular Analysis Technologies (IMAT) program focuses on developing and applying technologies that identify the expression of genes and gene products, the function of major cellular communication pathways involved in cancer, the role of infectious agents in specific cancers, and the significance of other molecular alterations that distinguish normal cells from cancerous ones. (See page 58 for additional information).5 ■ The Mouse Models of Human Cancers Consortium (MMHCC) develops new preclinical models that will enable investigators to better understand specific human cancers and predict the effects of promising therapies. New models continue to be developed for sarcomas and for lung, prostate, mammary, skin, cervical, ovarian, nervous system, blood system, and gastrointestinal cancers. The MMHCC fosters collaboration in these efforts with industry partners and other research institutions.6

3 spores.nci.nih.gov 4 cancer.gov/prevention/cbrg/edrn 5 otir.nci.nih.gov/tech/imat 6 emice.nci.nih.gov

20 The Nation’s Investment in Cancer Research NCI’s Pancreatic CancerProgressReviewGroupemphasizedin its2001report ■ ■ ■ ■ ■ Researchers arepursuinganumberofavenuesinsearchanswersaboutpancreaticcancer: detect, diagnose,andtreatpancreaticcancerisabsolutelycritical. estimate that29,700peoplewilldiefromthisdiseaseinthesametimeperiod.Findingbetterwaysto six monthsorlessafterdiagnosis.In2002,approximately30,300newcaseswillbediagnosed.Experts beyond thepancreas,anditisresistanttobothchemotherapyradiationtreatment.Mostpatientslive This malignancymetastasizesearly, withmanytumorsassmall1or2centimetersindiameterspreading Pancreatic cancerisoftencalleda“silent”becauseithasnoclearsymptomsuntiladvanced. Stalking aSilentKiller pancreatic cancer. fatal diseaseandtoencourage researcherstocommitimprovingcareforpatients andthoseatriskfor against thissilentkiller. NCIistakingspecific stepstohelpincreasethelevelofresearchonthis highly funding andthelimitednumber ofresearchersdedicatedtostudyingthedisease havehamperedprogress The grants and could leadtoaconceptforthefundingofplanning public-private partnershipsfordrugdiscovery. This and governmenttoexaminemodelsforestablishing from academia,industry, theadvocacycommunity, Group Working Leukemia, Lymphoma, andMyeloma gliomas inbothpediatricandadultpatients.The unique organ-specific biologicalmechanismsof in developmentalneurosciencestounderstandthe proposed at the leadershipofdisease-specificworkinggroups recommendations arenowbeingdevelopedunder Formal strategicplansthatrespondtoPRG Address PRGRecommendations Implementing Strategiesto 8 7 prg.cancer.gov/pancreatic/finalreport See page10formore information. NCI. The receptors. number oftumorsuppressingandDNArepairgenes, andoverexpressionofseveralgrowthfactors study participants,withtheeffectgreaterinwomen than inmen. gene combinedwithheavysmokingincreasedpancreatic cancerrisksignificantlyamongCaucasian exposures. Forexample,arecentNCI-fundedstudy demonstratedthataspecificdeletioninthe Researchers intheUnitedStatesandabroadarelooking forgenesthatareinfluencedbyenvironmental Known non-hereditarygeneticalterationsincludeactivation ofthe Several hereditarysyndromesandtheirrelatedgenes (suchas therapies. Researchisuncoveringagrowingnumberofsuchgenes. ment orprogressionandcouldserveasearlydetectiondiagnosticindicators,targetsforbetter One importantavenueofresearchistofindgenesorgeneproductsthatinfluencethetumor’s develop- risk factorssuchaschemicalexposuresanddietinhopeofdevelopingeffectivepreventivemeasures. general population.Researchersarenowtryingtolearnmoreaboutothersuspectedandcorollary have firstdegreerelativeswhohadthediseaseathreefoldhigherriskcomparedwith factors forpancreaticcancer. Arecentstudyindicatesthatobesityincreasessusceptibility. Peoplewho Old age,cigarettesmoking,genetichistory, chronicpancreatitis,anddiabetesareestablishedrisk cases. hMLH1, PRSS1 acetcC Pancreatic suggested conveningameetingofleaders the applicationofnewconcepts eventually drugdevelopmentcenters. Brain Tumor Working Group ) havebeenidentified,buttheseprobablyaccountfor nomorethan5-10percentof ancer Working Group — Pancreatic Cancer encour- tions orproposals. of funds,and(3)receipthighqualityapplica- initiative isvital,feasible,andsound,(2)availability initiative isdependenton(1)determiningthatthe approaches. Ourabilitytoimplementanynew support, partnerships,oracombinationofthese or expandedresearchprograms,infrastructure mented throughongoingNCIinitiatives,new ration isneeded.PRGrecommendationsareimple- roles onthoseinitiativeswhereadditionalcollabo- and enableotherorganizations totakeleading specific strategicplansaspossible,andencourage as manyoftheproposedinitiativesindisease- progress againstalltypesofcancer. We implement NCI doeseverythinginitspowertoexpedite imperative inadvancingresearchonpancreaticcancer. aged thefundingandtrainingofnewinvestigators, p16, BRCA2, K-ras A Planand BudgetProposal for FiscalYear 2004 cancer gene,inactivationofa 8 7 STK11/LKB1, hMSH2, that insufficientresearch GSTT1

21 NATIONAL AGENDAS FOR DISEASE-SPECFIC RESEARCH Reporting on Progress current status of reports and plans related to the PRGs established to date. We close our accountability feedback loop by pro- viding details to the community on actions we have How We Measure Progress taken to address PRG recommendations. Recognizing that some actions take longer to ■ Disease trends: decreased incidence, demonstrate results, NCI monitors implementation earlier stage of diagnosis, longer survival and collects progress data for several years and then time, improved quality of life, lower prepares a progress report. This report is shared with mortality rate a reassembled PRG. Based on NCI’s assessment of ■ New FDA-approved interventions: new progress and PRG input, implementation strategies prevention & treatment agents & drugs, are revised, retired, or added as needed, and NCI improved diagnostic & treatment continues to monitor progress. technologies ■ Ongoing & new clinical trials By 2003 we will publish progress reports for prostate ■ Advances in scientific knowledge: reports cancer and breast cancer, in follow-on to the first two of research findings, peer-reviewed PRG reports issued in 1998. NCI will also complete publications an evaluation of the PRG process itself before the ■ NCI-supported research projects end of this year. The chart on page 19 indicates the

Targeting a Tumor on the Rise — Kidney Cancer The incidence of kidney cancer has been increasing about two percent per year for the past several decades. For African Americans, it is rising more rapidly than any other cancer — about four percent per year. Kidney cancer, including tumors of the main part of the kidney and the lower renal pelvis, is now diagnosed in nearly 32,000 people each year in the United States. About 200,000 people are living with kidney cancer. Mortality from the disease is also high and rising, with an estimated 11,600 deaths expected in 2002.

Four main types of kidney cancer have been identified. Clear cell renal tumors are the most common type, accounting for about 75 percent of cases. The reasons for the increase in incidence are not fully understood. Smoking is the most well established risk factor. Obesity, hypertension, occupational exposures, and heavy, long-term use of the pain medication phenacetin have also been linked to greater risk. A small percentage of kidney cancers are hereditary.

More than 40 percent of kidney cancers are not diagnosed until advanced stages. Five-year survival of patients who present with advanced kidney cancer is nine percent. By contrast, approximately 90 percent of patients diagnosed with Stage I disease survive at least five years. Scientists are actively exploring the growing field of proteomics to identify growth factors and other circulating proteins that may be indicators of disease and that can serve as biomarkers for early detection.

Currently, for localized kidney cancer, surgery is the only effective treatment. Minimally invasive and kidney- sparing surgical techniques are becoming more widely used. For metastatic kidney cancer, Interleukin-2 (IL-2) is the only approved treatment. Though highly toxic, IL-2 cures about 10 percent of patients. Scientists are investigating several important molecular pathways as potential targets for less toxic treatments. For example, anti-angiogenesis agents may prove beneficial against clear cell renal tumors. In a recent Phase II clinical trial, high doses of the antibody bevacizumab slowed tumor growth considerably in patients with metastatic kidney cancer.9 More than 20 other trials are now underway to evaluate this antibody as a treatment for other types of cancer.

In 2001, NCI convened a Kidney and Bladder Cancers Progress Review Group to assess our understanding and treatment of these diseases and identify research priorities and infrastructure needs for accelerating progress over the next 5 to 10 years. An NCI implementation planning group has been convened to analyze the recommendations10 and determine how the recommendations can be implemented.

9 See page 10 for more information. 10 prg.cancer.gov/kidney

22 The Nation’s Investment in Cancer Research People’s well understood,ratesofadenocarcinomastheesophagusarerisingatanalarmingrate. cancer, squamouscelltumorshavebeenhistoricallymoreprevalent.However, forreasons thatarenot die ofthisdisease.Itwillstrikethreetofivetimesmorementhanwomen.Ofthetwotypesesophageal This year, morethan13,000peoplewillbediagnosedwithesophagealcancerandanestimated 12,600will I wasgladdid. it tomydoctor. Aftertalkingtohim, antacids, soIfinallymentioned But Iwastakingmoreand finally startingtocomplainaboutit. I figured,atmyage,stomachwas I’ve alwayslovedspicyfood,and frequent indigestionandheartburn. A coupleofyearsago,Istartedhaving Esophageal Cancer normally foundinthestomach. nar epithelialcellssuchasthose esophagus arereplacedbycolum- epithelial cellsthatlinethe lower It occurswhennormalsquamous esophageal adenocarcinoma significant precursorfor Barrett’s esophagusisthemost lower smokingratessincethe1960s. American men,possiblydueto rates arefallingamongAfrican squamous cellesophagealcancer vival rates.Thoughstillhigh, other groupsandhavepoorersur- develop thediseaseearlierthan mas. Moreover, theytendto more oftenthanadenocarcino- develop squamouscelltumors population intheUnitedStates, all esophagealcancerratesofany men, whohavethehighestover- In contrast,AfricanAmerican in thispopulation. dence ofsquamouscelltumors white men,surpassingtheinci- been extraordinarilysteepamong The riseinadenocarcinomahas Story . ■ in AfricanAmericanmen. percent oftheexcessoccurence in themenstudiedandfor99 squamous cellesophagealcancers tors accountfor St esophagus remaininquestion. treatment approachesforBarrett’s The mosteffective screeningand fail toaskabouttheproblem. their doctors,andoftenphysicians burn tootrivialtomention may considerevenchronicheart- tively simpletest.Butpatients tion iseasytodetectwitharela- are preventablesincethecondi- Many casesofBarrett’s esophagus been showntoincreasetherisk. the esophagus,andobesityhas (backing up)ofstomachacidinto linked tothechronicreflux The conditionisbelievedtobe ud combination. consumption, particularlyin tobacco useandheavyalcohol cell esophagealcancerare development ofsquamous Major contributorstothe ies suggestthatafewriskfac- virtually allofthe A Planand BudgetProposal for FiscalYear 2004 to seethereport. Go to both formsofthisdeadlydisease. many importantquestionsabout resources neededtoanswerthe identify theresearchand about esophagealcancersand the currentstateofknowledge Progress ReviewGrouptoassess Stomach andEsophagealCancer In 2002,NCIconveneda and older. will beintheagegroup65years is 73years.Ofthese,66percent males is67years.Forfemales,it the medianageatdiagnosisfor For allesophagealcancerstogether, ■ susceptibility tothisdisease. and vegetablesalsoaccountfor quent consumptionoffruits that lowincomeandinfre- A recent NCIstudyreports prg.cancer.gov/stomach

23 PEOPLE’S STORY through programassessment. and improveexistingones.We keepourresearchportfoliobalancedandsupportstructurestrong identify newopportunities,aswellgapsandbarrierstoprogress,thathelpuscreateprograms grate basic,behavioral,population,andappliedresearchthroughtranslationalactivitiesstriveto covering themanytypesofcancerandvariouspopulationsthatexperiencethem.We strivetointe- best tomovethescienceforward.We planforresearchthatcanaddresscriticalunansweredquestions partners fromthescientific,medical,andadvocacycommunitiestodeterminewhatisneededhow ties, whilemakingthebestuseofourresources.NCIstaffworktogetherandwithpublicprivate NCI plansandsetspriorities Cancer Research Planning andPrioritySettingfor to complement ourcorebudgetforcontinuing and Budgetiscomprisedof threemajorcomponents Thus, theframeworkforour FiscalYear 2004Plan cer incidenceandoutcomes. do allthatwecantoreduce healthdisparitiesincan- clinical practiceandpublichealth;ensurethatwe related knowledge,technology, andinterventions in improve ourabilitytoapplythebestavailablecancer- clinical outcomesresultingfromcancerinterventions; these prioritieswillenhanceourunderstandingofthe people atriskfororaffected bycancer. Pursuing cerns thathavepotentialtoaffect large numbers of areas alsoaddressmajorpublichealthneedsorcon- of theseChallengeandExtraordinaryOpportunity news,” theemergent fieldsofcancerresearch.Some organizations. Thesepriorityareasarethe“breaking research community, advisorygroups,andadvocacy developed withformalinputfrommembersofthe significant progressagainstallcancers.Theyare edge andtechnologyholdpromiseformaking the mostimportantrecentdevelopmentsinknowl- Investment clinicians. discovery andcollaborationamongresearchers tion andtechnology, andmaximizingthesharingof duct research,enhancingaccesstoresearchinforma- thering thepreparationofpeopleneededtocon- and mechanismsavailabletosupportresearch,fur- sis thatfocusinvestmentonimprovingtheresources development. work forourannualstrategicplanningandbudget of severalbroadpriorityareasthatserveastheframe- Institute hasidentifiedandfosteredthedevelopment Over thepastseveralyears,NationalCancer Extraordinary Opportunitiesfor are areasofdiscoverythatbuildupon NCI Challenges are areasofempha- to ensurethatweareresponsivenewdiscoveriesandopportuni- consultation withProgressReviewGroups. for Disease-SpecificResearch of cancerasdescribedinthe cross-cutting andfocusedresearchonspecifictypes research andsupportactivities.Eachoftheseincludes ■ ■ ■ requires increasedsupportfor: Addressing AreasofPublicHealthEmphasis Opportunities forInvestment”in: means furtherpursuing“Extraordinary Advancing DiscoveryandItsApplication NCI Challengeareas: Capacity Building theNation’s CancerResearch — — A newExtraordinaryOpportunity in — — TheChallengeforReducingCancer-Related The ChallengeforImprovingtheQualityof — — Cancer Communications Cancer ImagingandMolecularSensing — Molecular Targets— forPreventionand Signatures oftheCancerCellandIts — Genes andtheEnvironment — National ClinicalTrials— Programin Expanding theCapacityofCenters — Enhancing Investigator-Initiated Research — — An ExtraordinaryOpportunity forResearch — Developing BioinformaticsforCancerResearch. Cancer Survivorshipresearch T Health Disparities Cancer Care T Microenvironment Networks, andConsortia on Tobacco and Tobacco-Related Cancers reatment andPrevention reatment requires increasedsupporttofour A Planand BudgetProposal for FiscalYear 2004 National Agendas developed in

PLANNING AND PRIORITY SETTING FOR CANCER RESEARCH The Nation’s Investment in Cancer Research

Distribution of 2004 Budget Request ($5,986,000,000)

Research Project Grants 45.5%

Intramural Research 12.8%

Cancer Centers 6.1%

SPOREs 3.3%

Clinical Trials Infrastructure 9.3%

Training and Education Grants 3.1%

Cancer Control Operations 3.3% Other Grants 1.5% Research Support Contracts 11.2%

Research Management and Support 4.0%

Distribution of 2004 Requested Increases ($1,348,131,000) Research Project Grants 40.9%

Intramural Research 4.3%

Cancer Centers 8.0%

SPOREs 5.0%

Clinical Trials Infrastructure 17.3%

Training and Education Grants 1.2%

Cancer Control Research Support Contracts 15.8% Operations 0.6%

Research Management Other Grants 2.0% and Support 5.0%

Research Project Grants Intramural Research Cancer Centers and Special Funding for extramural research, primarily NCI intramural research focuses on Programs of Research Excellence through investigator-initiated Research projects conducted by some 400 (SPOREs) Project Grants (RPGs), comprises the researchers located on the NIH cam- Sixty NCI-supported Cancer Centers largest part of the NCI core budget. pus. These researchers build upon the serve as hubs for cutting-edge research, Increases through the NCI Challenge and proximity between their research labo- high quality cancer care, and outreach Extraordinary Opportunity initiatives con- ratories and the NIH Clinical Center and education for healthcare providers tribute to the expansion of research sup- and the synergism among NIH and patients. Centers of Excellence like ported through RPGs. NCI funds about Institutes to support the rapid transla- the SPOREs use flexible funding to pur- 4,500 RPGs each year to nearly 600 institu- tion of basic laboratory research to the sue questions related to specific forms of tions across the United States at an average clinic and to maintain a special focus on cancer and to move disease-specific cost of approximately $400,000 per grant. long-term epidemiologic and genetics research quickly from the laboratory to If fully supported, our budget request for studies. the patient. Funding increases will allow Fiscal Year 2004 would add $523 million to NCI to broaden the number and range of the funds available to support investigator- activities at Cancer Centers and SPOREs. initiated research. NCI Budget Request for 2004

2002 2003 2004 Budget Request Operating President's Budget Budget Total (dollars in thousands) Increases Research Project Grants (RPGs) Ongoing $1,450,697 $1,557,941 $ 89,160 $1,647,101 New and Renewal 456,000 516,711 434,625 951,336 Subtotal 1,906,697 2,074,652 523,785 2,598,436 Small Business Innovation Research 85,995 100,294 26,995 127,289 Total RPGs 1,992,692 2,174,946 550,779 2,725,725 Intramural Research 630,036 706,258 58,132 764,390 Cancer Centers 227,831 254,246 107,937 362,183 Specialized Programs of Research Excellence (SPOREs) 108,921 127,696 67,725 195,420 Clinical Trials Infrastructure Cooperative Clinical Research 161,711 198,060 157,628 355,688 Community Clinical Oncology Program (CCOPs) 105,522 123,187 76,108 199,295 Total Clinical Trials Infrastructure 267,233 321,247 233,736 554,983 Training and Education Grants National Research Service Awards 64,083 73,289 4,926 78,215 Research Career Program 54,177 65,327 5,500 70,827 Cancer Education Program 27,170 25,456 3,942 29,398 Minority Biomedical Research Support 3,980 4,522 1,167 5,689 Total Training and Education Grants 149,410 168,594 15,535 184,129 Cancer Control Operations 154,306 188,429 7,722 196,151 Research Support Contracts 425,440 457,941 212,644 670,585 Research Management and Support 150,757 173,200 66,758 239,958 Other Grants 60,371 65,313 27,163 92,475 Total NCI 4,166,997 4,637,869 1,348,131 5,986,000 Cancer Control included above** 491,645 546,792 308,821 855,613

Clinical Trials Infrastructure Training and Education Grants Cancer Control** NCI supports clinical trials carried out by NCI funds approximately 170 institu- NCI’s cancer control operational funds approximately 10,000 investigators at tions and 2,000 individuals each year along with numerous grants and contracts some 1,700 U.S. hospitals and Cancer through extramural cancer research included throughout the budget are used Centers each year. Nearly 1,500 trials are training programs to prepare the next to support research, communication, and conducted annually, assisting over generation of scientists and clinicians to other activities focused on ways to reduce 200,000 patients. These trials make possi- use new technologies and work effec- cancer risk, incidence, morbidity, and mor- ble the testing of targeted agents that tively in interdisciplinary, collaborative tality and improve the quality of life for all hold promise for more effective, less inva- research environments. Increased cancer patients. Increases will be used to sive, cancer prevention and treatment and funding will be used to enhance these support research on tobacco and tobacco- technologies that can be used for better programs and to support the participa- related cancers, reducing cancer-related detection and diagnosis. About three- tion and growth of scientists within health disparities, improving the quality of quarters of this funding is for treatment underserved populations. cancer care, cancer survivorship, cancer trials and the other quarter supports pre- communications, and a host of other infor- vention and screening trials. mation dissemination activities.

24 The Nation’s Investment in Cancer Research Requested Increases for Fiscal Year 2004*

Discovery and Public Health Capacity Building Application Emphasis Total Core Increase Increase Increase Increase Increases (dollars in thousands) Research Project Grants (RPGs) Ongoing $ 89,160 $ - $ - $ - $ 89,160 New and Renewal 35,988 99,737 169,100 129,800 434,625 Subtotal 125,148 99,737 169,100 129,800 523,785 Small Business Innovation Research 20,995 - 6,000 - 26,995 Total RPGs 146,142 99,737 175,100 129,800 550,779 Intramural Research 26,132 27,000 5,000 - 58,132 Cancer Centers 24,907 72,830 8,200 2,000 107,937 Specialized Programs of Research Excellence (SPOREs) 32,725 30,500 4,500 - 67,725 Clinical Trials Infrastructure Cooperative Clinical Research 7,328 132,900 7,500 9,900 157,628 Community Clinical Oncology Program (CCOPs) 4,558 71,550 - - 76,108 Subtotal 11,886 204,450 7,500 9,900 233,736 Training and Education Grants National Research Service Awards 4,926 - - - 4,926 Research Career Program 2,500 - - 3,000 5,500 Cancer Education Program 942 - 1,000 2,000 3,942 Minority Biomedical Research Support 1,167 - - - 1,167 Subtotal 9,535 - 1,000 5,000 15,535 Cancer Control Operations 6,972 - - 750 7,722 Research Support Contracts 16,944 103,850 44,450 47,400 212,644 Research Management and Support 6,408 39,150 16,700 4,500 66,758 Other Grants 12,363 - 3,800 11,000 27,163 Total NCI 294,014 577,517 266,250 210,350 1,348,131

*Increases over the 2003 President’s Budget

Research Support Contracts Research Management and Other Grants Research support contracts are used Support Other grants support partnerships and to support program efforts across the Research management and support shared resources and scientific evalua- Institute. Areas that utilize contracts budgets are used for the critical techni- tion, workshops and conferences. are diverse and include such areas as cal and administrative services required drug development, cancer control for NCI to carry out its work. They research, information dissemination, include central administrative func- and support to epidemiological tions, overall program direction, grant research. and contract review and administration, personnel, program coordination, and financial management. NCI BUDGET REQUEST

A Plan and Budget Proposal for Fiscal Year 2004 25 The ever-changing technological and scientific land- scape requires that we constantly re-examine how we interact as scientists to conduct our research and what resources are necessary to yield results. — Andrew C. von Eschenbach, M.D.

Building the Nation’s Cancer Research Capacity

The challenge before NCI is to build and continually enhance a research system that will allow and encourage the scientific community to share and apply new discoveries and emerging technologies. We need new funding arrangements that will promote and reward innovative thinking; speed cross fertiliza- tion of ideas among disparate scientific disciplines; facilitate collaborations among government, acade- mia, and industry; and bring advances in cancer care to all populations. And we need to foster and coor- dinate efforts that would be too large for the individual investigator by promoting team endeavors, and by encouraging scientific integration without inhibiting individual creativity.

Advances in working with specific types of cancer ■ Train top researchers in oncology and arm them may emerge from non-specific cancer knowledge with the finest technologies and tools available. and resources, and new knowledge in one type of ■ Build and sustain the interdisciplinary cancer often has implications for better understand- connections so vital to 21st century science. ing other cancers. To make progress for as many cancers as possible, we need to: We will continue to build the Nation’s cancer ■ Guide, support, leverage, and build the work of the research capacity for the future by Enhancing individual investigator along with that of our NCI- Investigator-Initiated Research, Expanding the Capacity supported Cancer Centers, networks, and consortia. of Centers, Networks, and Consortia, maximizing the ■ Maximize caregiver and patient access to clinical impact of our National Clinical Trials Program in trials for prevention, diagnostic, and therapeutic Treatment and Prevention, and Developing interventions. Bioinformatics for Cancer Research.

FY 2004 Increase Request for Capacity Building Centers, Networks, & Consortia (dollars in thousands) 14%

Investigator-Initiated Research $ 69,887 Centers, Networks, & Consortia $ 79,530 National Clinical Trials Program $340,100 Investigator- National Clinical Trials Initiated Program Bioinformatics $ 88,000 Research 59% 12% Total $577,517

National Clinical Trials Program 49.3% Bioinformatics 15%

26 The Nation’s Investment in Cancer Research NCI Challenge: Building Our Capacity for the Future GOAL

Accelerate discoveries and their application by expanding and facilitat- ing researcher access to resources and new technologies. Enhancing Investigator-Initiated Research

The Challenge new technologies and approaches to conducting research. In Fiscal Year 2002, for example, the Investigator-initiated research — research inde- number of applications submitted to NCI increased pendently conceived and developed by scientists — by 6 percent, and the cost of research projects sup- has always been the primary means by which bio- ported by NCI was nearly 14 percent higher than medical research is funded and conducted. Driven the year before. This cost increase reflects a larger by the synergism at medical schools, hospitals, uni- number of total active awards as well as modest versities, and research centers, these investigators growth in average cost. While we expect this trend ask the critical questions, explore the options, to moderate, we must balance the growing number develop and test innovative technology, and make of research opportunities with the rising costs of the discoveries that lead to better cancer science research. Though reviewer assessments of research and its application. Investigator-initiated research is applications consistently identify the top 35 to 40 also the principal means by which NCI supports percent of grants as highly meritorious, the propor- efforts to address high-priority goals, such as those tion actually funded (the success rate) has averaged identified by the Progress Review Groups. 29 percent in recent years. NCI has maintained this success rate by carefully reviewing individually Recent advances, highlighted by the completed approved grant applications for programmatic sequencing of the human genome, new technolo- changes, the effect of which is, on average, a reduc- gies for identifying molecular targets within cancer tion of 10 percent to the cost of a grant. As research cells, and methods for discovering and analyzing opportunities increase, we must, in addition to promising drugs aimed at each cancer-causing path- leveraging our Federal dollars, ask researchers to way, have outfitted scientists with a wider arsenal of complement this funding from other sources as approaches and technologies for research than ever much as possible. before. The exploration of what we can learn from analyzing all of the genes altered in a cancer cell is The next generation must choose to enter cancer expanding rapidly. Even as this is happening, inves- research because of opportunities for discovery tigators are developing powerful methods to analyze with the potential to change our world. A sufficient the vastly more complex array of proteins made in infusion of resources and funding into investigator- the cell. This offers a more direct route to identify initiated research will help to ensure that students targets for new drugs. However, to take advantage of considering a career in science, as well as current these advances, researchers often require additional researchers, will perceive cancer research as an resources, in the form of new research tools and appealing and rewarding profession. equipment, collaborators from different disciplines, or special support for translational research. Progress Toward Providing these resources is part of NCI’s challenge Meeting the Challenge in the area of investigator-initiated research. The NCI has sought to support and foster investi- NCI has seen an enormous increase in the need gator-initiated research through a variety of policy for funding to allow scientists to fully exploit decisions and flexible funding options. BUILDING THE NATION’S CANCER RESEARCH CAPACITY CANCER RESEARCH CAPACITY BUILDING THE NATION’S

A Plan and Budget Proposal for Fiscal Year 2004 27 The Plan

Enhancing Investigator-Initiated Research

GOAL

Accelerate discoveries and their application by expanding and facilitating researcher access to resources and new technologies.

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004

1. Accelerate the pace of discovery through increased funding for and greater numbers of competing research grants. ■ Support research projects to move toward funding at the full levels recommended by peer reviewers. ■ Fund, at a minimum, 35 percent of competing applications — those with (1) the highest scientific merit, (2) a less certain probability of success but potential to yield greater reward if they do succeed, (3) unconventional approaches but unique promise, (4) a focus on areas of extraordinary need in specific fields of investigation or model systems, and/or (5) the involvement of new investigators.

2. Encourage investigators to commit to careers in cancer research and to propose more innovative and higher reward projects. ■ Continue to allocate the first 80 to 90 percent of available funds for research project grants through the well-established peer review selection process while ensuring that proposals from new investigators are also funded at a rate comparable to those of more established investigators, utilizing exceptions as necessary. ■ Through a special administrative evaluation process, fund particularly innovative and potentially high reward projects.

3. Facilitate rapid movement from discovery to application by using established mechanisms and creating novel special awards to encourage transdisciplinary and collaborative research. ■ Expand supplemental funding for grants that promote new interdisciplinary collabo- rations for bringing together basic, clinical, and population scientists, such as those

Balancing Investigator-Initiated Research Projects and Large Initiatives There’s no substitute for individual insight and creativity. That’s why the traditional research project grant (R01) remains the heart of the NCI portfolio of investigator-initiated research and remains our number one priority. The Human Genome Project exists at the other end of the spectrum — a large consortium of investigators and an initiative that produced massive amounts of uniquely valuable data, generated using expensive, high technology instrumentation. We now appreciate how necessary these large endeavors are, but the difference in scale threatens to create the scientific equivalent of the “digital divide.” The challenge is to balance the flow of resources to ensure that the individuals with the best ideas continue to have access to the resources they need.

In recent years, NCI has expanded funding for a variety of large-scale initiatives to capitalize on the insights and tools derived from genetics research, proteomics, functional imaging, nanoscience, laboratory and clini- cal models, and targeted drug discovery and development. The success of such large-scale approaches,

28 The Nation’s Investment in Cancer Research fostered by NCI’s Activities to Promote Research Collaborations Program. ■ Expand researcher access to central resources such as databases, tissue banks, and animal models using funding supplements; centers, networks, and consortia; and cooperative resource programs. ■ Expand researcher access to technologies that promote interdisciplinary research and collaborations and to the expertise needed to move discoveries to application. ■ Develop and make available information technology tools to foster and enhance interdisciplinary communication and collaboration. ■ Expand the funding for collaborative research awards such as program project grants and cooperative agreements for consortia that facilitate translational research. ■ Expand the use of exploratory grants to encourage more patient- and population- based research.

4. Use regular and special award mechanisms to encourage investi- gation in priority areas identified by advisory committees, NCI staff, Progress Review Groups, and other groups. Leverage resources for these efforts through collaborative initiatives. ■ Monitor investigator-initiated research to assess whether these projects alone are meeting programmatic objectives, such as those identified in specific disease areas. ■ Set aside 10 to 15 percent of funds for Requests for Applications in specifically targeted areas of need. ■ Support Program Announcements and investigator-initiated projects that target iden- tified gaps and/or emerging opportunities (e.g., as identified by the Progress Review Groups and other priority setting and strategic planning activities). ■ Enhance coordination within and among initiatives, and increase management and support commensurate with the growth of the portfolio. ■ Use supplemental awards to encourage outreach to establish public-private partner- ships and to leverage current NCI funded activities with new, complementary non-NCI sources of support.

Management and Support $ 2.00 M Total $ 69.89 M

however, increasingly will require individual investigators to prosper by working in conjunction with others to have access to specialized facilities needed to compete. Therefore if individual grants are to continue to lead the way in innovation, NCI infrastructure models must have the capability of marrying individual expertise and imagination to state-of-the-art resources.

To assure such balance is maintained, NCI staff work to provide broad access to NCI-funded resources, where possible, and to ensure that individual researchers are aware of all the resources available to them. But other related initiatives that provide infrastructure assets such as large-scale instrumentation and bioinformatics support are also integral to maintaining investigator-initiated research. Reasonable growth in average costs, flexible funding options, and full funding for R01s are essential to maintaining access to such technologies to ensure that the next generation of creative investigators working on cancer continues to flourish in independent settings. BUILDING THE NATION’S CANCER RESEARCH CAPACITY CANCER RESEARCH CAPACITY BUILDING THE NATION’S

A Plan and Budget Proposal for Fiscal Year 2004 29 Identifying and Supporting ■ Providing opportunities for collaborative study High Priority Research through awards such as program project grants NCI takes extra steps to identify and support high (P01s) and cooperative agreements, in addition to priority research by: the traditional research project grants (R01s) that ■ Seeking out and supporting compelling research make up the bulk of NCI’s research portfolio. proposals with exceptions funding, particularly ■ Expanding the use of award mechanisms that those suggesting dramatically new or unconven- provide seed funds for promising research. tional approaches to understanding cancer. In Fiscal Year 2001, the number of small (R03) ■ Giving special consideration to proposals respon- and exploratory/developmental (R21, R33) sive to high-priority research areas identified by grants awarded increased more than 15 percent NCI advisory groups, to NCI Program over the previous year. Announcements of priority research areas, and to ■ Making “administrative supplement” funds recommendations from Progress Review Groups available to investigators to allow them to take for research related to specific cancers. advantage of unanticipated opportunities or to pursue interdisciplinary collaborations. For We are also exploring better ways to define and pro- example, through NCI’s Activities to Promote mote the exploration of uncharted areas and to give Research Collaborations Program, grantees can them heightened consideration when reviewing apply for funding in support of collaborations to grant applications. initiate novel research that pursues unforeseen opportunities and to share resources, develop Maximizing the Ability to Start new technologies, or organize cross-disciplinary New Projects and Collaborations meetings or workshops. NCI maximizes the pace of discovery by providing ■ Promoting collaborative studies and sharing of a broad range of flexible funding options and resources through innovative networks and promoting collaborations and resource sharing consortia. (See pages 32-35.) wherever possible by:

Better Understanding the Cell Microenvironment Holds Promise for More Effective Cancer Treatment and Prevention For many years, scientists have conducted studies of cells by removing them from their natural surroundings, assuming that the proteins, accessory cells, and blood vessels within a cell’s immediate surroundings — its microenvironment — provide nourishment and support with little effect on the cell’s function. But scientists now know that a cell and its microenvironment have a dynamic and intimate relationship. In the embryo, this relationship ensures that organs develop properly. In the adult, it helps to maintain the stability needed for cell functioning and influences a host of cell activities, such as proliferation and programmed cell death.

The cell-microenvironment relationship also plays an important role in cancer development and progression. When a lone cancer cell arises from multiple changes in its own genes, it does not pose a threat to the body. But when it pro- gresses to a tumor mass comprised of cancer cells and cells from the surrounding environment, it becomes a serious health concern. Researchers have observed that: ■ The abundance of growth factors in the microenvironment provides a readily available source of growth-promoting signals to tumor cells. ■ The influence between the microenvironment and cancer cells is bi-directional. Scientists must now determine whether neighboring cells lose their natural capacity to suppress cancer cell growth or whether they acquire an attribute that permits tumor growth. ■ An enzyme induced in inflammatory cells found in the microenvironment appears to be the elusive “angiogenic switch” that turns on the formation of new blood vessels needed to keep cancer cells alive.

This broadened concept of cancer has taken us from focusing exclusively on the cancer cell to exploring how the interplay between the cancer cell and its immediate environment supports tumor growth. Ultimately, this will enable us to explore the impact of tumor growth on the entire body. Rather than targeting the cancer cell alone, new prevention and treatment approaches will potentially target the features of the microenvironment that allow tumors to develop and progress. For information on NCI’s future plans for research in this area, see pages 55-59.

30 The Nation’s Investment in Cancer Research ■ ■ ■ ■ ■ ■ Cancer ResearchTraining andCareerDevelopment Progress ReportforNCIChallenge: ever changingcancerresearchenvironment. ensure afutureoftalented,diverse,andinnovativecancerresearcherstomeettheneeds requesting budgetincreasesinthisareafor2004,butwecontinuetousemultiplestrategies Development, acomponentofNCI’s PlanandBudgetproposalsinceFiscalYear 1999.NCIisnot tion forthegoalsandobjectivesoutlinedinNCI’s ChallengeAreaforResearchTraining andCareer students andscientistsinpursuingcareerscancerresearch.Thisstrategicplanbecamethefounda- cancer research.Equallyimportantwasensuringafuturethatincludedbroaderparticipationofminority well trainedscientistspreparedtotackleemergingquestionsinbasic,clinical,behavioral,andapplied training futurecancerresearchers.In1998,NCIlaunchedastrategicplanforensuringcadreof ened thescopeofdisciplinesneededforcancerresearchandhavepresentednewchallenges Rapid developments T Increased InvestmentStrengthensResearch raining andCareerDevelopment research onhumancancer. ratory andclinicalscientists totranslational supports therecruitmentor reorientationoflabo- Specialized ProgramsofResearchExcellence The careerdevelopmentprogramthrough minority populations. focus oncancersthatdisproportionatelyaffect support minorityscientistsandprojectsthat Institutions andNCI-designatedCancerCenters Collaborations betweenMinority-Serving school throughadvancedresearchtraining. candidates inthebiomedicalpipelinefromhigh increases thepoolofunderrepresentedminority Comprehensive MinorityBiomedicalBranch Research ExperiencesProgramandthe grams throughtheContinuingUmbrellaof Supplemental fundingtoexistingtrainingpro- needed forthefuture. associated withcancerresearchbutclearly attract scientistsindisciplinesnottraditionally New DiversifiedCareerDevelopmentAwards their firstindependentresearchprograms. autonomous investigatorsastheystarttodevelop they transitiontoindependenceandnewly “protected” timetopostdoctoraltraineesas The NCITransition CareerAward provides resources intheirfields. established scientistswhoareleadersand doctoral candidateswhoneedmentoringto various needsofresearchersrangingfrompre- A Career Awards andNationalResearchService wards areflexiblyadministeredtomeetthe in thefrontiersofmolecularbiologyandtranslationalmedicinehavebroad- go to opportunities training, careerdevelopment, andeducational For additionalinformation on research their peers. most respectstheseawardrecipientsoutperform colleagues withoutthissupport.Datashowthatin National ResearchServiceAwards support,totheir sciences, whohavereceivedatleastninemonthsof Ph.D. recipientsinthebehavioralandbiomedical ments. Forexample,arecentNCIreportcompares to quantifyfulfillmentoffuturetrainingrequire- and postdoctoraltrainees.Thisinformationcanhelp collection toprovideinformationaboutstudents NIH supportsthedevelopmentofWeb-based data ■ ■ ■ T and imaging. epidemiology, pathology, andpharmacology; and control;populationsciences;molecular interdisciplinary areassuchascancerprevention predoctoral andpostdoctorallevelinhighly grams dedicatedtotraininginvestigatorsatthe Program encouragesinstitutionstodeveloppro- The CancerEducationandCareerDevelopment mortality. to decreasecancerincidence,morbidity, and at developinginnovativeeducationalapproaches The CancerEducationGrantProgramisaimed scientists. based clinicaltrialsandcollaboratewithbasic scientists todesignandimplementhypothesis- Development Programsprepareclinical wenty InstitutionalClinicalOncologyCareer cancertraining.nci.nih.gov. available throughNCI, A Planand BudgetProposal for FiscalYear 2004

31 PROGRESS REPORT NCI Challenge: Building Our Capacity for the Future GOAL

Create and sustain infrastruc- tures that facilitate research collaboration, serve as platforms for technology development, and provide access to the full range of research resources. Expanding the Capacity of Centers, Networks, and Consortia

The Challenge Progress Toward Meeting the Challenge Today’s cancer researchers cannot excel in an intel- lectual or administrative vacuum. To maximize inno- Building and Sustaining Infrastructures vation, researchers must work effectively in an inter- for Translational Research disciplinary environment that allows and encourages NCI’s overarching structure for research supports them to engage in newly emerging areas of research NCI-designated Cancer Centers, Centers of and technology development and to take full advan- Research Excellence, research networks and consor- tage of opportunities to move science forward to tia, as well as individual investigators. This frame- benefit patients and the public health. They need work helps create an environment conducive to sophisticated tools, extensive — and expensive — complex scientific interactions, provides the information resources, and trained associates to make resources essential for the research, and encourages meaningful progress. And they need research infra- the easy exchange of information and ideas. The structures that promote collaboration in basic, clini- challenge of the future will be to ensure that our cal, and population research and among scientists in numerous interactive linkages function at peak fields such as physics, computer science, and engi- effectiveness, allowing investigators to seek answers neering. Investigators must have access to patients to major questions more efficiently and effectively. and at-risk populations as well as to tissue banks, Within this structure, there are several levels of new technologies, and state-of-the-art informatics. interaction. NCI-designated Cancer Centers And we must establish more effective linkages organize and integrate multidisciplinary research among oncologists, researchers, the pharmaceutical across departments and schools within a single insti- industry, cancer advocates, and policy makers to tution or consortium of institutions. They provide ensure that the results of discovery and intervention scientists access to the most advanced technologies development reach those people who need them. and new research opportunities.

NCI’s challenge is to address these critical needs by These Centers, in turn, have given rise to Centers continuing to expand the capacity of centers, net- of Research Excellence that bring together inter- works, and consortia to most effectively: disciplinary and translational research teams focused ■ Build and sustain research infrastructures that on specific diseases, modalities, biologic processes, encourage and reward multidisciplinary research or scientific areas. They are awarded sizeable and scientific collaborations. amounts of flexible funding to enable them to ■ Broaden the geographic distribution and impact rapidly address emerging scientific opportunities. of NCI-designated Cancer Centers. ■ Specialized Programs of Research Excellence ■ Improve the access of underserved populations (SPOREs) provide platforms for interaction, to state-of-the-art research and resources. collaboration, and intervention development for ■ Engage in new areas of research and technology specific cancers. They serve as highly effective development. hubs for translational research, moving discoveries ■ Make expertise, facilities, clinical practice and among laboratory, clinic, and population research public health guidelines, and other resources settings. In just 10 short years this program has broadly available to physicians and other care- grown substantially, with 40 SPOREs conducting givers, patients and families, and appropriate and facilitating translational research in brain, health agencies. breast, gastrointestinal, pancreatic, genitourinary,

32 The Nation’s Investment in Cancer Research ■ ■ NCI-supported and ensurethebeststewardshipofFederalfunding. efforts thatNCIcanfurtherleverageitsresources interventions. Itisthroughthesecollaborative research concepts,andmechanismsfordeveloping Centers ofResearchExcellencetosharedata, NCI isworkingtobuildbetterwaysforthese ■ ■ ■ in importantways. integrated withCancerCentersandotherprograms 3 2 1 Network (EDRN) the SPOREs,andEarly DetectionResearch gators intheNCIDirector’s Challenge program, Consortium participantscollaborate withinvesti- tions, hascomponentsinCancer Centers. tional, clinical,andepidemiologicalinvestiga- researchers engagedinavarietyofbasic,transla- Consortium, avaluableresourceforcancer The MouseModelsofHumanCancers of inheritedpredispositiontocancer. Cancer Centerswhospecializeinthestudy network ofresearcherslocatedinNCI-designated The CancerGeneticsNetworkisanational through planninggrants. and othercollaborativeefforts areunderway these partnershipshavebeeninitiatedtodate and mortalityinminoritypopulations.Fiveof reducing thedisproportionatecancerincidence research, training,andoutreachdedicatedto the MinorityServingInstitutionstoincrease are developinglong-termrelationshipswith Center Partnershipprogram,CancerCenters Through theNCIMinorityInstitution/Cancer den ofcancerinminoritycommunities. addressing importantquestionsaboutthebur- community basedprogramstofindwaysof ships betweenlarge researchinstitutionsand A Special PopulationsNetworksforCancer Health Disparities. ciplinary CentersforPopulationHealthand Research. Thenewestofthesearetheinterdis- Excellence inCancerCommunications Molecular Target Assessment,andCentersof Centers, InterdisciplinaryResearchTeams for Centers, T gic CentersofResearchExcellenceinclude Modeled ontheSPOREblueprint,otherstrate- prostate, andskincancers. head andneck,lung,lymphoma,ovarian, cancer.gov/prevention/cbrg/edrn See page84formore information. spores.nci.nih.gov wareness ResearchandTraining buildrelation- ransdisciplinary Tobacco UseResearch In Vivo networks andconsortia Cellular andMolecularImaging 3 2 to evaluatevarioushigh- 1 are also expected inearly2003. Recommendations fromthe workinggroupare vate, philanthropic,andindustrial entities. tating partnershipswithother governmental,pri- focused onreducingthecancer burden,andfacili- developing objectivesofanationalcanceragenda maximizing translationofresearchdiscoveries, ing thebreadthanddepthofcentersprogram, was charged withconsideringstrategiesforbalanc- Cancer CentersandSPOREs.TheAdHocgroup group toestablishablueprintforNCI-designated Advisory BoardassembledanAdHocworking In thesummerof2002,TheNationalCancer research. trials inearlydetection,prevention,andtherapeutic tions withmuchimprovedaccesstothenewest Cancer Centers—toprovidepatientsandpopula- large, existing NCI-designatedComprehensive partnerships betweensmallerinstitutionsandthe the establishmentofregionalcancercenters— regions oftheNation.NCIisworkingtofacilitate especially tothoseinunder-represented geographic physicians andothercaregivers,communities, idly bringthebenefitsofresearchtopatients, tively withNCIinoutreachactivitiestomorerap- Comprehensive CancerCentersparticipateproac- programs. Directorsandinvestigatorsatthese the UnitedStateswithmajorbiomedicalresearch nation. Thisincludesmostmedicalinstitutionsin Centers havereceivedthe“comprehensive”desig- In thelastfiveyears,morethan40of60Cancer local andstategovernments. societies, businesses,industry, communities,and other cancerfundingorganizations, professional means forfosteringcoalitionsandpartnershipswith leadership inthewaragainstcancerandprovidea consortia canserveasnaturalhubsfornational NCI-supported CancerCenters,networks,and Results toCancerPatients Bringing State-of-the-ArtResearch ■ research. ble technologiesaredevelopedformouse throughput technologiestoensurethatcompati- detect earlysignsofcancer. validation ofmolecularmarkersandassaysthat ery, development,andinitialstepsinclinical interdisciplinary groupstofacilitatethediscov- investigators, SPOREandother Further interactionsareongoingamongEDRN A Planand BudgetProposal for FiscalYear 2004

33 BUILDING THE NATION’S CANCER RESEARCH CAPACITY The Plan

Expanding the Capacity of Centers, Networks, and Consortia Genes and the Environment GOAL GOAL Create and sustain research infrastructures and collaborations that enable multiple scientific Discoverdisciplines those to address genetic, large environmental, problems in and human lifestyle cancer factors that andcannot their be interactions solved by individual that defineinvestigators. cancer Promoterisk and thatnetworks, can inform partnerships, the development and coalitions of new that strategies increase for the prevention, pace of earlytranslational detection, research and treatment. and the rate at which the results of research are translated into clinical practice and public health benefit. Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004 Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004 1. Identify new environmental risk factors and susceptibility genes $13.00 M 1.and Increase determine the number their interactions and geographic in cancer distribution causation. of $ 6.25 M ■ UtilizeNCI-designated the unique advantages Cancer Centers.of the Cohort Consortium to investigate exogenous and ■ endogenousDesignate one4 exposures new Cancer best Center.studied in $1.50 large M populations and their interactions with ■ Bringsusceptibility Cancer genes.Center resources and expertise to two regions of the country with large— Support underserved developmental populations studies by designating based on the two Consortium’s specialized gene-environment Centers or by direct study partnershipsof breast betweenand prostate regional cancers institutions to determine and the existing value Comprehensiveof adding studies of other Cancercommon Centers. cancer $2.50 sites. M $2.00 M ■ A—wardExpand two new the Cancernumber Center of participants, Planning population Grants to diversity,institutions and in types areas of of biospecimens the countryinvolved not currently in these studies.served by $2.00 Cancer M Centers. $0.75 M ■ SupportPlan a new the CancerCase-Control Center Consortium consortium to mechanism fully investigate in regions gene-environment of the country interactions in forwhich specific no single types institution of cancer. Initiatehas the large research population-based strength to become and hospital-based a traditional studies to developNCI-designated comprehensive Cancer data Center. and specimen $1.50 M resources by cancer site. $5.00 M ■ Continue improving the infrastructures needed for large, collaborative human population 2.studies Encourage with biospecimen collaborations components. and partnerships to improve access of $ 6.00 M minority— Maximize populations the efficiency to andstate-of-the-art cost effectiveness clinical of specimen and collection,population processing, studies,storage cancer techniques, treatments, and high-throughput technologies, assays for and human care. population studies. $2.00 M ■ Continue— Enhance to support the capacity formal of partnershipsinformatics systems between developed Cancer Centersto capture, and store, Minority analyze, Servingand Institutionsintegrate the in massive the form amount of two of comprehensive information generated partnerships by these and studies. one $2.00 M ■ planningSupport studies grant to to enhancedetermine the the research contribution capabilities of inflammation, of the institutions injury, and and infectious a improvegents to thethe genesis effectiveness of lung of cancer, Cancer a need Centers identified in serving by the minority Lung Cancercommunities. Progress Review Group. $5.50 M 2.■ Integrate Develop NCI-designated new ways to Cancerassess Centers and measure and Minority environmental Institution/Cancer exposures Center $ 5.00 M Partnershipsfor use in populationwith the NCI studies. Special Populations Networks for Cancer Awareness ■ ResearchContinue expandingand Training. the Innovative $0.50 M Molecular Analysis Technologies Program to develop new non-invasive techniques for collecting and analyzing genes and gene products in very 3.small Expand biologic the samples.capacity $2.00 of NCIM centers, networks, and consortia to $51.08 M ■ Continueengage supportin newly for developingapplying and validatingareas of measures research of the and cumulative technology cellular, and genetic, andto act molecular as platforms effects of environmentalfor translating exposure discoveries through funding into interventions. supplements for ongoing ■ researchProvide additionalprograms. funding$3.00 M to build the clinical research and population research infrastructure of NCI-designated Cancer Centers. Fund databases that conform to NCI’s clinical informatics infrastructure; support the development and expansion of population databases and other resources; provide more core staff to conduct innovative translational therapeutic and prevention trials; and strengthen the auditing and data safety and monitoring of human subjects research to conform to Federal regulations. $15.00 M

34 The Nation’s Investment in Cancer Research ■ Promote and develop matching fund and co-funding partnerships of NCI- designated Cancer Centers with industry and national, private, state, and community organizations, as well as with other cancer funding organizations, to expand the conduct and impact of translational research. $5.00 M ■ Encourage NCI-designated Cancer Centers, networks, and consortia to network with each other to integrate best practices, share protocols, and maximize collaborative research opportunities and avoid duplication of resources. $0.50 M ■ Build on NCI’s Prostate, Lung, Colorectal, and Ovarian Screening Trial to develop an Early Detection Cancer Screening Trials Network to expand and accelerate laboratory and clinical research and the application of early detection technologies. $0.08 M ■ Encourage collaborations among NCI-supported research centers, networks and consortia involved in translational research, including Cancer Centers, Specialized Programs of Research Excellence (SPOREs), Transdisciplinary Tobacco Research Centers, the Cancer Genetics Network, Clinical Cooperative Groups, Special Population Networks, the Early Detection Research Network, and the Mouse Models of Human Cancers Consortium. $0.50 M ■ Expand the SPORE program by adding one SPORE each for gastrointestinal, brain, head and neck, and leukemia and lymphoma cancers; and two SPOREs each for ovarian and skin cancer. $24.00 M ■ Establish a protected Web-based system for SPOREs, to exchange work in progress and research results to enhance inter-SPORE research. $0.50 M ■ Expand the supplement programs for SPOREs, to stimulate inter-SPORE research projects and to conduct early clinical trials. $5.00 M ■ Support expansion of infrastructure and methods for evaluating large scientific initiatives for translational research. $0.50 M

4. Expand the capacity of NCI Cancer Centers, networks, and $ 15.00 M consortia to disseminate proven interventions into communities and populations. ■ Provide additional funding and seek funded partnerships with government and non-government organizations to perform research into cost-effective and efficacious dissemination of validated interventions for prevention, early detection, and treatment to practitioners, communities, and populations. $7.00 M ■ Design ongoing Cancer Center infrastructure and mechanisms for practitioner, community, and population outreach to enhance the Cancer Centers’ leadership role in disseminating proven interventions for cancer prevention and care for all. $8.00 M

Management and Support $ 1.20 M

Total $ 79.53 M BUILDING THE NATION’S CANCER RESEARCH CAPACITY CANCER RESEARCH CAPACITY BUILDING THE NATION’S

A Plan and Budget Proposal for Fiscal Year 2004 35 NCI Challenge: Building Our Capacity for the Future GOAL

Ensure that clinical trials address the most important questions in treatment and prevention, are broadly acces- sible, and enable strong trans- lational research.

National Clinical Trials Program in Treatment and Prevention

The Challenge ■ Create flexible mechanisms that allow for easy cooperation among basic scientists, clinicians, As we decipher the molecular changes that cause a industry, academia, and NCI. cell to become cancerous, a new paradigm in cancer ■ Explore how molecular targeted therapies can be treatment and prevention is emerging. Increasingly, used in combination with conventional treat- new anti-cancer agents are directed at distinct ments or other molecular targeted agents. molecular targets present within cancer cells, leav- ■ Develop surrogate endpoints3 to improve the ing healthy cells unharmed.1 In light of the unique efficiency of small translational trials. challenges arising from this paradigm shift, NCI ■ Identify the most promising treatment or pre- must provide a versatile clinical trials system that vention agents for movement into large, easily will quickly and safely move proven anti-cancer accessible trials. interventions into healthcare settings where ■ Improve support to physician researchers. patients will benefit. ■ Improve access to clinical trials by physicians and their patients. NCI provides leadership, resources, and expertise ■ Help ensure that treatments are made available at all stages of clinical development for molecularly to all patients who need them. targeted agents. In the early stages of research, when candidate drugs are identified and shown to Progress Toward have promising potential, NCI forms collaborations Meeting the Challenge and partnerships that help researchers from public, industrial, and academic settings to develop cancer Building the Capacity for Successful fighting agents for a broader array of tumor types Clinical Trials Research and at a faster pace than would otherwise be possi- As more private sector companies are beginning to ble. After establishing proof-of-principle2 in early develop anti-cancer drugs, NCI is expanding its role in clinical trials, researchers move on to verify the public-private partnerships. Because pharmaceutical presence of relevant molecular targets in popula- companies tend to seek FDA approval or licensing of tions of patients and test for improvements in a new agent for a single or few tumor types, NCI can outcomes, such as tumor response, time to tumor help ensure that new agents are evaluated against a progression, and improved survival. During this fuller range of cancers (or pre-cancers) and in combina- stage, NCI provides resources to test promising tion with treatments such as surgery, radiation therapy, leads in large numbers of patients. or other drugs. In one recent success, the collabora- tion between Novartis Pharmaceuticals and NCI has made substantial progress in building a NCI-supported researchers led to the develop- clinical trials system that meets these requirements. ment of imatinib (previously called Gleevec™) to treat However, a number of critical issues remain to be chronic myelogenous leukemia and now gastroin- addressed. We must: testinal stromal tumors.4 In another public-private ■ Identify the most important questions in preven- partnership, the arthritis drug celecoxib is being tion and treatment that can be addressed tested as a targeted drug for colorectal cancer through clinical trials. prevention and treatment.

1 See Molecular Targets of Prevention and Treatment, pages 60-64. 2 In proof-of-principle studies investigators demonstrate that an agent has the desired biological effect on its target. 3 Surrogate endpoints are based on laboratory measurement of some biological indicator of a drug’s effectiveness rather than on longer-term outcome measures. 4 See sidebar, this chapter.

36 The Nation’s Investment in Cancer Research 5 For moredetailonthisStoryofDiscovery, goto 6 with acombinationofmoleculartargeteddrugsearlyinthecoursetheirillness. research, investigatorsareidentifyingstrategiestoovercomeimatinibresistance,includingtreatingpatients patients withadvancedstagediseaseeventuallystoprespondingtoimatinibtherapy. Basedonintensive Despite theseunprecedentedsuccesses,researchersarefindingthat,foranumberofreasons,many cleared ofcancerinonlyonemonth. responded remarkably, includingachronicmyelomonocyticleukemiapatientwhosebloodwascompletely trials areunderwaytotesttheuseofimatinibintreatingover15othercancers.Somepatientshavealready patients inclinicaltrials,imatinibeitherdramaticallyreducedtumorsizeorarrestedgrowth.Clinical high-mortality cancer, notoriouslyresistanttoanykindofchemo-orradiationtherapy. WhengiventoGIST caused bygeneticmodificationofanotherimatinib-sensitiveprotein.GISTisarelativelyuncommonbut More recently, theFDAapprovedimatinibfortreatmentofgastrointestinalstromaltumors(GIST),acancer Imatinib blocksthecancercausingeffectsofageneticallyalteredproteincommonlyfoundinthisdisease. geted drugimatinib(thencalledGleevec™orSTI571)forthetreatmentofchronicmyelogenousleukemia. In May2001,theU.S.FoodandDrugAdministration(FDA)gavefasttrackapprovaltomolecularlytar- T increased byanunprecedented18percentin2001. accrual toNCI-sponsoredcancertreatmenttrials NCI’s efforts arehavinganoticeableeffect, with patients intotheseNCI-sponsoredclinicaltrials. cooperative groupshavealsobeenabletoenroll Since May2002,CTSUphysiciansoutsideNCI activities ofitsclinicaltrialscooperativegroups. mon administrative,financial,anddatacollection Support Unit(CTSU)sitetocentralizethecom- In 2000,welaunchedtheonlineCancerTrials their patientstoparticipateinNCI-supportedtrials. clinical trials the NCI continuestosimplify trend isincreasinglyseenincancerpreventiontrials. relative studieswithlaboratoryscientistsandthis initiated overthelasttwoyearshaveincludedcor- than halfofNCI-sponsoredcancertreatmenttrials and tomonitordrugeffects duringtreatment.More patients whosetumorscontaintherelevanttargets develop newtechniquesandteststoidentify and inter-related, andtheyrequire scientiststo these molecular ta The cellularpathwaysandinteractionsinvolvedin clinical trialsformoleculartargetedagents. oration withlaboratoryscientistsinconducting NCI alsorecognizestheincreasingneedfor off withincreasedsurvivalandbetter qualityoflife NCI’s focused investmentinclinicaltrialsispaying through ClinicalTrials Making StridesinCancerTreatment See page11formore information. reatment withImatinibBuildsonEarlySuccess to makeiteasierforphysiciansand r gets areextraordinarilycomplex administration of plan2003.cancer.gov collab- . are listedhere: the advancesemerging fromrecentclinicaltrials for patientswithavarietyofcancers.Justfew patients becomesick.NCI’s clinical trialsforcancer develop, wehavethetime and opportunityto process. Sincemanycancerstakedecadesto event, butresultfromacomplexandlong-evolving cancers arenotcausedbyasingle,catastrophic From yearsofscientificresearch,weknowthat Prevention throughClinicalTrials Making StridesinCancer ■ ■ ■ intervene tostoporreverse itsprogressbefore conventional cancertherapies. over thelast27years,throughimprovementof decline inmortalityrateforchildrenwithALL the typeofresearchthathasledtoa75percent the medicalliterature.Thetrialisanexampleof as wellorbetterthananyotherdrugreportedin with T-cell acutelymphoblasticleukemia(ALL) ate improvestheevent-freesurvivalofchildren T T chemotherapy. cancer patientswhoundergo conventional modest survivaladvantagetosomecolorectal Adjuvant therapywithoxaliplatinprovidesa been completed. even betterifgivenwhenchemotherapyhas chemotherapy, improvesdisease-freesurvival breast cancerwhengiventogetherwith shown toimprovesurvivalinsomewomenwith reatment withhighdosesofthedrugmethotrex- amoxifen, atargeted agentthathasbeen A Planand BudgetProposal for FiscalYear 2004 6 5

37 BUILDING THE NATION’S CANCER RESEARCH CAPACITY The Plan

National Clinical Trials Program in Treatment and Prevention

GOAL

Ensure that NCI’s clinical trials program is poised to address the most important medical and scientific questions in cancer prevention and treatment quickly and effectively through state-of- the-art clinical trials. Ensure that the trials are broadly accessible to cancer patients, populations at risk for cancer, and the physicians who care for them. Incorporate relevant correlative laboratory studies into clinical trials to enable strong translational research.

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004

1. Identify and develop the most promising new agents for cancer treatment $84.50 M and prevention. ■ Expand partnerships and create flexible collaborations with industry, the FDA, and other public, private, and academic organizations to speed development of promising agents and to bring together the best laboratories, institutions, and investigators (including surgeons, pathologists, and radiologists, in addition to traditional participants) for early translational research. $4.00 M ■ Expand resources for the Rapid Access to Intervention Development and Rapid Access to Prevention Intervention Development programs. (See page 62, Objective 4.) ■ Expand capacity to file Investigational New Drug Applications and New Investigational Technology Applications to facilitate early proof-of-principle clinical trials. $0.50 M ■ Create broadly based working groups to identify clinically relevant surrogate endpoints. Develop resources and standardize assays, approaches, and clinical trial designs to validate these endpoints. $2.00 M ■ Build translational research capacity to use correlative studies more extensively. $8.00 M ■ Increase funding for Interdisciplinary Research Teams for Molecular Target Assessment to develop resources to assess the effects of promising agents on their molecular targets. $20.00 M ■ Develop molecular assays required to characterize/classify tumors, and make them widely available. (See page 62, Objective 2.) Support a national tissue resource system to facilitate rapid evaluation of new assays and relevant clinical correlations as new targets are identified. ■ Increase the pace of development and clinical testing of promising new therapeutic and preventive agents by (1) substantially increasing the number of promising agents entering NCI-sponsored clinical trials over the next two to three years as well as the number of pivotal early clinical trials, (2) tripling annual patient accrual to early clinical trials of promising agents, (3) providing financial incentives for timely initiation of clinical trials and adherence to developmental milestones, and (4) expanding the rapid grant review process, Quick Trials, for mechanism-based clinical trials. $35.00 M ■ Support the NCI intramural clinical trials program by increasing the number of data managers, research nurses, biostatisticians, and clinicians available to support a critical mass of clinical investigators, and continuing the Tissue Array Research Program to identify key molecular alterations in cancers. $15.00 M

2. Strengthen scientific planning and leadership for the large, definitive $26.00 M clinical trials that evaluate and define the efficacy and clinical benefit of new treatments and prevention strategies. ■ Identify and address compelling clinical questions confronting physicians and their patients under treatment for cancer or at high-risk of cancer. $17.00 M

38 The Nation’s Investment in Cancer Research ■ Expand State-of-the-Science meetings to identify important research questions and define a scientific research agenda to address them. $1.00 M ■ Expand clinical trials planning to address critical questions across the major types of conditions experienced by patients by (1) integrating cross-disciplinary input (e.g., oncology and diagnostic imaging) and project teams into scientific strategic planning and (2) incorporating evaluation of relevant biomarkers as well as behavioral, epidemiologic, outcomes, and other research into existing treatment and prevention trials to address questions in specific tumor types and patient populations. $1.00 M ■ Provide additional research funds for leadership support of scientists who are responsible for writing, monitoring, and analyzing NCI-sponsored, high-priority Phase III trials: researchers who chair studies in addition to caring for patients, and study statisticians. $3.00 M ■ Increase funding for tissue banks (collection and storage of patient tissues from large clinical trials with accompanying patient data). This will enable correlative studies and long-term follow-up for future evaluation of new assays and markers. $4.00 M

3. Double the rate at which Phase III trials are completed. $223.50 M ■ Increase the number of patients accrued to national trials, and shorten the duration of accrual, to substantially increase the number of new treatments or interventions that can be evaluated. Increase funding for nursing, data management, and other infrastructure costs at local clinical trial sites, and for operations, data management, and statistical offices. Increase the number of (and the capacity of existing) Community Clinical Oncology Programs. ■ Facilitate participation of new clinical trials investigators through a “start-up” loan program (repayable by reduced future reimbursements) for training, research nurse support, and data management. ■ Provide extensive information about treatment and prevention clinical trials to enable patients and physicians to make informed choices. With the NCI Office of Communications, patient advocacy groups, and others, create educational, marketing, and communications strategies to inform patients and physicians about clinical trials. Develop novel strategies, including the use of alternative media, for working with minority and under-represented patient populations and their primary care physicians. ■ Expand the Cancer Trials Support Unit to consolidate administrative tasks and to provide a single interface for investigators to enroll patients. Develop uniform elec- tronic case report forms and data reporting systems. Expand NCI’s audit program to ensure continued high quality accurate data from new sites and increased accrual to clinical trials. ■ Provide funding directly to participating patients with special needs to cover costs associated with travel, childcare, and other relevant limiting expenses. Work with state and local government agencies to address barriers to access for patients dependent on state health agencies for healthcare coverage.

4. Reduce outcome disparities caused by lack of access to trials or follow-up care. ■ Increase access of underserved populations to state-of-the-art clinical trials. (See page 87, Objective 4). ■ Encourage local sites to identify existing resources for helping underserved patients receive appropriate follow-up care and ensure that follow-up care is offered.

Management and Support $ 6.10 M Total $ 340.10 M BUILDING THE NATION’S CANCER RESEARCH CAPACITY CANCER RESEARCH CAPACITY BUILDING THE NATION’S

A Plan and Budget Proposal for Fiscal Year 2004 39 The Next Step in Targeted Therapy — Hitting Multiple Targets Scientists know that cancer develops as a result of mutations in genes that in turn alter the normal struc- ture of certain proteins (those that regulate cell growth and other critical functions). These genetically altered proteins disrupt “cellular pathways,” or the ordered interactions among the diverse molecules in the cell, resulting in uncontrolled cell growth and cancer. As scientists gain a better understanding of these molecular changes, they are able to develop drugs designed to stop cancer development in its tracks by targeting the faulty proteins that wreck havoc on normal cellular pathways.

Increasingly, however, investigators are learning that targeting one protein or one pathway is not always enough. Cellular pathways are tremendously complex, involving intricate and ordered contact among thou- sands of molecules. As one targeted pathway is shut down within its cells, the tumor may begin to die, but then start growing again. It may be that an alternate pathway, one not affected by the drug, is able to perform the same function as, and thus compensates for, the targeted pathway. This type of “cellular redundancy” occurs naturally and, although it is healthy and beneficial in normal cells, it makes cancer cells harder to kill. To contend with this reality, researchers have begun developing drug treatments that use combinations of targeted drugs to simultaneously shut down alternate pathways so that the cell cannot escape the effects of treatment. Furthermore, since some patients are resistant to one type of drug but not another, using combinations of drugs targeting critical junctures of multiple pathways should increase the patient’s chances for successful treatment.

prevention seek to determine which person is at years of daily dietary supplementation with sele- risk for cancer; define ways to prevent or reduce nium and/or vitamin E will reduce the incidence that risk; detect cancer at its earliest stages; and of prostate cancer. Of note, one third of the actively intervene to prevent invasive cancer. The 32,400 men needed were accrued within the first following represent a small sampling of the progress eight months of the trial. Serum and white blood in these areas: cells are being collected for correlative laboratory ■ Because some women suffer serious side effects research and preliminary results from early stud- from tamoxifen, NCI is sponsoring clinical trials ies are encouraging. Studies examining cells for other preventive agents, such as raloxifene, grown in the laboratory have suggested that an osteoporosis prevention drug. NCI-supported selenium might slow the growth of prostate researchers are also developing risk assessment cancer and kill the cancerous cells by apoptosis tools to determine which patients are most likely — a cell suicide mechanism. to benefit from various prevention strategies ■ Investigators recently discovered that patients with the fewest side effects. with a history of colon polyps might reduce their ■ The newest prostate cancer prevention trial, the risk of developing colon cancer by taking low Selenium and Vitamin E Cancer Prevention doses of aspirin in addition to having their Trial, was launched in July 2001. The 12-year regular colorectal cancer screenings. study will answer whether or not seven or more

40 The Nation’s Investment in Cancer Research Spotlight on Research

Drug Discovery and Development — A Life Saving Investment Discovering and developing new treatments for cancer is a lengthy and expensive process. But therapeutics that use the latest knowledge and the best technology are absolutely essential for us to move forward in our fight against cancer. The process begins in laboratories at university, research institute, government, or industrial facilities where individual or groups of scientists identify possible drug agents to target cancer. Once identified as potential agents, compounds must be screened, tested, and used successfully without serious adverse effects in clinical trials.

Preclinical testing validates the may behave differently in a time from initial discovery to safety and biological activity of a mouse, and differently still in a FDA approval averages around compound in the laboratory and human. When a drug does not 15 years and the total cost can in animal models. Clinical trials work, researchers must decide be as high as $500 million to determine safe and most effec- whether to abandon that com- develop a single new drug. tive dosages, how a treatment pound or take it back to the lab- As we attempt to design or should be administered, its effi- oratory and try to modify it. discover more targeted thera- cacy, and patient outcomes. Once these steps are complet- peutics, the costs may be even At any point in this drug devel- ed, new drugs must then be higher. However, only through opment process, researchers approved by the Food and Drug this painstakingly thorough may discover that the com- Administration through a rigor- process of drug discovery and pound does not work in quite ous process before they can be development do the many the way they were hoping. used to treat cancer. lifesaving cancer drugs coming Animals have such intricate out every year reach the molecular biology that a drug Only one in 5,000 compounds patients whose lives are that effectively disrupts cancer or fewer make it to FDA touched by them. development in isolated cells approval. The total length of

Identification and Preclinical Testing

Averages 4.4 years

5,000 compounds screened to identify 250 for preclinical testing

Laboratory/preclinical testing conducted to assess safety and biological activity in the laboratory and in animal models

Investigational New Drug (IND) application filed with the Food & Drug Administration (FDA)

Clinical Trials

Averages 8.6 years

5 of the 250 compounds advance to clinical testing Phase I – Determines safe dosage and how treatment should be given Phase II – Evaluates effectiveness and looks for side effects

Phase III – Determines whether the new treatment or new use of a treatment is a better alternative to the current standard Post-Clinical Trials

Averages 1.4 years

New Drug Application or Biologics License Application filed with FDA

FDA Approval for one new drug

02 4 6 8 101214

years SPOTLIGHT ON RESEARCH

A Plan and Budget Proposal for Fiscal Year 2004 41 NCI Challenge: Building Our Capacity for the Future GOAL

Create a cancer infor- matics infrastructure to support and integrate the full spectrum of cancer investigations.

Developing Bioinformatics for Cancer Research

The Challenge Progress Toward Meeting the Challenge Bioinformatics is the art and science of electronically representing and integrating biomedical information Constructing a Cancer Knowledge in a way that makes it accessible and usable. Each Resource discipline involved in the immense complex of can- One of our key tasks has been to develop the ability cer research generates volumes of data and research to classify, locate, and distribute units of cancer- findings, all contributing vital threads of insight that related information, such as the description of a bioinformatics specialists must weave together into gene or a process, the email address of a principal a tapestry of knowledge. The challenge is to use investigator, or a reference to a published paper. electronic standards to devise systems that allow Data are transformed into information components, different sets of data to “talk” to one another. Such which can then be combined to generate knowl- systems make it possible for scientists to use this edge. Our system is called the cancer Common new “in-silico” biology to generate hypotheses; con- Ontologic Reference Environment (caCORE). duct virtual experiments using large collections of The caCORE is composed of three interacting data from multiple sources; and create, manage, and layers. At its foundation is NCI’s Enterprise communicate massive amounts of new knowledge Vocabulary Services, which organize and translate in practical timeframes. the distinct but overlapping vocabularies of dis- parate scientific projects via a common vocabulary. The challenge of integrating separate scientific vocabularies and insight is daunting because of the The middle tier of caCORE contains ways of col- vastness and rapid evolution of the data. New models lecting scientific data or Common Data Elements and tools are needed to allow scientists to bridge that conform to the international standards used by language, integrate concepts and information, and other Federal organizations. This keystone effort enable complex analysis. In this way, information will ensure that all data from NCI-supported pro- systems will be a vital, dynamic tool in the hands of grams, whether from clinical trials, animal model cancer researchers. To address these challenges, programs, basic research, or other disciplines can be NCI is pioneering a versatile informatics infrastruc- easily shared. ture, requiring us to: ■ Help incubate the next generation of bioinfor- The top layer of caCORE is composed of models matics applications and insights to support of information — the cancer Bioinformatics cancer research. Infrastructure Objects (caBIO). The objects cap- ■ Establish partnerships with commercial, academic, ture the expertise within the disciplines that consti- and other governmental groups engaged in tute cancer research, allowing the knowledge to be bioinformatics research and development, thus shared through computer tools. The current collec- broadening our base of components, compatible tion of objects captures knowledge in the areas of tools, and data. genomics, genetics, animal models, and clinical ■ Expand training and support for scientists trials. caBIO is built with open source software, pioneering the application of bioinformatics in making it available to scientists without restriction. cancer research.

42 The Nation’s Investment in Cancer Research ■ ■ ■ biomedical experiments.Someexamplesfollow. build futurestudiesandaresourcefor“insilico” researchers. Theyformafoundationonwhichto who generatethembutalsotoothercancer initiatives arevaluablenotonlytotheinvestigators The dataandfindingsproducedthroughNCI Research Data Collecting andSharingCancer how wellour funding ismeetingthefullrange ofresearchrequirements. clinical trialactivity, tothemostbroadlyfocused fortrackingandcomparingactivity, sothatwecanknow the microlevelfordiscovering meaningfulpatternsinbitsofgeneticmaterialtothe macroformonitoring Research highlightsinthissection illustrateapplicationoftheseprototypeinformatics systems,rangingfrom must becreated,tested,and agreedupon. language forintegratingthese systemscanthenbestandardized.Inmanycases, thestandardsthemselves make iteasierforthescientistswhousethemtowork togetheraswell.Thecodesandlogicthatformthe levels offocus,andatseveralpointsintheprocess,building pioneeringsystemsthat,inworkingtogether, Developing thebioinformaticsinfrastructurerequiresthat webuildgreaterpowerandcompatibilityatseveral one willcontinuetoreciprocallydriveoursuccesswith theother. recognize thatbench-to-bedsidetranslationisconceptually inseparablefrominformatics.Oursuccesswith purely researchtoregulatory, tojournalistic,advocacy, andbeyond.AttheNationalCancer Institute,we It demandsawholesystemoflinkagesacrosslaboratories, clinics,disciplines,andorganizations,from complex modeling,andthemassivestorageretrieval usedforindividualstudiesininstitutions. lessons learnedbacktothebench,goesfarbeyond high-speedcalculation,theonce-unimaginably T Bioinformatics: LinchpinofTranslational Science ranslating resultsfromthelaboratorybenchtobedsidedeliveryofpatientcareandcommunicating 2 1 rate ofdiscovery. base theyhaveconstructedandacceleratingthe of themodelgenerators,buildingdirectlyon mits additionalinvestigatorstoextendthework have gainedintheirinvestigations.Italsoper- base allowsresearcherstosharetheinsightsthey cer’s originsandtotestnewtherapies.Thedata- models thatcanbeusedtofurtherexplorecan- Cancer GenomeAnatomyProjectandtoexpand accessible genomicdatageneratedbythe We Expression DatabasePortal We the Cancers Consortium.Therepositoryiscalled munity throughtheMouseModelsofHuman models developedbythecancerresearchcom- We Cancers Consortium. of CancerandtheMouseModelsHuman Challenge: Toward aMolecularClassification by initiativessuchastheNCI’s Directors genetic andmoleculartaxonomydataenabled integrated systemforresearcheraccesstotumor gedp.nci.nih.gov cancermodels.nci.nih.gov/mmhcc

continue toexpandthecollectionofpublicly have createdarepositorycalledthe have constructedarepositoryforthemouse Cancer ModelsDatabase 2 . to providean 1 It contains Gene ■ ■ ■ valuable resources,suchastissuerepositories. community andfacilitatetheusere-useofits to capturetheinnovationofcancerresearch work ofbioinformaticstoolsanddatathatinteract NCI hasbeguntheprocessofestablishinganet- Analytic Tools andDataSources Building aNetworkofInteroperable this excitingnewscientificapproach.Theseefforts research supportedbyNCIconfirmthepromiseof Early applicationsofinsilicobiomedicinecancer and Care Biomedicine inCancerResearch Fostering ApplicationofInSilico Evaluation Program. through collaborationwiththeCancerTherapy the useofstate-of-the-artinformaticstools Consortium Interoperable InformaticsInfrastructure interoperable infrastructureforbiomedicine,the an mia, andgovernmentagenciestodevelop NCI isleadingaconsortiumofindustry, acade- participating CancerCenters. to all,onthosetrialsthatareconductedat network of CancerInstitutestobuilda NCI isworkingwiththeAmericanAssociation ties cansharetheirtoolsanddata. which variousnetworkandconsortiacommuni- construction ofInternetportals A firststepinbuildingthenetworkhasbeen that distributesinformation,available . A Planand BudgetProposal for FiscalYear 2004 clinical trials through

43 BUILDING THE NATION’S CANCER RESEARCH CAPACITY The Plan

Developing Bioinformatics for Cancer Research

GOAL

Create a cancer informatics infrastructure that enhances information and resource exchange and integration among researchers and clinicians working in diverse disciplines, to facilitate the full spectrum of cancer investigations.

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004

1. Expand NCI’s core informatics infrastructure to support and integrate $ 49.00 M NCI-supported basic, clinical, translational, and population research initiatives. ■ Provide additional support and enhance integration of data and development of tools emanating from NCI’s Extraordinary Opportunities. Facilitate information exchange within NCI-supported research initiatives. Support Specialized Programs of Research Excellence and Cancer Center efforts. $29.00 M ■ Establish a toolbox of open-source informatics applications and services based on a common set of operating principles that support NCI’s diverse cancer research activities. $5.00 M ■ Expand the research infrastructure that uses the NCI “knowledge stack,” assembling common vocabulary, standard data elements, and information models to further the exchange of all types of cancer information and data among the cancer community. $5.00 M ■ Expand information technology-based support services to enhance planning, execu- tion, and communication of the wide-ranging research portfolio supported by NCI. $10.00 M

demonstrate that bioinformatics can be used to tools, specifically artificial intelligence, to improve refine diagnosis and improve screening. cancer diagnosis and screening. ■ Effectively and safely treating pediatric acute Facilitating Discovery through Integration Tools. NCI lymphoblastic leukemia (ALL) requires detec- has undertaken the Cancer Molecular Analysis tion of subtle distinctions among several sub- Project to facilitate the identification and evalua- types. Pinpointing the subtype usually requires tion of molecular targets in cancer by integrating the combined efforts of a hematologist/oncolo- comprehensive molecular characterizations of can- gist, a pathologist, and a cytogeneticist. NCI- cer. Both the data and infrastructure are publicly supported researchers have used artificial intelli- accessible.3 gence to analyze samples from patients whose diagnoses had already been determined. Their Improving Cancer Diagnosis and Screening through new test is 95 percent accurate. Moreover, they Bioinformatics. Recent successes demonstrate the identified a new subtype of ALL. immense potential for the use of bioinformatics

3 cmap.nci.nih.gov. The Cancer Molecular Analysis Project application permits investigators to discover molecular targets, assess their validity and interaction with other targets, determine if there are therapeutic agents that can act on this target, screen for possible toxicity, and determine whether there are clinical trials evaluating these agents.

44 The Nation’s Investment in Cancer Research ■ ■ $3.00M 11.50M Supportbioinformaticstrainingforbothexperiencedandnewscientists. $ 4. ■ ■ Expandthecapacityofcancerresearchinstitutionsto 3. ■ $21.50M ■ Createacommunitymatrixofinteroperable datasources,analytic 2. Management andSupport ■ ■ Cross trainexperiencedscientiststhroughtransitionawards.$1.50M Recruit newscientiststhrough20developmentawards.$1.50M data. $6.50M investigator-initiated researchtoaccess state-of-the-artbiocomputingtoolsand Supplement fundingtoNCI-supportedresearchorganizations tosupport NIH BiomedicalInformaticsScienceandTechnology Initiative.$5.00M Establish anetworkofbioinformaticsresearchcenterstoworkwithandthroughthe perform interdisciplinaryinformaticsresearch. research initiatives.$6.50M dation foradditionalinfrastructureand(2)facilitaterapiddeploymentofrelatednew core to(1)deployresourcesthecancerresearchcommunityserveasfoun- Use aminimumof20investigator-based awardsthatbuildontheNCIinformatics questions. $15.00M partnerships inaresearchparksettingwhereallpartnerscanworktogethertoaddressbioinformatics academic, government,andcommercialstrategic Enable otherorganizations’ informationsystemstoworkseamlesslywithours.Establishaminimumof5 capability forthecancerresearchcommunity. tools, andcomputationalresourcesthatprovideinformatics proteins todetectovariancancer, evenatearly the presenceofdiseaseand haveusedserum proteins inpatients’blood serum mayreflect NCI scientistshavefound that patternsof for patients. ment optionsanddeterminepossibleoutcomes healthcare providerstoselectappropriatetreat- this kindofanalysisholdpromiseforenabling lymphoma, andEwingtumors.Theresultsof blastoma, rhabdomyosarcoma,non-Hodgkin family ofchildhoodtumorsthatincludeneuro- networks todistinguishamongmembersofa artificialintelligencetechnologycalledneural an microarraysusing NCI scientistshaveanalyzed cancerous conditions. with ovariancancerandwomen withnon- patterns thatmaydistinguish betweenwomen identified exquisitelysubtledifferences inthe cancer. Theartificialintelligenceprogram and thoseofpeoplenotknowntohavethe proteins foundinthebloodofcancerpatients patternsofsmall puter todistinguishbetween grams. Scientistswereableto“train”thecom- cells, andartificialintelligencecomputerpro- proteomics, thestudyofproteinsinside private company, unitestwoexciting disciplines: Food andDrugAdministration,theNCI,a stages. Theresearch,acollaborationofthe A Planand BudgetProposal for FiscalYear 2004 T tl$88.00M otal $ 3.00M

45 BUILDING THE NATION’S CANCER RESEARCH CAPACITY The Interface of Aging and Cancer

The risk of developing cancer increases with age. Because of this vulnerability for our Nation’s aging population, NCI is conducting innovative research to better understand the relationships between aging and the development and progression of cancer. Further work is needed to fully address the interface of aging processes with cancer detection, diagnosis, and pre-treatment evaluation as well as the efficacy and tolerance of anti-cancer drugs in older patients. Growing older as a cancer survivor also increases one’s chances of developing other health prob- lems, disabling conditions, and the recurrence of cancer.

Cancer statistics, demographic projections, and epi- demiologic perspectives combine to illustrate the need to develop cancer control and cancer research strategies that address the magnitude of the cancer problem for current and future older Americans. NCI and the National Institute on Aging (NIA) have partnered to integrate crosscutting aging and cancer research and focus funding within existing research priorities. The research includes the biolo- gy of aging and cancer, the impact of aging on can- cer treatment, the quality of survivorship, symptom control, and disease-specific studies.

Biology of Aging and Cancer

Older patients differ from younger cancer patients in susceptibility to disease progression and response to treatment. The underlying mecha- nisms of cancer and aging overlap in the study of tumor initiation, progression, and maintenance. Studies to better identify the molecular alterations in carcinogenesis related to the aging process By 2030, 20 percent of the U. S. population will be intersect a number of NCI priority areas. over 65 and the number age 85 years and older will ■ Genes and the Environment studies examine have more than doubled in size from 4 million to genetic changes, environmental influences, and approximately 8.5 million. Close to 58 percent of host factors such as oxidant stress and cell all newly diagnosed malignancies and 71 percent death that may alter tumor progression in the of all cancer deaths are in persons 65 and older aging patient. according to the NCI Surveillance, Epidemiology, ■ Signatures of Cancer studies focus on the and End Results (SEER) program data for 1995- interaction of normal aging cells and cancer 1999. As people live longer, more will experience cells within the tumor microenvironment, dif- cancer. As a result, there will be more cancer ferences in the manifestation of cancer types in survivors, many of whom will experience residual older and younger patients, cellular and molec- problems that impact their quality of life. ular characteristics that distinguish between

46 The Nation’s Investment in Cancer Research older people. focus onissuesofcancertreatmentandcarefor analgesics. AnumberofNCI-supportedstudies 26 percentofpatientswithdailypainreceivedno of cancerpatientsinnursinghomesfoundthat quate standardsofcare.Forexample,a1998study symptom controllessfrequentlybecauseofinade- cervical disease.Olderpatientsreceivecarefor prevalent cancerssuchasbreast,colorectal,and older peoplearelesslikelytobescreenedfor care thatolderpatientsdeserve.Studiesshow early detection,treatmentprotocols,andquality quently fallshortofprovidingthebestavailable We for theAging Survivorship, andSymptomControl Improving CancerOutcomes, ■ ■ ■ ■ treatments thatarefasterand lessmorbid. of novelradiationwiththe potentialfor bined modalitytherapyaswellassessment trials fortolerancetoconventionalandcom- radiation therapyintheolderpatient,including Another importantareaforevaluationis efficacy andtoleranceevaluationsintheaging. new agentsandtoxicologymodelsinclude designed foroldercancerpatients.Trials for and developstrialsthatarespecifically early trialsthroughNCICooperativeGroups to increasetheaccrualofpeople65andolder ed functional reserveoftheolderperson. that assessco-morbidconditions andthelimit- developing guidelinesfor treatment decisions Quality ofCancerCare The assessment andreporting. multiple primarytumors,andmethodologyfor and lateeffects oftreatment,occurrence care andsurvivorshipforolderpatients,early insurance datatoassessthequalityofcancer SEER cancerregistrytoMedicareandother Quality ofCancerCare recovery forolderpatients. cancer treatmentsideeffects andoptimize pharmaceuticals, andopticalprobestoreduce as theuseofmagneticresonanceprobes,radio- expanding arrayofdiagnosticproceduressuch Cancer Imaging carcinogenesis thatarerelatedtoagingcells. further therapy, andmolecularalterationsin sive therapyandthosewhocouldbespared those patientswhocouldbenefitfromaggres-

know thatcurrenthealthcarepracticesfre- ainlCiia rasProgram ClinicalTrials National studies haveledtoan studies focuson studies linktheNCI works the workshop,goto sponsored byNCIandNIA.Forafullreporton givers cameoutofaJune2001workshopjointly issues facedbyoldercancerpatientsandtheircare ported CancerCentersinpioneeringresearchon Several recommendationsforengagingNCI-sup- ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ A much-neededknowledgebasewouldinclude: tion toolderpersonsaffectedbythesecancers. years andolder. Yet, thereisapaucityofatten- of colonandrectumtumorsareinindividuals65 1995-99 showthat70percentoftheincidence and mortalityintheUnitedStates.SEERdatafor Colorectal canceristhirdinincidence Cancer ontheOlderPatient Studying theImpactofColorectal older patientsusingevidence-basedguidelines. of currentmethodssymptommanagementin cancer patients.Otherstudiestesttheefficacy diagnosis, prognosis,andtreatmentofolder multiple healthproblemsonearlydetection, Researchers areinvestigatingtheeffects of therapeutic approaches. vide informationthatcouldleadtotailored These investigationshavethepotentialtopro- tumor biologyandgrowthvarybyage. of cancerandagingthatrevealwhichaspects T Molecular Targets ofPreventionand offset theseproblemsinolderpersons. will focusondevelopingmethodstopreventor ations, andcancerrecurrence.Futureresearch multiple primarytumors,anti-tumordrugalter- ment suchassusceptibilityoftheolderpatientto and long-termmedicaleffects inducedbytreat- Survivorship reatment in prognosisandtreatment Preoperative assessmentto assistsurgeons patients Modification ofsurgeryprocedures inolder Criteria foroldersurgicalcandidates Influence ofcoexistingdiseases Pathogenesis ofcolorectalcancer Gender andracialdifferences problems Influence ofconcomitantage-related Surveillance ofpersonsathighrisk studies examinethehumanbiology A Planand BudgetProposal for FiscalYear 2004 studies identifypotentialshort- nia.nih.gov/health/nianci .

47 THE INTERFACE OF AGING AND CANCER When cancer survivors and their loved ones ask me what NCI is doing to cure or prevent cancer, I tell them that we are finding many of the pieces of the cancer puzzle, and are learning what additional pieces to look for and where they probably fit. Cancer research has entered a whole new phase in how we identify and assemble the pieces. — Andrew C. von Eschenbach, M.D. Advancing Discovery and Its Application

Part of the story is about how we are probing and discovering events at the molecular level and in the behavior of particular proteins. But molecules don’t smoke and proteins don’t neglect to wear sun protection, and genes don’t make the decision to join clinical trials of new treatments.

So the story also includes research into lifestyle of the Cancer Cell and Its Microenvironment, Molecular and behavioral factors and environmental exposures Targets of Prevention and Treatment, Cancer Imaging that so profoundly affect the burden of cancer. and Molecular Sensing, and Cancer Communications. Once we more fully understand cancer-related Increased investment in these areas is at the core molecular, cellular, microenvironment, behavioral, of our ability to: psychological, and social influences, we can ■ Understand the causes, risks, detection, develop more effective and less harmful approach- diagnosis, and treatment of cancer and how to es to cancer prevention, detection and diagnosis, communicate this information effectively to all treatment, and control. populations. ■ Develop interventions based on these scientific For Fiscal Year 2004, NCI’s scientific priority areas insights. to accelerate the pace of research and its applica- ■ Ensure dissemination of interventions to all tion include Extraordinary Opportunities for who need care. Investment in Genes and the Environment, Signatures

FY 2004 Increase Request for Advancing Discovery Imaging & Molecular Sensing 30% (dollars in thousands)

Genes and the Environment $ 51,800 Signatures of the Cancer Cell

Signatures of the & Its Microenvironment $ 41,200 Cancer Cell & Its Microenvironment Molecular Targets Molecular Targets $ 54,800 15% 21% Imaging & Molecular Sensing $ 78,700 Cancer Communications $ 39,750 Total $266,250 Cancer Communications 15% Genes and the Environment 19%

48 The Nation’s Investment in Cancer Research 1 bility genes to developcoloncancer. Mutationsinthesuscepti- Familial AdenomatousPolyposisarealmostcertain dictable. Forexample,carriersofthegenefor presence inanindividualmakescancerhighlypre- Some geneshaveproventobesopowerfulthattheir ise butalsohighlightthecomplexityofpuzzle. tal factorsinteracttocausecancerareshowingprom- Early efforts todiscoverhowgenesandenvironmen- infectious agents. and drugs;sunlightotherformsofradiation; water, andsoil;componentsoffood, tobacco,alcohol, environmental factors,includingpollutantsinair, susceptible subgroupsanduncover elementsofthe exposures increasethecancer riskforgenetically We development andindividualgeneticprofiles. and toexaminetherelationshipbetweendisease molecular technologiestoanalyzegeneticchanges, to cancer, toapplyincreasinglysophisticated of thehumangenesthatmakepeoplesusceptible its occurrence.We havebeenabletoidentifysome give risetocancer, whileothersvirtually guarantee some genesseemtorequirecertainconditions lifestyle candamagegenes,andwearefindingthat know thatelementsintheenvironmentoraperson’s tion hasbecomefarmoredifficult, becausewenow born? Especiallywithrespecttocancer, thatques- imposed bytheworldintowhichindividualis passed fromonegenerationtoanother, orisit scientific inquiryitself.Isitaparticularcharacteristic The debateovernaturevs.nurtureisasold The Opportunity We predictors ofcancer. such astobaccouse,canbestrong,butnotcertain, factors. Similarly, someenvironmentalexposures, breast cancerthatmayarisefromacombinationof Genes andtheEnvironment Extraordinary OpportunityforInvestment See theprogressreport andplanforresearchontobacco tobacco-relatedcancersonpages94-98.

want tolearnhowcertainenvironmental have learnedaboutavarietyofcarcinogenic BRCA1 and BRCA2 are riskfactorsfor improvements inclinicalpracticeandpublichealth. cancer communitywillbeneededtoachievetangible interdisciplinary cooperationandinnovationfromthe cohort consortiumdescribedbelow, withnewlevelsof and otherresources.Large-scale studies,likethe of populationdata,biospecimens,laboratorymodels, maximize theavailabilityanduseoflarge amounts ronmental exposures,andtheirinteractionsto new waystostudycancersusceptibilitygenes,envi- To precautions forpeopleathighrisk. andidentifyappropriateinterventions earlier, avoid adverseexposures,checkgeneticsusceptibility develop newindividualandpublichealthstrategiesto genetic factorsandtheirinteractions,wecanthen risks associatedwith and controlcancer. Oncewecandefinethecancer ble improvementsinourabilitytoprevent,detect, gene-environment interactionthatcanleadtotangi- 700,000 participants.Onegroup withinthe specimens suitableforgenetic analysisfromover exposure dataalongwithinformation frombiologic the Consortiumwillpoolhigh qualityenvironmental studies oflarge populationgroups.Working together, vidually, hadinitiatedover15separateprospective comprised ofwellestablishedinvestigatorswho,indi- new discoveriesingenomics.Thisconsortiumis genetic epidemiologytounlockthefullpotentialof to addresstheneedforlarge-scale collaborationsin NCI iscontinuingtobuildthe Large-Scale Collaborations Building Capacitythrough interactions. genes, environmentalandlifestylefactors,their growth areastobetterunderstandcancer-related The NCIispursuingresearchopportunitiesinseveral Progress inPursuitofOurGoal

make progressinthisarea,NCIneedstodevelop 1 A Planand BudgetProposal for FiscalYear 2004 specific environmentaland for cancercontrol. risk andinformstrategies tions thatdefinecancer factors andtheirinterac- ronmental, andlifestyle Discover genetic,envi- GOAL Cohort Consortium

49 ADVANCING DISCOVERY AND ITS APPLICATION The Plan

Genes and the Environment

GOAL

Discover those genetic, environmental, and lifestyle factors and their interactions that define cancer risk and that can inform the development of new strategies for prevention, early detection, and treatment.

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004

1. Identify new environmental risk factors and susceptibility genes $13.00 M and determine their interactions in cancer causation. ■ Utilize the unique advantages of the Cohort Consortium to investigate exogenous and endogenous4 exposures best studied in large populations and their interactions with susceptibility genes. — Support developmental studies based on the Consortium’s gene-environment study of breast and prostate cancers to determine the value of adding studies of other common cancer sites. $2.00 M — Expand the number of participants, population diversity, and types of biospecimens involved in these studies. $2.00 M ■ Support the Case-Control Consortium to fully investigate gene-environment interactions for specific types of cancer. Initiate large population-based and hospital-based studies to develop comprehensive data and specimen resources by cancer site. $5.00 M ■ Continue improving the infrastructures needed for large, collaborative human population studies with biospecimen components. — Maximize the efficiency and cost effectiveness of specimen collection, processing, storage techniques, and high-throughput assays for human population studies. $2.00 M — Enhance the capacity of informatics systems developed to capture, store, analyze, and integrate the massive amount of information generated by these studies. $2.00 M ■ Support studies to determine the contribution of inflammation, injury, and infectious agents to the genesis of lung cancer, a need identified by the Lung Cancer Progress Review Group.

2. Develop new ways to assess and measure environmental exposures $ 5.00 M for use in population studies. ■ Continue expanding the Innovative Molecular Analysis Technologies Program to develop new non-invasive techniques for collecting and analyzing genes and gene products in very small biologic samples. $2.00 M ■ Continue support for applying and validating measures of the cumulative cellular, genetic, and molecular effects of environmental exposure through funding supplements for ongoing research programs. $3.00 M

4 An exogenous exposure originates from outside the body. An endogenous exposure originates from within the body.

50 The Nation’s Investment in Cancer Research Management andSupport ■ ■ ■ ■ $19.00M ■ Supportcollaborativestudiesofhigh-riskindividualstoaddress 5. ■ $3.00M ■ Developtoolsforthestudyofgeneandenvironmentinteractions 4. ■ $9.00M ■ ■ Identifycancerpredisposinggenesinhigh-risk familiesand 3. and publichealthprograms.$1.00M in predictingtheriskofcancerandtranslatingthisinformation intoclinicalpractice Public HealthCenterstoimproveunderstandingofthe valueoffamilyhistory Collaborate withtheCentersforDiseaseControland Prevention Genomicsand models thatpredictriskandotheroutcomesamongdiverse populations.$1.00M determinants ofcancer. Merge geneticsbasedandenvironmentalmodels.Refine Refine cancerriskpredictionmethods/modelstointegrategeneticandenvironmental physiologic and/orpsychosocialfactorsamongsurvivorsofcancer. $2.00M Support researchontheroleofgeneticfactorsandtheirinteractionswith strategies andresourcesforpatients,providers,thepublic.$4.00M to cancerriskcommunicationinformthedevelopmentofeffective educational Expand supportforstudiesincancergeneticsthatexaminepsychosocialresponses those fromminorityandunderservedpopulations.$11.00M early detection,diagnosis,andtreatmentofgeneticallyhigh-riskindividuals,including Sustain theCancerGeneticsNetworkasaresourceforstudiesofclinicalcare and determinetheirfunction.$3.00M groups employingmousemodelstohelplocalizecancersusceptibilitygenesinhumans Support thebreast,colon,prostate,andpancreaticcancercomparativegeneticswork various molecularapplications. Extend theGeneticAnnotationInitiativetoidentifynewgenevariantsandexplore prone familiesformicroarraybasedmolecularsignatureanalyses.$2.00M Support collectionoffreshfrozentumortissueandotherbiospecimensfromcancer collaborative familyregistrygroups.$2.00M Support interdisciplinarystudiesforgenediscoveryandcharacterizationinnew as othergeneticandenvironmentalmodifiersofrisk.$5.00M Fund newconsortiatoidentifysusceptibilitygenesthatremainbediscoveredaswell cancer susceptibility. the clinical,behavioral,andsocietalissuesassociatedwith in humanpopulations. expression ofthesegenes. investigate howothergenesandenvironmentalfactorsmodify T A Planand BudgetProposal forFiscalYear 2004 tl$51.80M otal $ 2.80 M

51 ADVANCING DISCOVERY AND ITS APPLICATION Consortium has developed a truly novel four-year for assessing difficult to measure environmental collaborative study to identify critical gene-environ- exposures. One such innovation will use satellite ment interactions in endogenous hormone pathways imagery to estimate potential exposure to agricultur- for over 7,000 cases each of breast and prostate can- al pesticides. The other grants will be used to devel- cer. A second group is pooling data for less common op methods and software to detect geographic pat- cancers, such as pancreatic cancers. terns and clusters of cancer rates and to explore asso- ciations with environmental, sociodemographic, and The Case-Control Consortium is also investigat- access to care factors. ing genetic and environmental determinants of can- cer. For non-Hodgkin’s lymphoma, several investiga- The recently completed Observing Protein and tors who have completed individual studies and col- Energy Nutrition Study assessed the measure- lected biologic specimens, are formulating a com- ment error inherent to studies in which patients bined study to give them the statistical power must complete questionnaires or surveys to report to uncover key gene-environment interactions. their dietary intake. Investigators conducting this A second group of investigators, members of the study, the largest ever of its kind, are comparing NCI-supported HMO Cancer Research self-reported dietary intake data from 484 men and Network, is pooling its resources to develop the women with biomarkers that will reflect the actual largest case-control study to date of pancreatic diet of the patient. The results of the study will give cancer. These researchers will employ “real time” us a better grasp of the reporting error so that we can electronic reporting of pathology, laboratory, radiolo- more accurately interpret the findings of self-report gy, and outpatient physician visit findings, resulting dietary studies. in the rapid identification of pancreatic cancer with- in ten working days. The purpose of this study is to Molecular profiling using innovative micro- develop a better understanding of risk factors for technologies may be used to examine chromosome sporadic and familial pancreatic cancer and ultimate- alterations and changes in protein levels following ly to use this knowledge for earlier detection and exposures to various environmental toxins that cor- prevention. relate with the appearance of cancer. For example: ■ Scientists have found that changes in the Assessing and Measuring levels of particular proteins (those whose Environmental Exposures genes may be altered by the biochemical Few population studies have investigated the ques- process of methylation) have been associated tion of whether environmental endocrine disruptors2 with the development of cancer. NCI-funded have a role in adverse health effects, including molecular micro-technology research may permit cancer in humans. NCI is collaborating with the identification of new environmental exposures National Institute for Occupational Safety and that change the number of these important pro- Health, the Environmental Protection Agency, and teins in tissues. the National Institute of Environmental Health ■ Chromosome alterations in cancers are common Sciences to study organochlorine pesticides and and complex and often difficult to assess. New polychlorinated biphenyls (PCBs) and their molecular technologies may be used to rapidly possible association with testicular and breast cancer identify changes in chromosomes after exposure risk. Researchers are following groups of infants to environmental chemicals. born to mothers exposed to very high versus low (background) levels of PCBs through childhood and Discovering and Characterizing adolescence. The study provides a unique mecha- Cancer Predisposing Genes nism to assess whether early life exposures are criti- The Breast, Ovarian and Colorectal Cancer cal in the eventual occurrence of cancer. Family Registries will expand 1) the epidemiologic and clinical follow-up of current participating high- NCI is funding 12 grants for geographic based risk families; 2) the molecular characterization of research in cancer control and epidemiology. known colorectal, breast, and ovarian cancer Half of these projects will apply innovative methods susceptibility genes; and 3) the exploration of DNA

2 Endocrine disruptors are synthetic or naturally occurring chemicals that affect the balance of hormonal functions.

52 The Nation’s Investment in Cancer Research first CohortConsortiumstudy, described above. centers andisprovidinggenomics supportforthe Institute andseveralacademic andcommercial ships withtheNationalHuman GenomeResearch System. TheCGFprogram hasestablishedpartner- an advancedLaboratoryInformationManagement expand to100,000genotypeswiththeinstallationof 40,000 genotypeseverysixweeks.Theworkwill Genotyping Facility NCI isdevelopingahighthroughput Discovery andCharacterization Developing Tools forGene studying melanoma. international geneticepidemiologyconsortiumis of cancerpronefamilies.Forexample,alarge new groupsofinvestigatorstouselarge registries site-specific susceptibility. NCIisalsosupporting discovering mutationsofknowngenesforcancer as wellotherfamilialcancersyndromesand identifying susceptibilitygenesforprostatecancer Family registriesandcollaborativegroups and todevelopnewmodelsforcancerriskprediction. of geneticmarkerswithdietaryandhormonalfactors; modifier genes;tobetterunderstandtheinteractions and coloncancertosearchfornewsusceptibilityor susceptibility. Studieswillcontinueinbreast,ovarian, repair mechanismsandtheirrelationshiptocancer methylation andnon-methylationrelatedmismatch a low-fatdietrichinfruitsandvegetables,avoidingtoomuchalcoholcanhelptoreducecancerrisk. Choosing healthybehaviorssuchasnotsmoking,maintainingaweight,beingphysicallyactive,eating ■ ■ ■ ■ tions thatcanbealtered. that asmany50to75percentofcancerdeathsintheUnitedStatesarecausedbybehaviorsorcondi- factors suchastobaccouse,diet,physicalactivity, andalcoholconsumption.Someresearchersestimate A numberofstudieshaveexaminedtherelationshipbetweencancerandarangebehavioralorlifestyle Behavioral FactorsandtheRiskofCancer in menandwomen,breastcancerwomen. High alcoholintake improved qualityoflifeandrecoveryforcancerpatients. decreased incidenceofcancer, includinga50percentlowerriskofgettingcoloncanceraswellto Sedentary lifestyle fruits andvegetableshavealowerriskofgettingcancersthelung,mouth,pharynx,stomach,colon. endometrial cancer, gastriccardia,andadenocarcinomaoftheesophagus.Peoplewhosedietsarerichin Obesity cancers ofthepancreas,kidney, andcervix. use canalsocausecancersofthelarynx,mouth,esophagus,pharynx,andbladder, anditplaysarolein third ofthenation’s cancerdeathsandisthemajorcauseoflungincidencemortality. Tobacco Cigarette smoking increases theriskforseveralcancersincludingcoloncancer, post-menopausalbreastcancer, (CGF) capableofperforming is themostpreventablecauseofdeathinUnitedStates.Itleadstonearlyone- is ariskfactorforcolonandbreastcancer, andphysicalactivityhasbeenlinkedto increases theriskofcancersmouth,esophagus,pharynx,larynx,andliver Core are environment interactions. combination withothergroups toexploregene- information tobeusedeither independentlyorin NCI-supported consortiaand registriesallowingthe participants consistentwith datacollectedbyother network collectivelyholdsepidemiologicdataon important gene-environmentinteractions.The prospectively collecteddatatodiscoverpotentially research. CGNpilotstudiescombineexistingand andforrelatedtranslational at highriskofcancer NCI-supported infrastructureforstudiesofpersons The Susceptibility T Supporting InterventionTrials and reliable enoughtobeformallyincludedinthemodel. recently, andthischaracteristichasbeenfoundtobe reliability ofmammographicdensitieswascompleted on anumberofpredisposingfactors.Astudythe to helpestimateawoman’s riskofbreastcancerbased The research resultsintoclinicalpracticeandpublichealth. collaboration isdesignedtomoreeffectively move based populationgeneticsresearch.Thisinteragency fromNCI- to thecollectionandreportingofdata Centers funding three Centers forDiseaseControlandPreventionare The ranslational ResearchonInherited Gail Model Cancer GeneticsNetwork to developmethodologicstandardsspecific Genomics andPublicHealth , developedatNCI,isastatisticaltool A Planand BudgetProposal for FiscalYear 2004 (CGN) isamajor

53 ADVANCING DISCOVERY AND ITS APPLICATION Spotlight on Research

Genes and Proteins: Profiles of Hope With advances in artificial intelligence and laboratory technology, cancer researchers are moving from studying a limited number of genes and proteins at a time to studying complex patterns of these molecules, using gene expression array (GEA) and proteomic technology. These patterns of genes and proteins can be displayed as easy-to-read, computer-generated tumor profiles that clinicians may one day use to:

■ Diagnose cancer earlier than is of other lymphomas with the ■ Researchers in the Clinical now possible, perhaps with a goal of classifying human lym- Proteomics Program, recently simple blood test. phomas according to differing launched jointly by NCI ■ Identify molecular targets molecular features that can be and the Food and Drug for cancer prevention and used to select the best possible Administration, have devel- treatment. therapy for each subtype of this oped a prototype blood test for ■ Develop individualized thera- disease. the early detection of ovarian pies using targeted treatments. ■ NCI-supported researchers are cancer. In preliminary clinical ■ Monitor and predict response using GEA to discriminate trials, the investigators correct- to therapy. between subtypes of acute ly classified 100 percent of lymphoblastic leukemia women known to have this Recent advances in tumor profiling (ALL). One rapid test yields cancer, and 97 percent of those are pivotal and include the following: diagnostic information that known to be cancer-free. ■ The Lymphoma/Leukemia ordinarily takes weeks to gather. If successfully refined, this Molecular Profiling Project, a ALL tumor profiling also blood test will be invaluable consortium of researchers asso- appears to be more accurate for detecting this highly inva- ciated with the NCI Director’s and information rich than tradi- sive disease in its earliest Challenge research initiative, tional diagnostic methods, stages, when it can be success- are using GEA to predict clini- even identifying patients at fully treated. Similar blood cal outcome of diffuse large-B greatest risk for relapse or sec- tests are being developed for cell lymphoma patients. ondary cancers. Similar tumor prostate,1 breast, and lung These scientists are also profiles are being developed cancers. researching tumor profiles for subtypes of lung cancers.

Gene Researchers used gene expression A-myb array to generate this tumor profile LMO2 Jnk3 that discriminates between three CD10 subtypes of diffuse large-B-cell BCL-6 lymphoma (DLBCL). Each row repre- sents a single gene. Each column shows the DLBCL expression profile Cyclin D2 from a single patient. If a gene is IRF-4 Flip over active, its square shows up red. CD44 Less active genes show up green. It is the overall pattern of expression Germinal center B cell-like Type 3 Activated B cell-like for each patient that can identify the disease sub-type and provide Subgroup of Diffuse Large B-cell Lymphoma valuable prognostic information.

0.25 0.50 1.00 2.00 4.00 Relative Level of Expression

1 See also page 9.

54 The Nation’s Investment in Cancer Research cancer cellsand theirsurroundingenvironment both environment whentreating acancerpatient.The malignant cellscombinedwith theirhosttumor that theyconfrontatumor entity thatconsistsof interactions withtumorcells. Physiciansnowrealize altered, theirbehaviorcan be changedthrough in themicroenvironmentmaynotbegenetically resistance tocancertreatments.Althoughthecells cessing oftreatmentagents,andthedevelopment of therapeuticagentstotumorcells,thebody’s pro- The microenvironmentcanalsoinfluencetheaccess cer cellsandpermitsatumortogrowspread. some ofthemostdestructivecharacteristicscan- the bloodandlymphaticsystems.Itconrtibutesto growth factorsandenzymes,includespartsof ed withavarietyofdifferent celltypes, isrichin other. This“tumormicroenvironment,” ispopulat- each profoundlyinfluencingthebehaviorof and itslocalsystemicmicroenvironment,with dynamic interactionoccursbetweenthecancercell ment. Mountingevidencenowsuggeststhata organs, itinteracts withitssurroundingenviron- the elaboratearchitectureofbody’s tissuesand cancer development.Asacellgrowswithin However, thecancercellisonlypart ofthestoryin prevention, detection,diagnosis,andtreatment. cancer researchandhasfuelednewapproachesto occur withinacancercellhaschangedthecourseof robust understandingofthegeneticalterationsthat serve assignalsofthepresencecancer. Thismore changes areuniquemolecular“signatures”and characteristics ofthecellalsochange.These genetic materialandthataccompanyingbiological becomes malignantasaresultofchangestoits three decades,scientistshavedeterminedthatacell progresses withinthehumanbody. Overthepast better understandingofhowcancerdevelopsand and usuallydeadlydisease.Today, wehaveafar Thirty yearsago,cancerwasapoorlyunderstood The Opportunity Signatures oftheCancerCellandItsMicroenvironment Extraordinary OpportunityforInvestment treatment, andcontrolofallcancers. the detection,diagnosis,prevention, our applicationofthisknowledgeto cells andtheirmicroenvironment the dynamicinteractionbetweencancer Accelerate ourprogressinunderstanding GOAL picture ofallthe majormolecularchanges thatoccur central goalofthisprojectis toprovideacomplete advances inmoleculardetection anddiagnosis.The coordinating dataandreagents thatwillsupport launched sixyearsago,isa criticalvehiclefor The for earlydetectionanddiagnosis. and validatingtheseuniquesignaturesasmarkers as wellcellswithinthetumormicroenvironment the signaturesofpremalignantandmalignantcells tant progressinidentifyingandcharacterizingboth studying thesignaturesofcanceraremakingimpor- Through avarietyofambitiousinitiatives,scientists Progress inPursuitofOurGoal ventive or poten nosis, andprognosisare understanding cancerdevelopment,detection,diag- signatures ofcancerprovideimportantcluesfor microenvironment, andtheentirebody. Allofthese characterize theinteractionamongatumor, its long-range goalistoextendsignaturesresearch interact withthehostmicroenvironment.NCI’s tures thatreflectchangesoccurascancercells cells withinthetumormicroenvironment,andsigna- cer cellsbutalsosignaturesofseeminglynormal opportunity willreadnotonlythesignaturesofcan- Scientists pursuingthispromisingnewscientific permits, andevenencourages,tumordevelopment. interaction ofthecancercellandmicroenvironment we areexpandingourefforts toconsiderhowthe nature changesthatoccurwithincancercells.Now ing andcharacterizingthefullcompendiumofsig- Opportunity topromoteresearchaimedatidentify- the SignaturesofCancerCells”Extraordinary Six yearsago,NCIestablishedthe“Defining tions tofightit. to beconsideredwhendevelopingnewinterven- stand howcancergrowsinthebody, andbothneed need tobefullycharacterizedinorderunder- Cancer GenomeAnatomy Project therapeutic A Planand BudgetProposal for FiscalYear 2004 interventions. tial targets for pre- (CGAP),

55 ADVANCING DISCOVERY AND ITS APPLICATION The Plan

Signatures of the Cancer Cell and Its Microenvironment

GOAL

Accelerate our progress in understanding the dynamic interaction between cancer cells and their microenvironment and our application of this knowledge to the detection, diagnosis, prevention, treatment, and control of all cancers.

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004

1. Define the molecular signatures of cells in the cancer microenviron- $10.00 M ment at various points during initiation and progression of cancer. Compare the molecular signatures of stromal and cancer cells during development and aging. ■ Initiate a Consortium for Microenvironment of Tumors to define the molecular signatures of cancer cells and cells in the microenvironment. Establish a national core facility to facilitate the analysis of normal and cancerous cell samples for signature profiling studies. $4.00 M ■ Develop a database of the molecular signature profiles of cells in the microenvironment and make these data readily available to the research community. $1.00 M ■ Expand the Unconventional Innovations Program (UIP) to permit an increased focus on nanoparticles, molecular beacons, and high-resolution sensors and their use in cancer signature detection, targeting, and treatment. $2.00 M ■ Expand the Innovative Molecular Analysis Technologies Program (IMAT) to enable development of micro- and nanotechnology tools to detect molecular signatures of cancer and surrounding cells. Facilitate collaborations that will assist in translating IMAT technology into tools that can be used in clinical practice. $3.00 M

2. Define the dynamic communications among cancer cells, surrounding $ 7.00 M cells, and immune cells that control or promote tumor growth. Characterize the interaction between the immune system and the cancer cell during cancer initiation and progression. ■ Fund studies focused on identifying the factors used by cancer cells to activate cells in the tumor microenvironment, which in turn support tumor growth and progression. $1.50 M ■ Support studies to identify the origin of the cells and factors that comprise the tumor microenvironment. $1.50 M ■ Develop organotypic culture systems that accurately model the interaction between the cancer cell and the tumor microenvironment in living systems. Make these systems readily accessible to the research community. $2.00 M ■ Develop technologies to enable researchers to assemble selected cell populations into tissues and engraft these “assembled” tissues into mice to observe and monitor the subsequent biological behavior of the grafted tissue. $2.00 M

56 The Nation’s Investment in Cancer Research aaeetadSpot$2.20M Management andSupport ■ ■ ■ $12.00M Applyknowledgeofcellularinteractionsincancerdevelopment, 5. ■ ■ $4.00M Establishaspectrumofeducationalandcommunicationinitiatives 4. ■ ■ $6.00M ■ ■ Supportnewapproachestoprovidetheresearch community 3. therapy ontumorcellsandthemicroenvironment. $5.00M microenvironment, astumorsbecomemalignantand (2)monitoringtheeffects of the subtleandimportantearlychangesinmolecular biologyoftumorsandthe and molecularprocessesinlivingtissues.Thesestudies shouldfocuson(1)identifying Fund functionalandmolecularimagingstudiestovisualize thephysiologic,cellular, new “targeted” reagents,includingsmallmolecules,RNAi,and antibodies.$5.00M Provide supplementalfundingtoNCI-fundedinvestigators todevelop them intoclinicaluse.$2.00M develop newdrugsthattarget cellsinthemicroenvironmentandmove Initiate aRapidAccesstoInterventionDevelopmentprogramefficiently cancer development.$2.00M development ofnovelstudiesinunderstandingtherolecellularinteractions curricula forstudentsandestablishedinvestigatorsfacilitatethe Establish nationaltrans-disciplinarytrainingcentersthatwilldevelop collaborative grantapplication.$2.00M mechanism toallowco-investigatorsfromdifferent scientificfieldstosubmita Encourage multi-andtransdisciplinaryinvestigationsbyestablishinganewfunding lesions, adjacenttissue,andinvasivecancer).$2.00M in humancancermicrodissectedtissuesamples(normalepithelium,premalignant Expand theClinicalProteomicsProgramtoidentifyproteinsandproteomicsignatures microenvironment. $2.00M of normalandcanceroustissuesthatareenrichedfortissuefromthetumor Expand theTissue ArrayResearchProgram(TARP) toincludetissuemicroarrays cancer andsurroundingcellsinanimalmodelstothosehumans.$1.00M Establish adatabasethatincludescomparisonsofcellularinteractionsbetween relate tocellsinthemicroenvironment.$1.00M Establish arepositoryforantibodies,celllines,animalmodels,andtissuesthat interactions tocreatetargetedinterventions. derived fromprofilingstudiesexploringcell-microenvironment cell interactionsincancerdevelopment. of expertisetoenableprogressinunderstandingtherolestromal involving scientistsacrossvariousdisciplinesandwithabroadrange with rapidaccesstovalidatedreagents. T A Planand BudgetProposal for FiscalYear 2004 tl$41.20M otal

57 ADVANCING DISCOVERY AND ITS APPLICATION during cancer development. All CGAP data and Innovations in laboratory technology and artificial resources are publicly accessible to the biomedical intelligence are allowing scientists to move beyond research community, enabling researchers to find studying genes or proteins one or two at a time, to “in silico”1 answers to biological questions in a studying the patterns (or profiles) of these mole- fraction of the time it once took in the lab. cules in normal, pre-cancerous, and cancerous cells. ■ Through the Tumor Gene Index, CGAP has In 2001, NCI and the Food and Drug Administration now generated more than 8 million gene tags launched the Clinical Proteomics Program (CPP) (ESTs) from a wide variety of tumor types and to apply advances in proteomics — the study of pro- their normal counterparts. Scientists are incorpo- tein expression and function — directly to patient rating these ESTs into the design of microarrays care. CPP investigators are pursuing a number of and other technologies that will be used to clas- projects to achieve earlier detection of cancer sify tumors according to their molecular features. through minimally invasive testing, individualized These molecular classification strategies hold diagnosis and treatment strategies, determination the potential to improve cancer prevention, early of risks and benefits of treatments in the laboratory detection, diagnosis, and treatment. before use on patients, and enhanced understand- ■ CGAP’s Cancer Chromosome Aberration ing of tumors at the protein level, leading to molec- Project was established to generate a genetic ular targeted therapies for cancer. map that defines distinct chromosomal alter- ations associated with cancer. In 2002, investiga- NCI’s Biomedical Proteomics Program is sup- tors accomplished this initial goal, a milestone porting these efforts through its Mass Spectrometry achievement in cancer research. Center. The center is a newly developed state-of- ■ Full-length complimentary DNA clones are the-art facility that employs several powerful new important tools for defining the sequence and technologies to cleanly separate proteins and char- function of genes expressed in human cells. acterize their activities in cancer cells. Proteomic Generating these clones, however, requires a studies will also be aided by a technology recently considerable investment of an investigator’s time developed by investigators funded through the and funds. The NIH Mammalian Gene Innovative Molecular Analysis Technologies Collection, for which CGAP plays a leadership program. This new technology combines the use of role, was created to generate individual full a laser (to release proteins directly from the surface length human and mouse DNA clones for more of tissue sections) with mass spectrometry to rigorous study of individual genes, their protein accurately identify and localize proteins in cells products, and the role they play in human genes. and tissues. The technology, which has successfully The MGC has now identified potential full- imaged the location of proteins in tissue sections length clones for more than 20,000 human genes from human glioblastoma, prostate, and colon and 11,000 mouse genes. tumors, should provide new insights into molecular ■ CGAP’s Genetic Annotation Initiative focuses interactions within a cell. It also promises to be a on exploring and applying technology to identify valuable tool in the search for detection, diagnostic, and characterize sequence variations, known as and treatment markers. genetic polymorphisms, in genes important in can- cer. A genetic polymorphism, which can affect a The Tissue Array Research Program (TARP), gene’s function, can arise when a mutation causes a collaborative effort between the National Human a change in even a single nucleotide of the DNA. Genome Research Institute and NCI, is a valuable Single nucleotide polymorphisms (SNPs) are tool for testing interesting genes discovered in pro- important markers for cancer risk-related genes filing studies. The TARP laboratory has produced and also can be used to understand difference in more than 4,000 tissue microarray slides containing vulnerability to cancer among individuals in a pop- a variety of tumor and normal tissue samples. In a ulation. The CGAP SNP500 Cancer project, a joint effort with the CPP, the TARP laboratory has new GAI effort, will sequence and make available also developed a cost-effective and user-friendly to researchers 102 samples for known or newly “cryo-array” platform that can be used to build discovered SNPs of immediate importance to arrays from very small tumor samples. molecular epidemiology studies in cancer.

1 “In silico” techniques allow activities currently carried out in vitro or in vivo to be transferred to the computer. 58 The Nation’s Investment in Cancer Research those whomaybenefitfrom moreaggressive,or patients whocanbecured by surgery alonefrom these tumorsmayhelptodistinguish between microscopic appearance.The abilitytodifferentiate not bedistinguishedfromeach otherbytheir tumors havedifferent clinicalbehaviors, theycan- that respondfavorablytotreatment.Althoughthese mas withapoorprognosisfromadenocarcinomas profiles thatdifferentiate earlylung adenocarcino- mental approaches—haveidentifiedexpression Challenge investigators—usingdifferent experi- microscopic features.ThreegroupsofDirector’s current tumorclassificationsthatarebasedon tein-based analysisstrategiestocomplementthe changes inhumantumorsusingDNA,RNA,orpro- investigators aredevelopingprofilesofmolecular Molecular ClassificationofTumors Through the exceptionally promisingpreliminaryresults. screen womeninthegeneralpopulation,theseare this testmustbeimprovedbeforeitcanusedto identified ascancerfree.Althoughtheaccuracyof not tohavecancer, 63(or97percent) werecorrectly women withthedisease.Outof66patientsknown able tocorrectlyidentifyovariancancerinallof60 nology todetectovariancancer, investigators were cancer detection.Inapreliminarytrialofthetech- ed foritsapplicabilitytoovarian,prostate,andlung The sameproteomicstechnologyisalsobeingtest- use asamarkerforearlydetectionofbreastcancer. tein profiledefinedbythisstudytodetermineits able breasttumors.Researchersplantotestthepro- without breastcancerfromwomenwithearly, cur- and breastfluidsamplesthatdistinguisheswomen based onthediscoveryofaproteinprofileinblood proteomic profileforearlydetectionofbreastcancer EDRNscientistsarejointlydevelopinga NCI and other promisinginvestigations. prostate cancerandcontinuetopursueavarietyof of novelbiomarkersforbreast,colon,lung,and EDRN scientistshavealreadydiscoveredanumber develop, andvalidateearlydetectionmarkers. from multipleinstitutionsworktogethertoidentify, national researchinfrastructureinwhichresearchers markers. ThroughEDRN,NCIhascreateda specific cancerscanbeusedasunique,identifying systematic viewofhowthemolecularsignatures that merges geneticswithproteomicstoprovidea (EDRN) isacomprehensive,collaborativeprogram The EarlyDetectionResearchNetwork Director’s Challenge:Toward a initiative, nipple aspiratetoassessbreast cancerrisk. molecular predictorsoforal cancer, andtheuseof trials toevaluatemelanocyte tumorclassification, initiative hasbeendeveloped tofacilitateclinical into clinicalpractice.Inaddition, aPACCT funding according tothealgorithm,movethesemarkers cancer anddeterminewhatstepsneedtobetaken, ising markersfornode-negativebreastandcolon predictive tests.Working groupswillidentifyprom- an algorithmfordevelopingnewprognosticand particular therapies.TheGrouphasalsodeveloped designs fortrialsofmarkersthatpredictresponseto guides thePACCT, hasdeveloped statistical gies intoclinicalpractice.AStrategyGroup,which of newknowledgeaboutcancerandtechnolo- Cancer Tests The as potentialtherapy. system todesignstrategiesinterruptthesignals Finally, theyareusingmicewithanintactsignal the impactofthesefactorsontumorinitiation. in eithertumorormicroenvironmentcellstodefine ing miceengineeredtoover-express growthfactors may affect tumor progression.Theyalsoarestudy- microenvironment toexplorehowgrowthfactorloss model lackingaspecificgrowthfactorinthetumor group ofresearchershaveengineeredanewanimal tumor progression.Basedonthisinformation,a the cancerandsurroundingcellscontributesto demonstrated thatgrowthfactorsignalingbetween MMHCC-developed prostatecancermousemodels organisms. Recently, severalstudiesusing ize cancer-associated molecularchanges incomplete these models,scientistscanidentifyandcharacter- is avitalpartofcancersignaturesresearch.With validated mousemodelsthatmimichumancancers, on developingandmakingavailabletoresearchers Consortium The course forindividualpatients. guide aphysician’s decisionaboutthetreatment analyses toprovideinformationthatonedaymay demonstrate thepowerofcomprehensivemolecular schemes inmanyothertumorsites.Theseresults cer andareworkingtodevelopnewclassification reported newclassificationschemesforbreastcan- ments. Director’s Challengeinvestigatorshavealso that canbetestedaspotentialtargets ofnewtreat- also revealpreviouslyunknownmolecularchanges eventually, targeted interventions.Theprofilesmay Program fortheAssessmentofClinical Mouse ModelsofHumanCancers (MMHCC), alarge initiativefocused (PACCT) facilitatesthetranslation A Planand BudgetProposal for FiscalYear 2004

59 ADVANCING DISCOVERY AND ITS APPLICATION Extraordinary Opportunity for Investment GOAL

Facilitate the expanded explo- ration of the causes of cancer and the discovery and develop- ment of agents that specifically “target” these causes to prevent and treat cancer. Molecular Targets of Prevention and Treatment

The Opportunity vary, even in cases where cancers appear to be iden- tical. Molecularly targeted therapies promise to be Recent advances in deciphering the human genome more selective, drastically reducing the incidence have launched an exciting new era in biomedical of side effects in patients. New diagnostic tools will research with tremendous potential for cancer pre- permit clinicians to more precisely identify those vention, diagnosis, and treatment. New drugs can patients who are most likely to benefit from a given now be designed to target specific molecular features therapeutic agent. Drugs developed to target one characteristic of cancer cells, including genetic type of cancer are often found to be effective mutations, factors causing changes in gene against other cancers as well. We foresee a day expression,1 structural changes in the proteins that when the treatment for each patient’s cancer will be are products of mutated genes, and alterations in individualized based on the unique set of molecular signaling pathways.2 Molecularly targeted interven- characteristics expressed by his or her tumor. tions result from the integration of multiple research disciplines and can be classified into five general Progress in Pursuit of Our Goal molecularly targeted strategies that will guide future research. (See figure below.) NCI is advancing the identification of molecular targets and targeted drug discovery through a Drugs developed using past paradigms attack both number of exciting initiatives. Several of these cancerous and healthy cells, often causing devastat- efforts address needs identified by Progress ing short- and long-term side effects. Moreover, Review Groups, expert panels who assess research individual patient responses to conventional agents requirements for specific types of cancer.

1 A gene is said to be “expressed” when the cell uses its genetic information to produce protein. 2 “Signaling pathways” are molecular interactions that begin when a cell receives a signal, such as a protein binding to a receptor, from outside of itself.

Research Avenues for Molecular Targeting

Influence the cancer cell to re-regulate itself, or assume a more normal state.

Turn on self-destruct pathways that cause a cancer cell to commit suicide.

▼ ▼ Stimulate the body’s immune system to

reject the cancer. ▼ Prevent the cell from acquiring the capacity 8 to repeatedly replicate itself. 8 Interfere with a cell’s capacity to use surrounding tissue to support its growth — e.g., through angiogenesis.

60 The Nation’s Investment in Cancer Research sis), essentialfortumorgrowth; amoleculethatbinds inhibitors ofnewbloodvessel formation(angiogene- anti-cancer activity. Promisingcompounds include screened hundredsofthousands ofcompoundsfor The sixteamsfundedthroughthisinitiativehave that willinteractwithcancer-specific moleculartargets. scientists screenthecompoundstoidentifythose potential anti-cancereffects. Using“smart”assays, of structurallydiversechemicalcompoundswith chemical andbiologicaltechniquestocreatelibraries ciplinary teamsofscientistsuseacombination prognosis. In and isassociatedwithmetastaticdiseasepoor over-expressed inupto50percentofbreastcancers vaccines targeting areceptorcalledHer2/neuthatis variety ofareas.Onegroupisdevelopingnovel treatments. Thirteengroupsareprogressingina parallel approachesfordiscoveryofnewanti-cancer program supportsinnovative,multi-disciplinary, National CooperativeDrugDiscoveryGroups peutic potentialinmoleculartarget assays. hit targets. The nextstepistoevaluatetheirthera- and naturalcompoundstoidentifyagentsthatcan rating tocreatelibrariesofsynthetic,biological, NCI-supported chemistsandbiologistsarecollabo- Potential ofCompounds Evaluating theTherapeutic new compoundsidentifiedbyconsortium try sponsorstofacilitatethetestingandevaluationof it isdevelopingpartnerships researchers upto30newmousemodelseachyear, and research. The information, andmethodologiestoapplyincancer models ofhumancancers,andtogenerateresources, program designedtoderiveandcharacterizemouse Human CancersConsortium study moleculartargets. The a resourceofbiologicalassaysandcompoundsusedto natorial chemistry, informatics,andimaging,tocreate from advancesingenomics,molecularbiology, combi- Laboratory exploiting moleculartargets. The programs supportthedevelopmentofresourcesfor ly potentialagentsworkonthesetargets. Other NCI therapy, anddevelopteststodeterminehoweffective- sites thatcanbeexploitedforcancerpreventionand program, investigatorsidentifyandvalidatepotential Through the Molecular Targets Identifying andValidating 4 3 dtp.nci.nih.gov/docs/raid/raid_index.html emice.nci.nih.gov capitalizes ontheopportunitiesemerging Molecular Target DrugDiscovery Biology-Chemistry Centers Consortium expectstomakeavailable with pharmaceutical Mouse Modelsof is acollaborative Molecular Targets members. , interdis- The indus- 3 research onanovelcellcycleinhibitor. ing NCI’s these sets.Samplesetsfromtherepositoryarehelp- targeted cancerresearchhavebeensuppliedwith targets. Morethan60researchgroupsengagedin investigators whomighthavediscoveredpotential marine organisms; andotherbiologicalmaterialsto 80,000 naturalproductsextractedfromplantsand ple setsofmorethan140,000syntheticchemicals; 2002. receptor, willbeinclinicaltrialsbytheendofFY tumors expressingavariant epidermalgrowthfactor pediatric neuroblastoma,pancreatic cancer, and radiation. Asmanyassixadditionalagents,targeting dering malignantcellssensitivetospecificdrugsand therapeutic “suicidegenes”toprostatetumors,ren- novel genetherapyapproachthatdeliversapairof being testedinclinicaltrials.Oneinterventionisa interventions developedthroughRAIDarenow academic institutionsin62currentprojects.Three provides preclinicaldrugdevelopmentresourcesto Intervention Development agents onmoleculartargets. examine theeffects ofvariouschemopreventive clinical trialsofmechanisticallytargeted agentsto Through 17currentlyfundedprojects,NCIsupports resources ofNCIavailabletoacademicinvestigators. clinical andearlydrugdevelopmentcontract reverse, ordelaycarcinogenesis,bymakingthepre- tigational agents,withthepotentialtoprevent, clinical andearlydrugdevelopmentofinves- Intervention Development of initiatives.The arm ofinterventiondevelopmentthroughavariety interrelated activities.NCIissupportingthiscritical This isanexactingtaskthatrequiresveryspecific, Compounds intoDrugsforHumanUse T To increase bloodvesselgrowthintumors. antibodies toangiogenin,anenzymethatcan chemicals. Onerecentlyfundedprojectwilltarget oratory assaystoscreenlarge numbersof promising assisting inthedevelopmentofhigh-throughputlab- drug researchcapabilitiesinacademicinstitutionsby is anewprogramthatexpeditesthedevelopmentof cers. novel cellcycleinhibitorthatcouldaffect manycan- to growthfactorsandinhibitstumorgrowth;a ranslating PromisingTarget-Directed

expedite drugdiscovery, NCIisprovidingsam- Rapid AccesstoNCIDiscoveryResources 4 NCI’s Chemistry andBiologyGroup Drug DevelopmentGroup A Planand BudgetProposal for FiscalYear 2004 Rapid AccesstoPrevention The RapidAccessto (RAID) program program expeditespre- provides with

61 ADVANCING DISCOVERY AND ITS APPLICATION The Plan

Molecular Targets of Prevention and Treatment

GOAL

Facilitate the expanded exploration of the causes of cancer and the discovery and development of agents that specifically “target” these causes to prevent and treat cancer.

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004

1. Identify, characterize, and validate the combinations of deregulated $ 6.00 M cellular proteins and pathways that cause cancer in pre-cancerous and cancerous cells. ■ Through the Molecular Target Drug Discovery and other grant mechanisms, expand research to identify cellular targets and discover related anti-cancer agents. Provide screening assistance and informatics management. $6.00 M

2. Determine the cancer-causing deregulated pathways that can be $ 7.00 M targeted by treatment or prevention agents. ■ Amplify support for the Molecular Target Laboratory to bolster the systematic search for new preventive and therapeutic agents: 1) develop assays to identify possible treatments for cancer, and 2) acquire large libraries of natural and synthetic compounds. $5.00 M ■ Support the Mouse Models of Human Cancers Consortium. $2.00 M

3. Provide the infrastructure for researchers to develop assays to $16.00 M test large numbers of potential drugs against validated targets [e.g., deregulated proteins and pathways]. ■ Expand support for the National Cooperative Drug Discovery Groups and encourage “partnering” arrangements with large and small pharmaceutical companies. $5.00 M ■ Expand the availability of NCI discovery resources to academic laboratories through the Rapid Access to NCI Discovery Resources program. $1.00 M ■ Support the creation of novel chemical compound libraries for molecular target assays through new Small Business Innovation Research initiatives. $4.00 M ■ Develop a translational research program to closely link molecular imaging, cancer signatures, and molecular targets. These concurrent studies will couple the image to the biology to aid in credentialing new molecular targets. $3.00 M ■ Develop screening assays to test candidates for probes and inhibitors of molecular targets and characterize and validate compounds that hit the targets through the intramural Molecular Targets Development Program. Support the isolation, purification, and characterization of individual components of natural product extracts. $1.00 M ■ Develop a clinical proteomics initiative to use laser capture microdissection of human tissue specimens and to develop new laboratory tools for clinical proteomic applications in human cancer and drug toxicity detection. $2.00 M

4. Facilitate the steps necessary to turn a target-specific lead $ 9.00 M compound into a clinical agent. ■ Expand support for the Rapid Access to Intervention Development program. $3.00 M ■ Increase funding to the Rapid Access to Prevention Intervention Development program to develop agents from the laboratory through clinical trials of efficacy. $1.00 M

62 The Nation’s Investment in Cancer Research ■ Support the development of novel methods of drug formulation and drug delivery through new Small Business Innovation Research initiatives. $2.00 M ■ Expand assistance to small business drug research and development through the Flexible System to Advance Innovative Research program. $3.00 M

5. Investigate the use of novel combinations of radiation therapy $ 0.50 M with molecular therapeutics. ■ Support individual investigators and industry to develop treatment programs using new agents with radiation therapy. $0.50 M

6. Fund Clinical Trials Networks that will take drug candidates into $ 2.00 M human trials and determine if the drug affects the intended target and the progression of the cancer. ■ Widen support for the Interdisciplinary Research Teams for Molecular Target Assessment. $2.00 M

7. Utilize current technologies to make the next generation of cancer $ 8.30 M vaccines more effective in inducing anti-cancer responses, either before or during the use of other therapies. Support vaccine development and clinical trials of new vaccines. ■ Develop more potent vaccines by integrating various approaches and translating them into optimal therapies for human cancer. $1.50 M ■ Generate specialized cell types, such as dendritic cells, for use as vaccines. $0.70 M ■ Create animal models that both develop spontaneous tumors later in life, to allow time for appropriate vaccination protocols, and express tumor-associated antigens similar to those in humans. $0.30 M ■ Establish laboratories to analyze new gene products for potential use in cancer vaccines and to develop methods to increase immunogenicity. $0.50 M ■ Expedite the development of clinical trials to assess the efficacy of new vaccines for the treatment of colorectal, prostate, breast, lung, bladder, pancreatic, and head and neck carcinomas; myeloma, lymphoma, and melanoma; and other tumor types. — Develop new funding mechanisms to support clinical trials. $2.50 M — Obtain and make available samples of immune cells and tumor tissue from patients for immunoassay testing. $0.50 M ■ Establish centralized immunoassay laboratories to analyze patient immune responses both prior to and during vaccine clinical trials. Supplement existing laboratories to develop immunoassays to select good candidates for vaccine therapy. $0.50 M ■ Develop and conduct clinical trials to test the efficacy of using cancer vaccines in combination with existing therapies including chemotherapy, hormonal therapy, or local radiotherapy. $1.50 M ■ Develop new surrogate markers of vaccine efficacy and tests revealing the presence of bloodborne tumor cells that express tumor antigen genes. $0.30 M

Management and Support $ 6.00 M

Total $54.80 M ADVANCING DISCOVERY AND ITS APPLICATION DISCOVERY ADVANCING

A Plan and Budget Proposal for Fiscal Year 2004 63 support for academic and corporate-derived com- study critical biological processes to uncover high pounds when NCI is responsible for conducting and priority targets for cancer prevention or treatment monitoring the drug’s clinical development. For and drug discovery. The first set of applications, more than 15 years, researchers have attempted to focusing on angiogenesis, tumor proliferation, tumor design cancer therapies to avoid toxicities associated vaccines, and structure of tumor chromosomes, was with standard chemotherapeutic agents. BL22, an funded in 2001. immunotoxin that specifically targets hairy cell leukemia (HCL), originated in an intramural NCI Fostering Interdisciplinary Collaborations laboratory and was developed through NCI’s biolog- through NCI Intramural Programs icals production facility. It is now showing promising NCI’s Center for Cancer Research, which results in a Phase I trial: 11 of 16 patients with coordinates all intramural basic and clinical research, chemotherapy-resistant HCL have shown complete expedites rapid and efficient translation of basic sci- remission, lasting up to 18 months, mostly without entific advances into new tools, reagents, and molec- major side effects. The Flexible System to ularly targeted leads. Major priorities of the Center Advance Innovative Research provides funds to include fostering interdisciplinary collaborations small businesses to develop cancer therapeutic and between basic researchers and clinical investigators prevention agents from basic discovery to clinical tri- and training postdoctoral fellows to function in this als. One of these grants supported development of new research environment. To this end, NCI has an immune modulating agent called A-007, already formed the Molecular Targets Faculty, composed in Phase I clinical trials. This agent has been of scientists from diverse laboratories and branches approved for Phase II trials to test its efficacy in working together cooperatively as part of the intra- treating cervical cancer. The Radiation Modifier mural Molecular Targets Development Program. Evaluation Module program will serve individual The Program also promotes collaborations with vari- investigators and industry in the design and devel- ous academic and pharmaceutical partners and is opment of treatment programs using novel molecu- designed to facilitate the discovery of compounds lar, biologic, and cytotoxic agents in conjunction that can serve as probes for functional genomics, with radiation therapy. This integration is a high pri- proteomics, molecular target validation, or as candi- ority of NCI’s Intramural Program because new anti- dates for drug development. cancer agents may ultimately be used in combina- tion with radiation therapy. Recognizing the importance of anti-cancer vaccines in prevention and treatment, NCI has established Developing Clinical Trials Programs To the Center for Cancer Research Vaccine Study New Molecular Target Agents Initiative, a consortium of multidisciplinary scien- As part of large-scale prevention trials, NCI supports tists, consisting of expert clinicians and industrial supplemental studies and specimen repositories representatives. This consortium has spearheaded aimed at answering a variety of mechanistic and the development of new, more sophisticated recom- molecular questions. For example, in the Selenium binant vaccines that are now in the clinic and others and Vitamin E Cancer Prevention Trial, scien- that will enter the clinic shortly.5 The potential of tists will assess the molecular genetics of cancer risk proteomics to further cancer research is being and associations between diet and cancer. In the exploited by two other programs. The Biomedical Breast Cancer Prevention Trial, the Study of Proteomics Program provides NCI investigators Tamoxifen and Raloxifene focused on the estro- with the most powerful analytical approaches avail- gen receptor as a key to breast cancer risk. able to further the understanding of the molecular mechanisms underlying carcinogenesis and tumor NCI is fostering teams of interdisciplinary scientists progression and works hand in hand with the NCI through the Interdisciplinary Research Teams Clinical Proteomics Program to identify proteins for Molecular Target Assessment. These teams and pathways important in human cancers.

5 See page 16 for more information on the Vaccine Initiative.

64 The Nation’s Investment in Cancer Research Extraordinary Opportunity for Investment GOAL

Accelerate discovery and development of imaging methods, biosensors, and minimally invasive image-guided therapies to predict clinical course and guide and predict response to interventions.

Cancer Imaging and Molecular Sensing

The Opportunity At the same time, we must invest in applying the new technologies emerging from the study of Over the last quarter century, investment in cancer nanoscience2 that promise to give biomedical imaging has dramatically improved the quality of researchers and healthcare providers even more patient care by making it possible to detect tumors options for detecting and monitoring biologic events much earlier when they are easier to treat and by in cancer. Researchers are designing molecular permitting more precise therapy or surgery. New biosensors to be injected into the bloodstream to imaging techniques can be used to determine, in seek out and destroy cancer cells. These biosensors, real time, if a tumor has invaded vital tissue, grown about 10,000 times smaller than the head of a pin, around blood vessels, or spread to distant organs. will also allow physicians to image the cancer and Imaging supports various tumor-destroying follow the patient’s response to therapy — all approaches (chemicals, radiation, gene therapy, heat, with minimal side effects and little disruption of and cold) to minimize surgical trauma and damage to healthy tissue. healthy tissue, shorten recovery time, and reduce healthcare costs. Molecular or “functional” imaging1 NCI has a unique opportunity to further improve of the physiological, cellular, or molecular processes cancer imaging and molecular sensing technologies in living tissue can sometimes allow physicians to to ensure earlier and more accurate diagnoses for monitor their patients’ progress and response to cancer patients, reduce the number of invasive therapy without the need for biopsies. interventions, guide individualized therapies, and improve monitoring of patient response to treat- Indeed, more imaging resources are devoted to the ment. With additional investment in research and study and treatment of cancer than to any other dis- development, significant advances in these areas ease and, in many ways, the needs of cancer research will increasingly save and improve lives. and treatment drive the direction of imaging research. As we learn more about the molecular basis Progress in Pursuit of Our Goal for cancer, this level of sustained investment in can- cer imaging becomes even more necessary and pro- NCI’s investment in developing better imaging ductive. For example, micro-imaging technologies technologies for both cancer research and clinical are needed to fully utilize the increasing number practice are tangibly impacting patient’s lives. of mouse models of human cancer to uncover the genetic basis of specific tumors. We need to develop Developing Better Imaging functional imaging to study how newly discovered Technologies and Techniques defects in genes and proteins interact to cause can- NCI has played a major role in fostering functional cer. Recent discoveries in cancer signature and imaging through initiatives such as In Vivo Cellular molecular therapeutic research demand new ways to and Molecular Imaging Centers (ICMICs). With assess the effectiveness of molecularly targeted five Centers established as of 2002, each ICMIC brings treatments in clinical trial settings. together experts from diverse scientific and technologi- cal backgrounds to conduct multidisciplinary research on cellular and molecular imaging in cancer.

1 Molecular imaging techniques do not actually reveal molecules themselves, but they detect signals that indicate the presence of biochemical activity and changes, such as cell growth or death. Thus, molecular imaging is often described as “functional,” because the processes being imaged are active and constantly changing. 2

Nanoscience is the study of objects and phenomena on extremely small scales. AND ITS APPLICATION DISCOVERY ADVANCING

A Plan and Budget Proposal for Fiscal Year 2004 65 The Plan

Cancer Imaging and Molecular Sensing

GOAL

Stimulate and accelerate discovery and development of imaging methods and biosensors to identify the biological and molecular properties of precancerous or cancerous cells that will predict clinical course and response to interventions. Advance the development and implementation of minimally invasive image-guided therapies.

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004

1. Expand the discovery, design, and development of novel imaging $34.80 M agents and devices. ■ Establish two additional In Vivo Cellular and Molecular Imaging Centers (ICMICs) to foster multidisciplinary research in this area of study. $4.00 M ■ Increase the number of imaging agents supported by the Development of Clinical Imaging Drugs and Enhancers program from three to five per year. $4.00 M ■ Increase collaborations between Small Animal Imaging Resource Programs (SAIRPs) and other NCI programs such as the Mouse Models of Human Cancers Consortium (MMHCC). $2.00 M ■ Provide 10 supplements to SAIRPs to upgrade to state-of-the-art imaging devices. $5.00 M ■ Speed the development of imaging agents by funding supplements to grantees in a variety of NCI programs that perform research on molecular imaging. $2.00 M ■ Fund research supplements to investigators to make their imaging discoveries such as contrast agents, assays, devices, and software available to others. Establish a repository of imaging agents for investigators at the National Cancer Institute at Frederick. $3.50 M ■ Establish data banks of standardized digital image or spectroscopy data (such as virtual colonoscopy, digital mammography, digital chest imaging, and optical spectroscopy) associated with known clinical outcomes as a research resource. Expand the NCI-funded, publicly available, Molecular Imaging Database of imaging agents. $5.30 M ■ Fund six to eight grants to develop and test image processing and analysis algorithms (artificial intelligence). $2.00 M ■ Fund four grants (RFA) to stimulate the development of combined modality devices. $4.00 M ■ Accelerate commercialization of imaging discoveries by fostering academic-industry collaborations with funding supplements similar to the National Science Foundation Grant Opportunities for Academic Liaison with Industry (GOALI) program. $1.50M ■ Fund four grants to develop standardized image acquisition and image processing protocols for calculating quantitative endpoints for clinical trials. $1.50 M

2. Increase clinical trials of imaging methods and technologies. $ 14.00 M ■ Initiate clinical studies to evaluate: computed tomographic colonography (virtual colonoscopy) compared to endoscopic colonoscopy for early detection of colon cancer and polyps in a large multi-institutional setting; magnetic resonance (MR) spectroscopy for the early detection and assessment of prostate cancer; MR imaging and ultrasound for early detection of breast cancer; and positron emission tomography for monitoring tumor response to therapy. $10.00 M

66 The Nation’s Investment in Cancer Research aaeetadSpot$1.70M $ Management andSupport ■ ■ 4.00M $ Stimulateresearchoncomponentsandsystemsintegrationofdevices 5. ■ ■ ■ $12.00M ■ Acceleratethedevelopmentandclinicaltestingofimage-guided 4. ■ ■ $12.20M ■ ■ Integratemolecularandfunctionalimaging methodsinto 3. ■ ■ model. $2.00M Oncology, basedontheNationalScienceFoundationEngineering ResearchCenter Promote researchonbiosensorsystemsintegrationby funding aCenterforBiosensorsin develop biosensorsorcomponentsoffor T Fund 6to8supplementsinvestigatorsintheInnovative MolecularAnalysis to solidtumors.$5.00M integration ofhardwareandsoftwaretoolsforimage-guideddeliverytherapies Fund aninitiativeof10grants(RFA) tostimulatethedevelopmentandsystems and molecularimagingintoradiationtherapyplanning.$2.00M Support 6grantstodevelopthetoolsandinfrastructureincorporatefunctional invasive, image-guidedinterventionswith4to6fundingsupplements.$2.00M and otherNCI-fundedClinicalTrials CooperativeGroupsfortestingpromising,minimally Increase collaborationsbetweentheAmericanCollegeofRadiologyImagingNetwork promotes interactionsbetweencliniciansandbioengineers.$3.00M guided therapyresearchthatemphasizesaproblem-solving,organ-specific approachand Use 6to10fundingsupplementsenhanceprogramssuchastheSPOREsforimage- of newdrugs.$1.00M Expand acontractprogramtovalidateimagingmethodologiesinpre-clinicaltesting Provide fundingfordedicatedimagingequipment(infrastructure)clinicaltrials.$5.00M develop consensuscriteriaforusingimagingresultsasendpointsinclinicaltrials.$4.20M 10 to15imagingcoreswithinNCI-fundedCancerCentersandsupportexpertpanels Provide imagingexpertisetoclinicaltrialsbyfundingsupplementsorgrantsfor (safety andefficacy studies)from6to10trialsperyear. $2.00M Increase thecontractsupportforearlyclinicaltrialsofimagingagents latest imagingtechnologytolungcancerdetection. Fund aworkshoptotalkwithindustrialandacademicleadersaboutapplyingthe 10 fundingsupplementstoClinicalTrials CooperativeGroups.$4.00M Support correlativeimagingstudies,suchasmonitoringresponsetotherapy, with for interventions. therapeutic clinicaltrials. echnology, UnconventionalInnovationProgram,orNCI-NASAcollaboration to in vivo molecular sensing(biosensors). in vivo use. $2.00M A Planand BudgetProposal for FiscalYear 2004 T tl$78.70M otal

67 ADVANCING DISCOVERY AND ITS APPLICATION NCI is providing support for the planning of another livers of mice with invasive colon cancer. This team 14 potential ICMIC sites. For highlights of one developed a second agent to track metastases in ICMIC team effort, see the sidebar below. other organs throughout the mouse.

NCI’s Development of Clinical Imaging Drugs Bringing Advances in and Enhancers (DCIDE) program is continuing to Imaging to Cancer Care foster the development of new imaging contrast NCI is supporting clinical trial research to move agents and molecular probes to improve the promising imaging advances from discovery and diagnosis and treatment of cancer. By its second development to clinical use. New cancer imaging year, DCIDE will be developing as many as seven technologies and techniques are often evaluated imaging agents or probes designed to measure blood through one of NCI’s clinical trials cooperative vessel formation and cell death, evaluate cell growth, groups. These groups are networks of healthcare and enhance visualization of prostate and other cancers. professionals affiliated with medical schools, teach- ing hospitals, and community-based cancer treat- Several of NCI’s Progress Review Groups have ment centers. For example, the American College stressed the need for publicly available imaging of Radiology Imaging Network (ACRIN) recently databases to support optimal growth in imaging completed a study to determine whether computed research and technology. The NCI-supported tomography (CT) scanning — a technique some- Molecular Imaging Database, expected to be times known as “virtual colonoscopy” — is sufficiently released in 2002, will help researchers develop reliable for colon cancer screening to warrant further new imaging agents and help clinicians find existing study. Based on their promising results, a large-scale agents for imaging specific cancers. trial will follow this study. By early 2003, NCI’s Lung Imaging Database Consortium will provide databanks of standardized Other ACRIN efforts are underway to determine: digital image data from cancer patients, together ■ Whether combined Magnetic Resonance with clinical outcome information, a resource much Imaging (MRI) and Magnetic Resonance requested by researchers. Spectroscopic Imaging can be used to accurately localize and diagnose prostate cancer. Researchers of the Mouse Models of Human ■ Whether CT scanning can be used to reliably Cancers Consortium (MMHCC) are developing measure tumor volume of supraglottic cancer. inventive imaging modalities for use in pre- ■ How the drug Gleevec™ impacts the biology clinical studies. One group is using MRI to learn of Gastrointestinal Stromal Tumors (GIST). how to deliver anti-tumor therapy to the brain using ■ Whether CT or MRI can improve the pre- neural stem cells. Other researchers use a unique treatment evaluation of invasive cervical cancer. micro-computed tomography imaging (micro-CT) contrast agent to visualize metastatic tumors in the

Functional Imaging of Low Activity Genes by ICMIC Researchers For years, cancer researchers have been studying certain highly important, but low activity, genes in their work with animal models. The “activity” of a gene — usually measured by how much protein it is making — helps the scientist understand how the gene is affecting the biology of the cell. However, the protein levels of low activity genes are often too minute to measure. To overcome this difficulty, one team of In Vivo Cellular and Molecular Imaging Center (ICMIC) researchers, studying the gene for prostate specific antigen (PSA) in mice, recently developed a technique known as two-step transcriptional amplification (TSTA). In the first step, they changed the mouse’s PSA gene so that it would produce a small amount of a special protein whenever the PSA gene was active. For the second step they added a separate gene that will produce large quantities of an easily measured fluorescent chemical, when in the presence of even small amounts of the special protein. Then, by measuring fluorescence, they determined the activity level of the PSA gene. The ICMIC researchers expect to develop the TSTA approach for study of a variety of low activity genes, adding to our understanding of a number of cancers and how to prevent, detect, and treat them.

68 The Nation’s Investment in Cancer Research NCI-supported programsaroundthecountry. imaging agentsandprobes structure tosupport als forimagingtechnologies,NCIisprovidinginfra- to supportingtheseandotherlarge-scale clinicaltri- raphy determining thevalueof American CollegeofSurgeons OncologyGroupis the useofimagingtechnologies.Forexample, Other NCI-sponsorednetworksarealsoevaluating throughout theUnitedStates. former smokersforscreeningat30studysites Cancer ScreeningTrial Prostate, Lung,Colorectal,andOvarian the infrastructuredevelopedinup-and-running tion comparedtoX-rayscreening.NLSTwillutilize computed tomography(CT)forlungcancerdetec- (NLST), whichwilldeterminethemeritofspiral the NCI-funded 2002. ACRINisalsohelpingtodesignandconduct United States,andanother10siteswillbeaddedin women haveenrolledat18locationsacrossthe conventional, film-basedmammography. Over6,000 the diagnosticpowerofdigitalmammographyto T The surgery, chemotherapy, radiation,orotherconventionaltherapies. nosed, treated,andmonitoredwithasimpleinjectionnon-invasivemonitoringratherthan within 5to10years.Ultimately, welookforadaywhenmanycancerpatientswillbeeffectivelydiag- funding andinterdisciplinarycooperation,scientistsenvisionmakingsignificantprogressinthisfield taking shapeinlaboratoriesacrossthecountry. Althoughhumantestingisyearsaway, withproper special chemicalattachmentdesignedtokillthecell.Otherexcitingprojectsinnanotechnologyare them foreasyimaging.Thebiosensorcanthenbetargetedwithanexternallaserbeamtoactivatea cells. NCI-supportedresearchersaredevelopingsuchabiosensortolocatebraintumorcellsandtag innovations canbedesignedtoseekout,analyze,andtreatcancercells—allwithoutharminghealthy ular-sized attachmentsthatallowthemtoactasatypeofbiosensor. Theseremarkablenanotechnology they arethousandsoftimessmallerthanasinglecell,cancarryvarietyspeciallydesignedmolec- can seekoutandexaminecancercells.Thesespecialspheres,referredtoasnanoparticlesbecause researchers inthefieldofnanosciencehavestartedtodevelopsyntheticspheresmoleculesthat treating, andmonitoringcancerwithincreasinglyspecific,evenindividualizedtherapies.Anumberof Recent advancesinunderstandingthemolecularbasisofcancerraisepossibilitydiagnosing, Nanoscience —NewOpportunitiesforDetection,Monitoring,andIntervention rial Digital MammographyImagingScreening , anotherlarge-scale ACRINtrial,iscomparing , orPET, forlungcancerstaging.Inaddition National LungScreeningTrial early phaseclinicaltestingof positron emissiontomog- to enroll50,000currentor at variouscentersand minimizing damagetohealthytissues. radiation therapytoimprovetumorcontrolwhile integrate functionalandmolecularimagingwith Scientists identifiedthenextstepsneededto Biological ImaginginRadiationOncology.” In April2002,NCIheldaworkshop,“Roleof to demonstratetheeffectiveness ofatreatment. surrogate marker—perhapsinsteadofabiopsy to identifyhowuseimagingasabiomarkeror the CancerTherapyEvaluationProgram,orCTEP, example, NCIcooperativegroupsareworkingwith trials asawaytomakethemoreefficient. For into abroadcrosssectionofcancerclinical Furthermore, NCIisworkingtointegrateimaging peutic monitoring. evaluation ofdifficult-to-pinpoint cancersandthera- the PET/CTscannerforimprovedlocalizationand investigators isdevelopingthenextgenerationof imaging technology. OneteamofNCI-funded industry andforeigninstitutestocreateunique collaboration ofacademicscientistswith Novel ImagingTechnologies program tices thatimprovepatientcare.Forexample,NCI’s to translatebuddingimagingtechnologiesintoprac- NCI alsorecognizesthecrucialplaceofpartnerships A Planand BudgetProposal for FiscalYear 2004 supports

69 ADVANCING DISCOVERY AND ITS APPLICATION Story of Discovery

Harnessing Apoptosis to Destroy Cancer Cells

In 1972, John Kerr, Andrew Wyllie, and Alistair Currie published a paper describing a little known and curious form of cell death that today is one of the most intensively studied topics in modern biology. They reported on programmed cell death, which they labeled “apoptosis,” noting that it was distinctly different from the long recognized cell death process known as necrosis. In necrosis, a cell ruptures, causing inflammatory cells to rush in to clear away the debris.

With this observation, he sub- digesting the cell from within. stantiated the prediction made Because caspases become acti- by Kerr and his colleagues that vated early in apoptosis and apoptosis occurred beyond irreversibly launch a cell’s death embryogenesis. By 1986, machinery, scientists sought Horvitz determined that three their trigger. In 1996, Xiaodong genes were responsible for regu- Wang and colleagues discovered lating apoptosis in C. elegans and that caspases are activated by demonstrated for the first time cytochrome c, a critical protein that this process is genetically component of the mitochondria programmed. Horvitz and his (the energy-producing struc- colleagues also determined that tures of cells). With this finding,

A muscle cell undergoing apoptosis. these genes are broadly con- scientists began to study the served among plants and ani- mitochondria to determine how Apoptosis, however, is clean and mals, indicating that apoptosis apoptosis functions in the cell, quick: a cell shrinks and is rap- has been sustained through evo- and malfunctions in disease. idly digested by neighboring lution and has a universally cells. Although biologists have important biological function. Connecting Failed long known that apoptosis is These findings greatly ener- Apoptosis and Cancer important in embryogenesis, gized apoptosis research. Over The link between apoptosis and Kerr, Wyllie, and Currie were the next 15 years, scientists cancer was not established until the first to observe that it occurs confirmed that apoptosis plays a 1988 when David Hockenbery in mature cells. They also were central role in developing organ- and colleagues characterized the the first to hypothesize that its isms by shaping neural and bcl-2 gene. Bcl-2 was first dis- failure contributes to a variety immune systems and molding covered in B cells (an immune of diseases, including cancer. tissue specificity, and in mature cell) from patients with follicu- organisms by establishing a natu- lar lymphoma (an immune sys- Unfortunately, this ground- ral balance between cell death tem cancer). Hockenbery deter- breaking paper created little and renewal as it destroys excess, mined that the normal bcl-2 is a excitement in the scientific damaged, or abnormal cells. suicide “brake” gene — it pro- community until more than duces a protein that blocks ten years later when Nobel Additional studies have apoptosis. In lymphoma prize winner H. Robert Horvitz revealed that apoptosis occurs patients, the abnormal form of used the microscopic round- through two distinct cellular the gene is overactive, causing worm, C. elegans to explore how pathways, one of which is initi- the anti-apoptosis protein to be a single fertilized egg develops ated by signals outside the cell, overproduced. Cancer develops into an adult organism. As he the other by signals from with- as more and more B cells are painstakingly followed each of in. Both pathways converge generated and fail to die. the developing worm’s 1,090 inside the cell, turning on a cen- This finding, a milestone in cells to their ultimate fate, he tral executioner family of pro- cancer research, revealed that was surprised to see that 131 teins known as caspases. increased cell division was not cells died via apoptosis as the Caspases act as knives, cutting the only way that tumors could worm matured into adulthood. up proteins inside the cell and develop. Cells could also

70 The Nation’s Investment in Cancer Research chondria andcytochrome c by causingdamagetothemito- aged cellortriggersapoptosis division ofageneticallydam- because iteitherblocksthe cell important tumorsuppressor human genome,servesasan known astheguardianof example, thep53protein, has manygeneticcontrols.For dauntingly complicatedprocess mechanism tobeidentified,this component ofthecellsuicide Although evade thesedrugs. thwart acancercell’s abilityto cancer treatmentsaswell the suicide-provokingeffects of release sothattheycanimprove how bcl-2controlscytochromec develop acompletepictureof entists nowareworkingto mitochondria oftumorcells,sci- op fromchangeswithinthe chemotherapy appearstodevel- tosis-inducing effects of Because resistancetotheapop- inside themitochondria. the releaseofcytochromecfrom prevents apoptosisbyblocking mined thatthebcl-2protein drugs. resistance tochemotherapeutic sion ofthe come. Inaddition,overexpres- linked withpoordiseaseout- cers, andneuroblastoma)is phomas, colonandprostatecan- cancers (Bcellleukemias,lym- tein productionoccursinseveral mined thatincreasedbcl-2pro- mation about tists gatheredconsiderableinfor- Throughout the1990s grammed celldeath. tumor growthbyavoidingpro- become potentpromotersof In 1997, bcl-2 bcl-2 bcl-2 was thefirst gene mayconfer scientists deter- . Theydeter- , scien- leaving healthycellsalone. suicide incancercellswhile tailored treatments,toinduce be selectivelytriggered,through genetic therapies,andhowitcan might berepairedthrough apoptosis isregulated,howit Researchers areexploringhow age selectiveapoptosis. targeted newdrugsthatencour- and offer importantcluesabout to overcometreatmentresistance These insightscaninformefforts act byinducingcellsuicide. and chemotherapy, whichboth the killingeffects ofradiation why manytumorsareresistantto ing agreaterunderstandingof fails incancer, theyalsoaregain- learn moreabouthowapoptosis types ofcancer. Asscientists mark ofmost,andperhapsall ing apoptosisresistanceisahall- Evidence indicatesthatacquir- anti-cancer treatments. aggressiveness andresistanceto tion isassociatedwithtumor accumulate. Lossofp53func- DNA damagecancontinueto tein deficientandcellswith ic mutationsrenderthep53pro- human cancers,however, genet- release. In55to70percentof under Clinical trialsare with NewCancerDrugs T proteosome activity, Velcade damaged proteins.Byblocking removing abnormal,aged,or a cellular“garbagedisposal,” inside acellthatfunctionslike gets theproteosome,adevice Millenium Pharmaceuticals,tar- developed byNCIand V new apoptosis-inducingdrugs. elcade, anewagentjointly riggering Apoptosis way to testtheefficacy of currently A Planand BudgetProposal for FiscalYear 2004 improves treatment outcome. of-the-art chemotherapies with thisdrugfollowedbystate- determine whetherpretreatment cancer andleukemiapatients to sponsoring clinicaltrialsinlung pies. NCIandGentaareco- apoptosis-inducing chemothera- cer cellsmorevulnerableto the bcl-2proteinandleavescan- drug blockstheproductionof by theGentaCompany, this ed foritsclinicaluse.Developed inducing agentthatisbeingtest- Genase roendocrine andrenalcancers. Hodgkin’s lymphoma,andneu- myelogenous leukemia,non- melanoma, sarcoma,chronic cer, non-smallcelllungcancer, tiveness intreatingbreastcan- will determinethedrug’s effec- myeloma. OtherPhaseIItrials py nowusedtotreatmultiple dexamethasone, achemothera- III trialtocompareVelcade to researchers areplanningaPhase on thisencouragingresult, of thetrialparticipants.Based bilized thediseasein77percent multiple myeloma,Velcade sta- of patientswithprogressing tance. InaPhaseIIclinicaltrial ability todevelopchemoresis- seems toovercomeatumor’s express the cancers thatdoornotover- to beequallyeffective against cer treatmentbecauseitappears may provetobeaversatilecan- undergoes apoptosis.Velcade response toVelcade, thecell As BAXlevelsincreasein sis byblockingbcl-2activity. BAX proteinpromotesapopto- is BAX.Inthenormalcell, the cell.Oneoftheseproteins causes proteinstobuildupin nse isanotherapoptosis- bcl-2 gene and

71 STORY OF DISCOVERY Extraordinary Opportunity for Investment GOAL

Understand and apply the most effective communi- cations approaches to maximize access to and use of cancer information by all who need it.

Cancer Communications

The Opportunity member who receives the diagnosis of cancer, the experience is individual and unique. Our increasingly From primary prevention to survivorship and end refined capacity to tailor messages can help translate of life, only communication can enable people to science into useful information for people through make informed cancer-related decisions and adopt an ever-expanding menu of communication choices. behaviors to improve their health. Yet, substantial New technologies and tools should extend but not research reveals gaps between the information peo- replace one-to-one communication between health- ple want and what they receive. As in other areas of care providers and their patients. life, people with less income and education are also disadvantaged with respect to health communica- Our greatest challenge is to work with others to find tion. This is especially evident with patient- ways to speed the process from discovery to dissem- provider communication. ination to assure that caregivers, public health officials, patients, and the public have needed NCI leads our Nation’s cancer communications information at the appropriate time, in a form that research and development efforts and funds many is comprehensible and useful as well as culturally of the Nation’s most innovative and rigorous health and linguistically appropriate. This is our challenge, communications researchers. We are also building a and it is also our responsibility. substantial storehouse of effective communication strategies that are saving lives through interventions Progress In Pursuit of Our Goal that reduce smoking, boost fruit and vegetable con- sumption, and increase the numbers of people who Establishing New Data Collection and are screened for cancer. Analysis Strategies The Health Information National Trends But where we are in communicating about cancer Survey will be fielded in late 2002 to collect is not where we want to be. We must learn more nationally representative data every two years from about the science of communication and more rap- 8,000 randomly selected adults about the public’s idly translate successful intervention research into need for, access to, and use of cancer-related infor- practice. In particular, we must apply what we have mation. NCI staff are developing protocols to assure learned to improving the health of underserved that the scientific community has rapid access to populations. the data and that some reports are created especial- ly for lay persons. In future surveys, we plan to also Communicating science-based information about collect data on cancer survivors’ use of different cancer poses challenges, opportunities, and respon- media, their risk perceptions, cancer-related behav- sibilities. In this new communications century, our iors, personal cancer experiences, and perceived ability to use multiple methods of communication communications needs. designed to reach specific audiences and individuals is likely to produce greater impact than any single Amid the controversy on the efficacy of mammogra- approach. phy as a life saving measure this past year, NCI quickly mounted an omnibus survey on women’s We understand that for every person who needs reactions to the mammography controversy. information about cancer, for every patient and family Survey results showed that women with lower

72 The Nation’s Investment in Cancer Research levels of education and income were more likely to providing underserved populations with access to be confused and less likely to have good sources of relevant online cancer information.1 Overall com- information about mammography. Most participants puter use also increased, including the amount of indicated that they plan to continue to get mammo- health information sought via the Internet three grams in spite of the conflicting evidence. months after training. Respondents who said they had enough information to make a decision were more than three times as NCI has launched an improved Web site and likely to plan on getting screened than women who search engine that combines the information said they did not have enough information. These formerly available on NCI’s CancerNet and findings will inform our future communications cancerTrials sites in user-friendly topical formats. planning in this area. We are also planning an inter- The first four months following launch saw use national research effort. increase more than 30 percent.2

Accelerating the Pace of Research and NCI revised Clear Horizons and the Guia para Development of Interventions dejar de fumar (Guide to Quitting Smoking) as NCI-funded researchers are assessing the changing part of a smoking cessation project targeted to information needs of cancer patients under- Medicare beneficiaries in collaboration with the going chemotherapy and radiation therapy. Centers for Medicare and Medicaid Services. Study results will help NCI assess the communica- Approximately 10,000 copies of Clear Horizons tion concerns, problems, patterns, and needs of and 400 copies of the Guia have been distributed. newly diagnosed patients during active treatment and the early recovery period. 5 A Day for Better Health is one of the most widely recognized health promotion messages in the world. NCI convened the Consumer-Provider The program is the largest public-private partnership Communication Research Symposium in January for nutrition in the United States. The Department 2002 to bring together eminent scholars from a of Health and Human Services, including NCI and broad range of disciplines to identify major gaps the Centers for Disease Control and Prevention, and in the research literature on patient-doctor the U.S. Department of Agriculture recently signed communications. Gaps identified include the an agreement to formalize and expand their commit- need to better understand the roles played by care- ment to promote the 5 A Day message nationwide, givers other than doctors and the nature of their and particularly, in American schools. interactions with patients, the changing relationship between patient and doctor, the use of diverse set- After a successful pilot, the regional Cancer tings and channels, and the need for improved Information Service (CIS) now offers LiveHelp, research methodologies. which uses instant messaging technology to provide real-time responses to cancer inquiries on NCI’s NCI is funding interdisciplinary Centers of Web site, averaging 1,000 user sessions per month. Excellence in Cancer Communications CIS plans to pilot LiveHelp again as part of NCI’s Research to focus on the advancement of cancer smokefree.gov Web site, scheduled for launch in communication science using new and/or improved 2002. In March 2002, one CIS regional office began syntheses, theories, methods, and interventions. piloting the use of e-mail to respond to inquiries We are also developing and marketing collaborative received through the Web. interdisciplinary training and career development opportunities for health communication As part of a joint NCI and Agency for Healthcare researchers and practitioners. Research and Quality initiative, researchers were funded to develop and evaluate a primer to help Increasing Access To and people use numbers in health. Three basic risk Use of Cancer Information communication tools will supplement the primer: Four Digital Divide Pilot Projects were conduct- cancer risk charts, prevention benefit charts, and ed in collaboration with NCI’s Cancer Information standard disease summary templates. Service (CIS) to identify effective new strategies for

1 Results at dccps.cancer.gov/eocc/ddpp-awards.html AND ITS APPLICATION DISCOVERY ADVANCING 2 Go to cancer.gov to use this enhanced set of online resources.

A Plan and Budget Proposal for Fiscal Year 2004 73 The Plan

Cancer Communications Genes and the Environment GOAL GOAL Increase knowledge about, tools for, access to, and use of cancer communications by the Discoverpublic, patients, those genetic, survivors, environmental, and health professionals and lifestyle —factors with a and special their focus interactions on diverse that definepopulations cancer — riskto accelerate and that can reductions inform the in the development U. S. cancer of burden.new strategies for prevention, early detection, and treatment. Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004 Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004 1. Establish new data collection and analysis strategies to support $ 4.00 M 1.cancer Identify communicationsnew environmental planning risk factors and evaluation. and susceptibility genes $13.00 M ■ Analyzeand determine data from thetheir Health interactions Information in Nationalcancer Trends causation. Survey (HINTS), the ■ firstUtilize national the unique communications advantages surveyof the Cohortof U.S. Consortium populations toand investigate make results exogenous rapidly and availableendogenous to 4researchersexposures bestand programstudied inplanners. large populations $1.00 M and their interactions with ■ Conductsusceptibility an Internet-based genes. version of HINTS to determine feasibility of online data— Supportcollection developmental in order to increase studies response based on rates the Consortium’sand minimize gene-environment costs. $0.50 M study ■ Conductof breast a HINTS and prostate survey cancers of cancer to survivorsdetermine in the parallel value with of adding the HINTS studies publicof other surveycommon to collect cancer data sites. on survivors’ $2.00 M use of different media, their risk perceptions, cancer-related— Expand the behaviors, number ofand participants, personal cancer population communications diversity, and experiences. types of biospecimens $0.50 M ■ Conductinvolved regular in these surveys studies. to assess $2.00 and M analyze the public’s reactions to media ■ communicationsSupport the Case-Control on cancer Consortium for use in program to fully investigateplanning and gene-environment evaluation. $1.00 interactions M ■ forMap specific the information types of cancer. terrain Initiate to understand large population-based the nature of the and information hospital-based that studiesis to developbeing provided comprehensive to different data audiences and specimen through resources different by media,cancer site. $5.00 M ■ includingContinue improvingthe Internet. the $0.50infrastructures M needed for large, collaborative human population ■ studiesAssess women’swith biospecimen communication components. needs related to mammography screening worldwide.— Maximize $0.50 the Mefficiency and cost effectiveness of specimen collection, processing, storage techniques, and high-throughput assays for human population studies. $2.00 M 2. Accelerate— Enhance thethe capacity pace of informaticsresearch systems and development developed to capture, of cancer store, analyze, $ 18.50 M communicationand integrate the interventions. massive amount of information generated by these studies. $2.00 M ■ SupportContinue studies to support to determine the Centers the ofcontribution Excellence of in inflammation, Cancer Communications injury, and infectious a gentsResearch to the (Ongoing genesis commitmentof lung cancer, of a $10.00 need identifiedM per year by beginning the Lung inCancer Fiscal Progress Year 2003). Review Group. ■ Strengthen interdisciplinary research training in strategic areas, including risk 2.communications Develop new waysand interactive to assess health and communications. measure environmental $1.50 M exposures $ 5.00 M ■ Supportfor use basic in population communications studies. research to accelerate discoveries about how cancer ■ informationContinue expanding is processed the Innovativeand used. $2.50Molecular M Analysis Technologies Program to develop ■ newSupport non-invasive innovative techniques applied communication for collecting and studies, analyzing testing genes how and integrated gene products electronic in very smalland interpersonal biologic samples. communication $2.00 M systems can improve health. $5.00 M ■ ContinueCreate a New support Media for applyingCollaborative and validating (NewMediaCo) measures to answerof the cumulative important questionscellular, genetic, andabout molecular tailored communicationseffects of environmental and the exposurenew media. through $4.00 funding M supplements for ongoing research programs. $3.00 M

74 The Nation’s Investment in Cancer Research .Ipoetesineo ismnto n h ismnto f $7.50M Improvethescienceofdisseminationand 4. ■ ■ ■ ■ ■ ■ $5.75M ■ Developacommunicationsmenutoincrease accesstoanduseof 3. ■ ■ Management andSupport ■ ■ ■ Conduct researchanddevelopmentoninnovativestrategiesfordissemination.$3.00M communication researchreportsaccessibletoresearchersandprogramplanners.$0.50M Expand, update,anddisseminatethesearchabledatabasesofcancer-related NCI-funded evidence-basedinterventions.$4.00M Provide supplementalfundingsupportforinvestigatorstodiffuse anddisseminate research investments. science toassurethatallourcitizensrealizethebenefitsof Develop cancerinformationforHispanics/Latinos.$0.75M communications programs,withaspecialfocusonunderservedpopulations.$0.50M Develop andpromote,togranteesorganizations, toolkitsforplanning and campaignstoreachunderservedpopulations.$1.00M Continue tobuildandnurturethe resources inpreparingcancer-related stories.$0.50M Develop andpromoteamediatoolkittofacilitatethemedia’s useofNCI’s Develop astrategicplanandprogramforlow-literacypopulations.$1.00M professionals, andcancercommunicators.$1.00M patients andtheircaregivers,underservedpopulations,advocacygroups,health Develop newtoolsandproductstofacilitatecancercommunicationsforthepublic, and useevaluateoutcomes.$1.00M W populations. cancer communicationsbyallpopulations,especiallyunderserved and patients.$2.50M Conduct researchtounderstandandenhancecommunicationbetweendoctors communications andinformaticstechnologies.$3.00M for researcherswhoareconductinghealthcommunicationsresearchusingstate-of-the-art Establish FAST (FacilitateandAccelerateScienceTechnology) Track Funding ork withcollaboratorstofundadditionalpilotprojectsincreaseInternetaccess 5 ADayforBetterHealth program partnerships A Planand BudgetProposal for FiscalYear 2004 T tl$39.75M otal $ 4.00M

75 ADVANCING DISCOVERY AND ITS APPLICATION New Cancer Communications Efforts Further Accelerate Discovery to Delivery Effective communication is critical all along the corridors, from discovery in the laboratory to development of new drugs and other interventions to delivery of those interventions in the clinic. With adequate funding in Fiscal Year 2004, we can continue and expand current efforts while implementing new initiatives.

■ New public surveys to assess reactions to media coverage about cancer will aid us in communication planning and evaluation, especially in evaluating the public’s reaction to controversial coverage. ■ New training workshops and toolkits about cancer science for journalists will enhance the quality and quantity of media coverage about cancer. ■ NCI’s International Breast Cancer Screening Network, a voluntary consortium of 25 countries, will develop best practices for their international population-based screening mammography programs and standard- ize and summarize existing information and decision tools for all member countries. ■ We will partner with the National Science Foundation or the National Institute of Mental Health to conduct basic communications research to accelerate discoveries about how cancer information is processed and used. ■ Applied communications studies will test how integrated electronic and interpersonal communication sys- tems can improve decision making, facilitate positive changes in health behavior, and improve health. ■ A New Media Collaborative will develop theory driven definitions of the active ingredients in tailored com- munications, agree on common measures, identify a minimum set of essential core mechanisms, and conduct process-to-outcome analyses. ■ The FAST (Facilitate and Accelerate Science and Technology) Track Funding program will be employed to overcome current system barriers that result in long delays in moving ideas to innovative technologies and funding.

NCI has developed an education program entitled NCI funded the dissemination of two promising the Facing Forward Series to equip patients, intervention programs and products: Sunny Days, families, and healthcare providers with information Healthy Ways, Grade 6-8 Sun Safety Curriculum, about what to expect following cancer treatment. and 5 A Day for Better Health dissemination. Publications on cancer survivorship issues for health In the first project, researchers will compare the professionals and family care are planned for 2003. efficacy of disseminating Sunny Days to public elementary schools and licensed childcare facilities NCI researchers are studying how to communi- in several areas and test whether dissemination is cate more effectively with low literacy popula- improved by providing Web-based training and tions. Lessons learned will be synthesized with an technical support. understanding of the needs of low literacy popula- tions to develop an actionable strategic plan and Launched in January 2002, NewMediacy now has program. NCI currently offers low literacy materials more than 300 subscribers. The listserv has sum- on the topics of pain and clinical trials. maries of and links to the latest communications related data and reports. Important findings include Improving the Science of Dissemination data on doctor-patient communications and on the and the Dissemination of Science public’s use of online health information. NCI has collaborated with the American Cancer Society (ACS) to adapt two successful NCI-funded NCI, in partnership with the Center for the intervention studies to create Body & Soul: Advancement of Health, the Robert Wood Johnson A Celebration of Healthy Living, a nutrition program Foundation, and the NIH Office of Behavioral and to be delivered through African-American churches. Social Sciences Research, is sponsoring a confer- The program is an example of effective research dis- ence on what we know, what we need to know, semination to communities, as well as successful and what we need to do to accelerate the research collaboration between NCI and ACS. adoption of evidence-based cancer prevention and control interventions.

76 The Nation’s Investment in Cancer Research Progress against cancer takes place not only in the laboratory and the physician’s office but in an environment of heightened public health concern. Prevention bolsters our defense against cancer. The delivery of quality care is paramount when cancer strikes an individual. A network of support is critical to our increasing number of survivors, their families, and a population that is aging. — Andrew C. von Eschenbach, M.D. Addressing Areas of Public Health Emphasis

This past year, as NCI has once again examined its priority research areas, four stand out as having special significance not only for increasing our understanding of cancer but for informing aggres- sive policy decisions and planning for public health programs. We can no longer ignore, for example, the pervasiveness of media support for tobacco use in this country. Television and films continue to glamor- ize smoking and its purported benefits for stress relief, and smoking is still touted to our young far too often as a rite of passage to adulthood or as a gateway to approval.

In our 2004 budget proposal, we give special atten- or are among the untold numbers who are denied tion to four areas of public health emphasis. They proper care because of social position, economic are NCI Challenge areas for Improving the Quality status, cultural or language barriers, or geographic of Cancer Care and Reducing Cancer-Related Health location. In each instance, we need better science Disparities and Extraordinary Opportunity areas in to understand the complexities in these areas. Cancer Survivorship: Improving Treatment Outcomes As we study disparities, we can take action against and Quality of Life and Research on Tobacco and them where the causes are clear. And there is a Tobacco-Related Cancers. pressing need to address the challenges posed to our Nation’s healthcare system by the rising incidence We must act on behalf of the millions of people in of cancer as a result of the aging U.S. population. our country today who do not receive appropriate For all Americans, we need evidence-based inter- care for their cancer, do not get the kind of support ventions that will prevent cancer from occurring they need to deal with the emotional, physical, and and improve the health and quality of life for those psychological effects of treatment and survivorship, who are affected by cancer.

FY 2004 Increase Request for Areas of Public Health Emphasis Tobacco & Tobacco-Related Cancers 36% (dollars in thousands)

Quality of Cancer Care $ 27,000 Reducing Health Disparities $ 61,350 Cancer Survivorship $ 46,000 Tobacco & Tobacco-Related Cancers $ 76,000 Quality of Cancer Care 13% Total $210,350

National Clinical Trials Program 49.3% Cancer Survivorship 22% Reducing Health Disparities 29% ADDRESSING AREAS OF PUBLIC HEALTH EMPHASIS ADDRESSING AREAS OF PUBLIC HEALTH

A Plan and Budget Proposal for Fiscal Year 2004 77 NCI Challenge: Building Our Capacity for the Future GOAL

Improve the quality of cancer care by strengthening the scientific basis for public and private decision making on care delivery, coverage, purchasing, regulation, and standards setting.

Improving the Quality of Cancer Care

The Challenge ■ Build a stronger data and methods “infrastruc- ture” for conducting quality of care analyses, The nine million Americans living today who have including studies at both the individual and had cancer, including the 1.3 million who will be population levels. diagnosed in 2002 and the 500,000 who are in the ■ Incorporate symptom management and palliative last year of life, all hope that they receive the best care across the cancer continuum, through cancer medical treatment and care possible. Unfortunately, quality improvement research and translation efforts. far too many will not receive this caliber of care. ■ Ensure that effective therapies demonstrated in The Institute of Medicine’s National Cancer Policy clinical trials are incorporated into community Board (NCPB) recently reported that the “ad hoc practice. and fragmented cancer care system” in the United ■ Enhance cancer communications for patients, States “does not ensure access to care, lacks coordi- their families, and caregivers. nation, and is inefficient in its use of resources.” ■ Strengthen collaborative relationships with Testimonies of cancer patients, families, and Federal agencies and private organizations to providers, summarized in the President’s Cancer ensure that the best available scientific evidence Panel Report, Voices of a Broken System: Real People, guides cancer care decisions. Real Problems, point to a number of barriers to high quality cancer care. These include system and Progress Toward financial limitations, the inadequacy of patient Meeting the Challenge information and provider education, poor manage- ment of cancer-related symptoms, and lack of time- Developing Core Measurements ly referral to palliative and hospice care.1 In 2001, NCI convened the Cancer Outcomes Measurement Working Group, composed of 35 Drawing from the NCPB report, we define quality internationally recognized experts in measurement, cancer care as the provision of evidence based, oncology, and the social sciences, to assess alternative patient centered services throughout the continuum approaches for improving patient centered outcome of care in a timely and technically competent man- measures such as quality of life, economic burden, and ner, with good communication, shared decision satisfaction with care. A major barrier to comparing making, and cultural sensitivity, with the aim of findings is the lack of standardization in measuring improving clinical outcomes, including patient sur- outcomes, like health related quality of life. In vival and health related quality of life. Substantial response, working group members recommend that disagreement exists about what constitutes optimal outcome measures be selected from the small set care, especially from the patient’s perspective. that has been adequately validated. In addition, NCI Therefore, it is critical that we advance understand- should support research to improve our ability to ing of how to measure, monitor, and improve the compare study findings, conduct sound meta- quality of cancer care. We must: analyses, and adopt user friendly, computer adaptive ■ Define core outcome measures and standardize survey administration. core process measures to identify those interven- tions that have been shown to improve cancer Standards for process measures of quality cancer care care. are being developed through a major new NCI

1 Institute of Medicine, National Research Council, Ensuring Quality Cancer Care, 1999. President’s Cancer Panel, Report of the Chairman 2000-2001, Voices of a Broken System: Real People, Real Problems, September 2001.

78 The Nation’s Investment in Cancer Research Prostate Cancer Outcomes Study Sheds Light on Treatment Choices The Prostate Cancer Outcomes Study (PCOS), the most comprehensive survey ever undertaken on prostate cancer outcomes, was initiated in 1994 to evaluate variations in practice and the impact of therapies on health related quality of life. Study findings are helping men, their families, and clinicians make more informed choices about treatment alternatives. They include: ■ Reports showing that, while physicians order bone scans on approximately two-thirds of all new prostate cancer patients and computed tomography (CT) exams on about one-third of new patients, less than five percent of the imaging studies done for newly diagnosed prostate cancer patients show evidence of metastases. In contrast, for men with serum PSA levels greater than 50 ng/ml and Gleason scores ranging from 8-10, the imaging studies were positive in over 60 percent of the cases. ■ Evidence that men with clinically localized prostate cancer who are treated with a radical prostatectomy are more likely to experience urinary and sexual dysfunction than those treated with external beam radiation therapy. Bowel dysfunction, on the other hand, is more common among men receiving external radiation therapy. ■ Evidence that men aged 75 or older more often received conservative treatment, such as hormonal therapy alone or watchful waiting, than aggressive treatment such as radical prostatectomy or radiation therapy. ■ A finding that for men younger than 60, use of aggressive treatment was similar among white, African-American, and Hispanic men. Among men 60 years old and older, African American men underwent aggressive treatment less often than did white men or Hispanic men.

NCI plans to follow the 3,500 PCOS participants for 10 years after diagnosis to ascertain and verify deaths, maintain contact with respondents, and conduct a survey ten years out to assess long-term changes in disease-related quality of life.2

2appliedresearch.cancer.gov/PCOS/index collaboration with other Federal agencies and the of Clinical Oncology (ASCO) is conducting a similar private sector. This Cancer Care Quality study, focusing on breast and colorectal cancer, as Measurement Project (CanQual), conducted part of its National Initiative on Cancer Care Quality. under the auspices of the non-profit National NCI and ASCO have signed a Memorandum of Quality Forum, is identifying core process measures Understanding that stresses sharing information and for treatment, survivorship, and end-of-life care for progress on these complementary efforts. The the major tumor sites, as well as measures that forerunner to CanCORS is the landmark Prostate apply to all tumor sites, such as palliative care. Cancer Outcomes Study, the first longitudinal study of quality of life for men living with prostate Strengthening the Science Base cancer. (See sidebar on this page.) NCI established the Cancer Care Outcomes Research and Surveillance Consortium NCI’s recently established Patterns of (CanCORS) in 2001, launching a single study of Care/Quality of Care Program (POC/QOC) is treatment patterns and quality of care over time in drawing from the Surveillance, Epidemiology, and large cohorts of newly identified cancer patients. End Results (SEER) registry data to investigate CanCORS investigators are combining data from adoption of recommended treatments for the most registries, medical records, insurance claims, and common cancers. POC/QOC studies provide the patient and provider surveys to assess the care most authoritative data on trends in treatment pat- received by a sample of 5,000 colorectal and 5,000 terns for breast, colorectal, and ovarian cancer and lung cancer patients across the United States. This results will be disseminated through professional research will investigate the impact of selected education activities in collaboration with profession- interventions on patient centered outcomes, dis- al societies. The Cancer Research Network, a semination of state-of-the-art therapies in the com- consortium of researchers affiliated with 10 major munity, modifiable risk factors, and disparities in not-for-profit HMOs, has provided the mechanism cancer care and outcomes by racial/ethnic group and for NCI to obtain better data more quickly on pat- socioeconomic status. Recognizing the potential terns of cancer care from multiple perspectives. value of large cohort studies, the American Society The work of the Breast Cancer Surveillance ADDRESSING AREAS OF PUBLIC HEALTH EMPHASIS ADDRESSING AREAS OF PUBLIC HEALTH

A Plan and Budget Proposal for Fiscal Year 2004 79 The Plan

Improving the Quality of Cancer Care Genes and the Environment GOAL GOAL Improve the quality of cancer care by strengthening the scientific basis for public and private Discoverdecision makingthose genetic, on care environmental, delivery, coverage, and lifestylepurchasing, factors regulation, and their and interactions standards that setting. define cancer risk and that can inform the development of new strategies for prevention, Objectives,early detection, Milestones, and treatment. and Funding Increases Required for Fiscal Year 2004

Objectives,1. Develop core Milestones, process and and Funding outcome Increases measures Required for assessing for Fiscal the Year 2004 $ 5.50 M quality of cancer care. 1.■ Support Identify research new environmental to improve patient-centered risk factors outcomes and susceptibility measurement, including genes $13.00 M developmentand determine of tools their to enhance interactions data collection in cancer and statisticalcausation. studies to facilitate the ■ “cross-walking”Utilize the unique of advantagesscores among of thecompeting Cohort Consortiuminstruments. to $2.00 investigate M exogenous and ■ endogenousContinue to4 provideexposures supplemental best studied funding in large for populations the Cancer and Care their Quality interactions Measurement with Projectsusceptibility to identify genes. additional core process measures. $1.00 M ■ Support— Support research developmental to evaluate studies and enhance based ondissemination the Consortium’s and use gene-environment of core process study measuresof breast and and develop prostate new cancers measures to determine where needed. the value $2.50 of Madding studies of other common cancer sites. $2.00 M 2. —StrengthenExpand the the number methodological of participants, andpopulation empirical diversity, foundations and types of of biospecimens $15.00 M qualityinvolved of cancer in these carestudies. assessment. $2.00 M ■ SupportSustain supportthe Case-Control at $7.5 million Consortium per year to for fully Cancer investigate Care Outcomes gene-environment Research interactionsand forSurveillance specific types Consortium of cancer. studies. Initiate large population-based and hospital-based studies to ■ developSustain supportcomprehensive for Cancer data Research and specimen Network resources population by cancer laboratories site. $5.00 at $5.0 M million ■ perContinue year for improving cancer control the infrastructures research, with needed additional for large, emphasis collaborative on the quality human of population cancer carestudies in communitywith biospecimen settings. components. ■ Support— Maximize Pattern the of efficiencyCare/Quality and ofcost Care effectiveness (POC/QOC) of specimenstudies on collection, levels, trends, processing, variations,storage and techniques, dissemination and high-throughput of effective treatments assays for and human collaborate population with otherstudies. $2.00 M Federal— Enhance agencies the andcapacity professional of informatics societies systems for education developed on to quality capture, of carestore, analyze, improvement.and integrate Provide the massive support amount for new of Rapid information Response generated Special by Studies these (RRSS)studies. $2.00 M ■ toSupport facilitate studies methodological to determine and the pilot contribution investigations. of inflammation, Integrate results injury, from and infectious a thesegents tostudies the genesis with Cancer of lung Intervention cancer, a need Surveillance identified Modelingby the Lung Network Cancer Progress Review Group. models to predict the effects of treatment dissemination on trends in survival 2.and Develop mortality. new $3.00 ways M to assess and measure environmental exposures $ 5.00 M ■ Increasefor use supportin population for analyses studies. of the Surveillance, Epidemiology, and End Results ■ andContinue Medicare expanding (SEER-Medicare) the Innovative database Molecular to investigate Analysis Technologies the use and outcomesProgram to of develop selectednew non-invasive cancer interventions. techniques for $2.00 collecting M and analyzing genes and gene products in very ■ smallBased biologic on results samples. of completed $2.00 M and ongoing POC/QOC, SEER-Medicare, and RRSS ■ studies,Continue support support intervention for applying studies and validating and demonstration measures of programs the cumulative for improving cellular, referral genetic, patternsand molecular and treatment effects of where environmental sub-optimal exposure performance through has funding been documented.supplements for $2.00 ongoing M ■ researchBased on programs. ongoing feasibility $3.00 M studies, link tumor registry information to Medicaid and private payer administrative data to investigate whether interventions are reaching and improving the health of individuals aged 65 or younger. Assist private insurers in creating and analyzing claims linked to tumor registry data by leading a workshop based on the experience of SEER-Medicare and SEER-Medicaid investigators. $2.00 M ■ Continue to support innovative research on economic and delivery system determinants of the quality of and return on investment for new clinical approaches to prevention, screening, and treatment services. $2.50 M

80 The Nation’s Investment in Cancer Research .Ehneqaiyo aersac ihn n eod h $1.50M ■ ■ Enhancequalityofcareresearchwithin,andbeyond,the 4. ■ ■ ■ $1.00M 3. Incorporatesymptommanagementandpalliativecareintothe ■ ■ aaeetadSpot$1.00M $ Management andSupport ■ ■ 3.00M ■ $ Ensurethatthebestavailablescientificevidenceaboutquality 6. 5. Improvethequalityofcancercarebystrengthening trends incancercareandidentifying populationdisparities.$1.00M to supportongoingdevelopment ofanationalcancerdatasystemformonitoring Agency forHealthcareResearchandQuality),thestates, andprivateorganizations Control andPrevention,theCentersforMedicare MedicareServices,andthe Foster collaborationamongQCCCmembers(particularly theCentersforDisease technical assistanceandadvicetopublicagencies privateorganizations uponrequest. Capitalize onthecollectiveclinicalandpolicyexpertise oftheQCCCtoprovide of CancerCareCommittee(QCCC),aforumforcoordinating Federalactivities.$2.00M Continue tosupportinteragencydemonstrationprojects organized throughtheQuality across theentirespectrumofdeliverysystems.$1.00M support studiesexaminingtheratesandpatternsofadoptionimportanttherapies Using knowledgegleanedfromaworkshoponthediffusion ofmedicalinnovations, information. $0.50M for assessmentofpatientoutcomesclinicaltrials.Disseminateresulting assess thestateofart,identifykeyresearchquestions,anddevelopastrategy Sponsor meetingstobringtogetherleadingresearchersandstakeholders NCI clinicaltrialsprogram. management andpalliativecare,usingbest-practicestandards. Educate healthprofessionalsonwaystobetterintegrateanddeliversymptom education andinformationproductsspotlightInternetaccessibleinformation. Incorporate evidencebasedpalliativecarepracticesmorefullyintoNCI’s management andpalliativecare. Integrate existingandnewlydevelopedknowledgeabouteffective symptom at theendoflife. efforts, frominitialtreatment,throughsurvivorship,and full spectrumofcancerqualityimprovementresearchandtranslation monitoring cancerscreeningpractices.$1.50M Support theestablishmentofphysiciannetworksanddatabasesfortracking evidence basedperformancemeasuresatproviderandhealthsystemlevels.$2.00M research andqualityofcareassessment,includingstudiesontheintegration Sponsor newstudiestostrengthenthemethodologicalfoundationsofoutcomes and monitorprogressoncoremeasuresof cancercarequality. Share newknowledgeandcollaboratetoidentify, develop, measures andassessmentinformsFederal decisionmaking. communications. (See CancerCommunicationsplan,pages72-76.) A Planand BudgetProposal for FiscalYear 2004 T tl$27.00 M otal

81 ADDRESSING AREAS OF PUBLIC HEALTH EMPHASIS NCI Collaborates with Federal Partners To Ensure That the Best Available Evidence Informs Decision Making Through the Quality of Cancer Care Committee, NCI currently supports three interagency projects: ■ The Health Resources and Services Administration and Centers for Disease Control and Prevention collaborative to build on a chronic care model to develop “breakthrough changes” to improve screening, referral, and follow-up for breast, cervical, and colorectal cancer for underserved populations. ■ The Centers for Medicare and Medicaid Services collaborative to increase awareness and improve delivery of the Medicare colorectal cancer screening benefit among Medicare beneficiaries and their physicians. ■ The Department of Veterans Affairs (VA) collaborative to improve use of evidence about good practice for ongoing improvements in screening, surveillance, treatment, and end-of-life care for colorectal cancer in the VA healthcare system.3

3 hsrd.research.va.gov/queri/CRC_web_announcement.doc

Consortium investigates factors associated with topics such as cachexia, pain, and symptom high quality screening mammography in communi- reduction as well as new research concepts that ty practice, including hormone replacement therapy examine depression in cancer patients through and breast density, family history, age, and examina- the NCI Community Clinical Oncology Program tion technique. ■ NCI- and NIH-supported studies on complemen- tary and alternative medicine at the end of life Studies linking SEER and Medicare data continue to provide insight into quality of care issues Enhancing Quality of Care Research with- including: in the NCI Clinical Trials Program ■ Nearly equivalent costs of breast conserving The NCI National Clinical Trials Program surgery versus mastectomy for early-stage breast provides an ideal venue to assess quality of care cancer. through the incorporation of valid and reliable ■ Potential disparities by race, ethnicity, or age health related quality of life endpoints into in the receipt of chemotherapy for colon and clinical study design. A workshop on the diffusion ovarian cancer. of medical innovations will be held in 2003, set- ■ Significantly reduced rates of postoperative and ting the stage for studies to examine why some late urinary complications for men undergoing highly promising therapies successfully move into prostatectomy, when performed in a high- clinical practice while others do not. volume hospital by a surgeon who performs a high number of such procedures. Strengthening Cancer Communications Ultimately, improved cancer care depends on our Improving Symptom Management and ability to communicate messages about preven- Palliative Care across the Cancer tion, treatment, patient care, survivorship, and Continuum end-of-life issues to the research community, care The Improving Palliative Care for Cancer report 4 providers, patients, and payers. See pages 72-76 from the Institute of Medicine’s National Cancer for information on NCI cancer communication Policy Board identified gaps in symptom manage- efforts. ment and palliative care research. Information on how to better measure, evaluate, and improve Ensuring That the Best Available Science symptom management is now emerging from a Informs Decision Making variety of initiatives: NCI established the Quality of Cancer Care ■ Research supported by NCI through the Cancer Committee (QCCC) in 2000 to improve the quali- Outcomes Measurement Working Group, ty of Federal-level decision making about cancer CanQual, CanCORS, and Quality of Cancer care. Its membership includes the Federal agen- Care Committee projects cies involved in cancer care delivery, coverage, ■ The 2002 NIH State-of-the-Science Conference regulation, standards setting, or conducting on Symptom Management in Cancer: Pain, research on the quality of cancer care. (See Depression, and Fatigue sidebar at the top of this page.) ■ Clinical trials on supportive and palliative care

4 Institute of Medicine, National Research Council, Improving Palliative Care for Cancer, 2001.

82 The Nation’s Investment in Cancer Research Progress Report for NCI Challenge: Studying Emerging Trends in Cancer

Sustained Investment in Studying Cancer Trends Improves Knowledge and Understanding of Cancer

This is a report on progress toward objectives outlined in previous years as part of the NCI Challenge for Studying Emerging Trends in Cancer. While we are not requesting additional funding increases in this area, the following efforts will continue to produce the information and resources needed for high quality, well informed research, program planning, and health policy.

The Surveillance, Epidemiology, and End NCI is also co-funding, with the National Science Results (SEER) Program serves as the foundation Foundation, projects in data visualization, software for a national system of data resources on all aspects for geospatial analysis, and graphical display of data. of cancer surveillance. We have: ■ Increased coverage and made it more represen- Our data system and methodological resources tative of the entire population, including are being distributed widely and integrated into racial/ethnic minorities and groups living in rural a number of public and private sector efforts. areas — through expansion and partnerships For example: with the Centers for Disease Control and ■ The Atlas of Cancer Mortality shows geographic Prevention and state cancer registries. patterns of cancer death rates and a companion ■ Expanded quality data on risk factors; health Geographic Information Systems provides tools behaviors; extent of disease, treatment, and for using the Atlas. lifestyle; and quality of life for cancer survivors ■ The Cancer Profiles system identifies areas in — through public and private partnerships. greatest need of cancer control activities. ■ Provided scientists with information (generated ■ The Tobacco Use Supplement to the Current by Economic Studies in Cancer Prevention, Population Survey tracks progress in tobacco Screening, and Care and Cancer Surveillance control. Using Health Claims-Based Data Systems) to ■ The Diet History Questionnaire is used for assess trends, quality, and the cost of cancer care. epidemiologic and surveillance studies. ■ Conducted Patterns of Care studies to assess the ■ The National Health Interview Survey Cancer quality of care that cancer patients receive.1 Control Topical Module is used to evaluate national progress in achieving cancer objectives. We have new research methods in place to moni- tor cancer interventions, ensure the accuracy of The annual Cancer Progress Report, first released in questionnaires for self reporting, track nutritional 2001, informs the public, policy makers, advocates, health objectives, and estimate the economic cost and health professionals of progress in the Nation’s of cancer. For example: fight against cancer.3 The Annual Report to the ■ The Cancer Intervention and Surveillance Nation on the Status of Cancer, published in collabora- Modeling Network uses computer-based model- tion with several partners, provides an update on ing to study the need for and the effectiveness cancer rates and trends in the United States.4 of cancer interventions. ■ The recently completed study, Observing For more detail about these and other similar Protein and Energy Nutrition, is improving initiatives, go to appliedresearch.cancer.gov our ability to use and interpret dietary and surveillance.cancer.gov. assessment data.2 ■ The Family History of Cancer Assessment Study is assessing the accuracy of reports of cancer family histories.

1 See page 79 for more information. 2 See page 52 for more information. 3 progressreport.cancer.gov 4 seer.cancer.gov/reportcard PROGRESS REPORT

A Plan and Budget Proposal for Fiscal Year 2004 83 NCI Challenge: Building Our Capacity for the Future GOAL

Understand the fundamental causes of health disparities in cancer, develop effective interventions to reduce these disparities, and facilitate their implementation.

Reducing Cancer-Related Health Disparities

The Challenge Healthcare policymakers, providers, payers, and other stakeholders must be empowered to provide The unequal burden of cancer in our society is equal access to proven interventions for cancer pre- more than a scientific and medical challenge. It is vention and control for all populations. NCI must a moral and ethical dilemma for our Nation. Certain collect and synthesize the scientific evidence and populations experience significant disparities in provide leadership to help ensure that policies and cancer incidence, the care they receive, and the services bring the benefits of research to all Americans. outcomes of their disease. These differences have been recognized, or at least suspected, for some Progress Toward time. Now, they are being documented with Meeting the Challenge increasing frequency and clarity. NCI is working to identify cancer health disparities Our challenge today is to: and their underlying causes. For example, NCI, ■ Fully understand the fundamental causes of can- together with national, state, and local partners, is cer health disparities, including the influence of investigating the causes of disparities in cervical social position, economic status, cultural beliefs cancer mortality. While mortality for this disease and practices, environmental exposures, genet- has fallen three-fold nationwide in the past 50 years, ics, and individual behavior. some geographic areas experience persistently high ■ Develop effective interventions to address these cervical mortality rates. Researchers, clinicians, disparities. patient advocates and others will meet to review ■ Actively facilitate their implementation. surveillance and background data for high mortality areas and articulate the key issues and recommen- If there are ways we fund or perform cancer research dations for action. This information will be dissemi- that favor one person or group over another, we must nated to Federal, state, and local policy makers. discover and mend those ways. If there are ways we distribute the benefits of our research that con- NCI has funded a landmark, five-year Southern tribute to the very real social and economic dispari- Community Cohort Study that will enroll and ties in who develops cancer, who survives cancer, follow 105,000 people — two thirds of whom will and the quality of that survival, we must improve be African Americans — in six southeastern states our distribution. And if we can influence policy to to determine why African Americans are more like- improve care, we must exercise that influence. ly to develop and die from cancer. Genetic, environ- mental, and lifestyle factors that contribute to can- Recognizing that disparities must be overcome if cer development will be identified, and important we are to significantly reduce the Nation’s cancer health information about low income and rural pop- burden, NCI established a dedicated center to ulations of all races is also anticipated. direct and coordinate an Institute-wide plan to address key disparity issues. The scope of planning NCI has launched an investigation into the impact of will incorporate all research areas within NCI’s orga- the “racialization” of scientific inquiry and disparate nizational structure — basic biology, epidemiology, patient outcomes. We are also working to establish genetics, prevention, communication, cancer con- interdisciplinary research Centers for Population trol, diagnostics and treatment development, and Health and Health Disparities to better under- survivorship. stand the interaction of social, cultural, and physical

84 The Nation’s Investment in Cancer Research environmental determinants of cancer incidence and NCI is partnering with the Health Resources and outcomes and the behavioral and biologic factors that Services Administration, the Centers for Disease contribute to them. This trans-NIH initiative is also Control and Prevention, and the Institute for supported by the National Institute of Environmental Healthcare Improvement in a Health Disparities Sciences, the National Institute on Aging, and the Collaborative to improve delivery for underserved Office of Behavioral and Social Science Research and populations throughout the United States. The seeks to develop more effective interventions. Collaborative focuses on colorectal, breast, and cervi- cal cancer screening and clinical follow-up for people The California Health Interview Survey, sampling who traditionally lack access to quality healthcare. more than 55,000 respondents, is expanding under- standing of the interplay of race, ethnicity, socioeconom- In 2003, the radiation oncology-based Cancer ic factors, and other social and cultural influences on Disparities Research Partnerships Program cancer risk factors such as tobacco use, diet, and screen- will expand radiation oncology clinical trials in three ing. With several partners, NCI has implemented pro- geographically dispersed institutions serving large grams to address the cancer health disparities that are numbers of Native Americans, African Americans, being identified. For example, NCI sponsors 18 Special Hispanics and rural Appalachians. The program is Populations Networks for Cancer Awareness also expanding dissemination and diffusion chan- Research and Training that build relationships with nels using novel telemedicine and teleconferencing community-based programs, foster cancer awareness to connect participating institutions, their academic activities, increase minority enrollment in clinical tri- partners, and NCI clinical facilities and experts. als, pilot projects that will lead to the development of grant applications for new and innovative research, NCI continues to provide health disparities train- and develop junior biomedical researchers from ing for new scientists through the Cancer minority and underserved communities. Prevention Fellowship Program. Interest in health Collaborations with NCI Divisions and clinical/aca- disparities continues to grow, with 6 of 15 entering demic partnerships among Network awardees and fellows in 2002 expressing strong interest compared Cancer Centers, academic institutions, and Clinical with none in 1999. In 2003, the Cancer Disparities Cooperative Groups are essential to all of these Research Partnerships Program will support minority activities. clinical investigators, nurses, data managers, and others at institutions new to cancer disparities research.

Results of Recent Research on Cancer-Related Health Disparities 1 Social Circumstances May Contribute to Lower Survival Among African Americans with Advanced Non- Small Cell Lung Cancer (NSCLC). Researchers assessed more than 500 patients receiving systemic chemotherapy for advanced NSCLC, between 1989-1998, and found that African Americans in the study were more likely to present with a poor performance status and greater weight loss. African Americans in the study were also more likely to be unmarried, disabled, unemployed, or Medicaid recipients, suggesting that social circumstances may be the cause of poorer prognostic profiles in African Americans.

Educational Interventions Increase Cervical Cancer Screening Among Chinese Americans. NCI-supported investigators in Seattle found that direct mailing of culturally and linguistically appropriate educational materials and home visits by outreach workers can increase participation in cervical cancer screening in the Chinese-American population.

African American Men Are at Greater Risk for Advanced Prostate Cancer. Researchers examined racial and ethnic differences among men who develop advanced prostate cancer and found that African American men were at greater risk of advanced disease than Hispanic men and had about twice the risk of non-Hispanic Whites. After adjusting for clinical and sociodemographic variables, such as higher socioeconomic status, the difference for African Americans persisted but disappeared for Hispanics. Additional research on biologic markers, genetic susceptibility, and socioeconomic factors is needed to better explain disparities and determine how this information can help reduce cancer risk for these populations. EMPHASIS ADDRESSING AREAS OF PUBLIC HEALTH

1 See also Highlights of Progress, pages 8-13. A Plan and Budget Proposal for Fiscal Year 2004 85 The Plan

ReducingGenes and Cancer-Relatedthe Environment Health Disparities

GOALGOAL

UnderstandDiscover those the fundamentalgenetic, environmental, causes of health and lifestyle disparities factors in cancer, and their develop interactions effective that interventionsdefine cancer to risk reduce and thesethat can disparities, inform the and development facilitate their of newimplementation. strategies for prevention, early detection, and treatment. Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004 Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004 1. Expand research on the causes of health disparities in cancer. $16.20 M ■1.Identify Identify gaps new in researchenvironmental for cancer riskhealth factors disparities and by susceptibilityreviewing Federal genes and volun- $13.00 M taryand organization determine research their portfolios.interactions Use findingsin cancer to update causation. NCI’s strategic plan, ■ guideUtilize research the unique and partnershipadvantages ofefforts, the Cohort and set Consortium priorities for to newinvestigate cancer exogenoushealth and disparitiesendogenous research4 exposures support. best $5.20studied M in large populations and their interactions with ■ Expandsusceptibility the knowledge genes. base through fundamental cancer control research, including: –— InternationalSupport developmental collaborative studiesstudies onbased social on determinantsthe Consortium’s of cancer gene-environment and cancer- study relatedof breast disparities and prostate through cancers supplements to determine to NCI-supported the value of addingCenters studies for Population of other Healthcommon and Healthcancer sites.Disparities. $2.00 M $2.00 M –— ExpandedExpand epidemiologic the number of studies participants, exploring population racial/ethnic diversity, cancer and disparities. types of biospecimens $3.00 M – Investigationsinvolved in ofthese physician, studies. patient, $2.00 Mand health system factors influencing cancer ■ Supportcare quality the Case-Control among racial/ethnic Consortium minorities to fully and investigate other underserved gene-environment populations. interactions for$3.00 specific M types of cancer. Initiate large population-based and hospital-based studies to –develop Research comprehensive on biologic pathways data and through specimen which resources behavioral, by cancer social, site. physical, $5.00 Mand ■ Continueenvironmental improving factors the influence infrastructures cancer-related needed for health large, disparities, collaborative including human geneticpopulation studiespolymorphisms, with biospecimen psychoneuroimmunologic components. factors, and differential responses to —therapy.Maximize $3.00 the M efficiency and cost effectiveness of specimen collection, processing, storage techniques, and high-throughput assays for human population studies. $2.00 M 2. Develop— Enhance effective the capacity interventions of informatics to systems reduce developed cancer to health capture, disparities. store, analyze, $ 9.50 M ■ Increaseand collaborativeintegrate the researchmassive amountamong the of informationSpecial Populations generated Networks by these forstudies. Cancer $2.00 M ■ ASupportwareness studies Research to determine and Training, the contributionNCI, and other of inflammation, Federally funded injury, research and infectious net- a works.gents to $3.00 the genesisM of lung cancer, a need identified by the Lung Cancer Progress Review Group. ■ Assess the efficacy and cost effectiveness of patient navigator programs in populations 2.experiencing Develop new serious ways cancer-related to assess health and disparities. measure $1.00environmental M exposures $ 5.00 M ■ Collaboratefor use in with population service delivery studies. components of the Federal government to support ■ newContinue intervention expanding research the Innovative for women Molecular who have Analysis not been Technologies screened or whoProgram are sub- to develop stantiallynew non-invasive under screened techniques for breast for collecting and cervical and analyzingcancer, emphasizing genes and genesociocultural products in very determinantssmall biologic in samples. planning, $2.00 implementing, M and evaluating these interventions. $3.50 M ■■ AddressContinue disparities support forin risk,applying access and to validatingprevention measures interventions, of the qualitycumulative cancer cellular, care, andgenetic, clinicaland molecular trials through effects formal of environmental affiliations andexposure supplemental through funding supplementsto NCI Cancer for ongoing Centersresearch using programs. existing $3.00 links M with and direct funding to Minority-Serving Institutions. $2.00 M

3. Expand our ability to define and monitor cancer-related health disparities. $ 6.00 M ■ Enrich understanding of cancer health disparities through new population-based state and regional surveys that provide information on socioeconomic and cultural factors. $1.00 M ■ Conduct methodologic research to ensure cross-cultural equivalence in survey, epidemiological, and clinical research involving cancer risk factors. $1.00 M ■ Collect risk factor and screening data for small populations defined by geographic, racial/ethnic, socioeconomic, and other characteristics. $4.00 M

86 The Nation’s Investment in Cancer Research ■ ■ ■ $17.90M Facilitatetheimplementationofnewpolicy, communityandclinical 4. Management andSupport ■ ■ ■ ■ ■ $9.75M Expandminorityinvestigatorcompetitionforand 5. served populationstoNCI-supported treatmentandpreventiontrials.$5.00M outreach programsinunderservedcommunities,and accrual ofminorityandunder- Fund 20newcancereducationgrantsforhealthcareprovider continuingeducation, students tocareersinscienceandmedicine.$1.00M Expand supportfortheScienceEnrichmentProgram toattractminorityhighschool program forhealthcareprovidersandotherforums.$1.00 M Increase minorityparticipationinclinicaltrialsthrough anNCIfellowshiptraining research. $2.00M high schooltograduatelevelminoritystudentsenter careersinhealthdisparities Expand theContinuingUmbrellaofResearchExperiences Programtoencourage Fellowship Programtofocusonhealthdisparitiesresearch. $0.75M Recruit 3additionalminorityscientistsandphysicianstotheCancerPrevention – ExpandNCI’s integratedlowliteracyprogrambycustomizingcancerinformation – EstablishaDissemination/Diffusion ResearchGrantsProgramto(1)studysocial, – Expandsupportforresearch-practicepartnershipsbetweenFederallyfunded – Expandlocalandregionalpartnershipstoovercomehealthdisparitiesamong Expand disseminationandpromotionofresearchresultsevidencebased – Providesupplementstofundanursecasemanagerandpatientnavigatorateach – Expandclinicaltrialsoutreachtounder-represented populationsandincrease and treatmentclinicaltrials: Increase minorityandunderservedpopulationaccesstostate-of-the-artprevention eliminate cancerhealthdisparities.$0.50M develop collaborations,andcreateactionplansforinterventionstoreduceor Support aseriesofmeetingswithrepresentativestakeholderstoreviewevidence, interventions, andevaluatetheirimpactonhealthdisparities. population involvementinhealthdisparitiesresearch. materials fortargeted audiences.$1.50M dissemination anddiffusion interventionstoreducecancerhealthdisparities.$4.00M resourced communityhealthsettings,and(3)develop,apply, andevaluate clinicians, (2)testnewhypothesesforreachingunderservedpopulationsinunder- prevention andcontrolinterventionsbypublichealthofficials andcommunity environmental, andbehavioralbarrierstoadoptingevidence-basedcancer based interventionsinunderservedcommunities.$2.00M increase communitybasedcancerpreventionandcontrolresearchevidence cancer controlinvestigatorsandstatelocalhealthprogrampractitionersto communities withsimilarinfrastructurebarriers.$2.50M medically underservedpopulations.Disseminatemodelsforsuccessto interventions toreducecancerhealthdisparities. commitment toexpandminorityparticipationinclinicaltrials.$4.40M Community ClinicalOncologyProgramsitesthathavedemonstrateda of approximately15CancerCenters,20CooperativeGroupsites,and10 participation intrialsatestablishedminority-basedoncologysites.$3.00M A Planand BudgetProposal for FiscalYear 2004 T tl$61.35M otal $ 2.00M

87 ADDRESSING AREAS OF PUBLIC HEALTH EMPHASIS Extraordinary Opportunity for Investment GOAL

Reduce the adverse effects of cancer diagno- sis and treatment and optimize outcomes for cancer survivors and their families.

Cancer Survivorship: Improving Treatment Outcomes and Quality of Life

The Opportunity some measure of adversity. In some cases, these effects can have a profound impact on survivors’ Entering the new millennium armed with new health and quality of life. For example: insights into biology, including information from ■ A quarter of deaths among childhood cancer sur- the sequencing of the human genome, we are vivors are due to late consequences of treatment beginning to see the fruits of the “War on Cancer” — e.g., second malignancies, cardiac failure. In launched in 1971. Once almost uniformly fatal, one large study, 46 percent did not believe that cancer has become for many, a chronic illness, and their treatment could have put them at later risk for growing numbers, a curable disease. There are for a serious health problem. This knowledge an estimated 8.9 million cancer survivors in the gap has implications for optimal care. United States today. An impressive 14 percent of ■ Breast and lymphoma patients exposed to these individuals were originally diagnosed over systemic chemotherapy are at increased risk for 20 years ago. problems with cognitive functioning and some may be genetically more susceptible to this Cancer survival has risen steadily over the past chronic effect of treatment. three decades for all cancers combined. In the ■ Between a quarter and a third of patients under- absence of other competing causes of death, current going bone marrow or stem cell transplant suffer figures indicate that for adults diagnosed today, from symptoms of post-traumatic stress disorder 60 percent can expect to be alive five years later. (PTSD). Similar numbers of parents (especially As past and future advances in cancer detection, mothers) of children treated for cancer also expe- treatment, and care diffuse into clinical practice, rience PTSD symptoms, even years after their the number of survivors can be expected to increase. children are treated. Fewer deaths from cardiovascular disease and the ■ Female brain cancer survivors are eight times aging of the population will contribute to this trend. more likely to experience separation or divorce than male survivors. While cancer survivors are living longer, we have limited knowledge and many questions about the The adverse effects of cancer treatment remain health status, functioning, and quality of life for most poorly documented and understood. As presently of those who are post-treatment: What are the most configured, our surveillance databases (e.g., from common late effects of treatment? Who is NCI’s Surveillance, Epidemiology, and End Results at risk and can they be protected? Can treatment- Program and other tumor registries) often cannot related injury to normal tissue be prevented or identify a patient’s current health status and phase of reversed? What proportion of survivors will experi- survivorship — whether in active treatment, disease ence recurrent or second malignancies? Who should free, or dying of cancer. More research is needed to be following these survivors to detect disease recur- address issues of survivorship for specific cancers as rence? What constitutes “optimal surveillance” and well as for populations that have been under-repre- what is the cost of such follow-up care? Do medical, sented in previous research, such as the elderly. psychosocial, or behavioral interventions reduce mor- bidity in these populations? Cancer survivors and their family members face unique and uncharted consequences of illness and What is clear is that most of our current treatments, treatment. Information about survivors is critical if although benefiting the patient overall, will produce we are to:

88 The Nation’s Investment in Cancer Research ■ Help patients make decisions now about treat- their families experience significant psychosocial ment options that will affect their future. outcomes: fear of recurrence, sense of isolation, ■ Tailor therapies to maximize cure while minimiz- anxiety and depression, employment and insurance ing adverse treatment related effects. discrimination, altered body image, and relationship ■ Develop and disseminate evidence based inter- difficulties. While we know that human behavior ventions that reduce cancer morbidity as well as can have a profound impact on how cancer is mortality and facilitate adaptation among cancer managed and may also affect disease-free or overall survivors. survival, we are not currently using this information ■ Improve quality of care, control costs, and equip in the systematic delivery of care. Nor do we under- the next generation of physicians, nurses, and stand cancer’s consequences for millions of family other healthcare professionals to provide not just members affected by this illness, many of whom the science but also the art of comprehensive may themselves be at increased risk for cancer due cancer medicine. to shared cancer causing genes, lifestyle, and/or toxic exposures. As cancer care increasingly is Recent Institute of Medicine reports have identi- pushed into the outpatient setting, the economic, fied the need for the following survivorship research physical, and emotional burden on family members that will lead to increased length and quality of life is increasing. We have, to date, failed to fully appre- for those diagnosed with cancer.1 ciate this additional at-risk population or taken advantage of the opportunity to provide these vital Monitoring Adverse Long-Term or Late caregivers with supportive or health-promoting Effects of Cancer and Its Treatment interventions as part of standard cancer care. As children and adults with a history of cancer are living longer and data from NCI research studies are Understanding Genetic maturing, the nature and extent of long-term and Risk and Treatment late effects are being documented and reported: It is expected that with the decoding of the human neurocognitive problems, premature menopause, genome, our ability to identify hereditary cancer gastrointestinal system dysfunction, cardiorespirato- risk patterns and genes associated with susceptibili- ry system dysfunction, sexual impairment, infertility, ty to treatment-related late effects will accelerate. chronic fatigue and pain syndromes, second malig- Using tissue and blood samples from survivors to nancies, and others. Identification of patients at track outcomes holds the promise of helping us increased risk for complications of treatment and to better understand how cancer-causing genes information on interventions to reduce those risks operate and what therapies may be effective in will help patients, their families, and their providers controlling their effects. It will also permit us to negotiate critical decisions. With NCI’s recent expan- understand which therapies work best and for sion of the Surveillance, Epidemiology and End whom they are successful. An increasing number Results and National Clinical Trials Programs, our of cohort studies2 are focusing on cancer survivors. ability to track and monitor disease and care-related outcomes among survivors through these types of Training Researchers and surveillance mechanisms is developing. Disseminating Research Findings It is critical to disseminate the resulting research Understanding the Role of Behavioral findings across disciplines so that clinicians and and Socio-Cultural Factors in Patient researchers and other experts from the biomedical Outcomes and social sciences can use the new knowledge for There is growing appreciation of the role that socio- further research, intervention development, trend cultural and behavioral factors play in patient out- analysis, and advocacy. comes. Research shows that many survivors and

1 Ensuring Quality Cancer Care, 1999. nationalacademies.org/publications Improving Palliative Care for Cancer, 2001. nap.edu. Improving Palliative Care for Cancer, Summary and Recommendations, 2001. nap.edu. 2 In a cohort study, the same patient group is studied over a period of time. ADDRESSING AREAS OF PUBLIC HEALTH EMPHASIS ADDRESSING AREAS OF PUBLIC HEALTH

A Plan and Budget Proposal for Fiscal Year 2004 89 The Plan

Cancer Survivorship: Improving Treatment Outcomes and Quality of Life

GOAL

Reduce the adverse effects of cancer diagnosis and treatment and optimize outcomes for cancer survivors and their families.

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004

1. Expand research efforts to understand the biological, physical, $9.50 M psychological, and social mechanisms, and their interactions, that affect a cancer patient’s response to disease, treatment, and recovery. ■ Fund cohort and case control studies that examine the prevalence and incidence of late effects, in particular among survivors five or more years post-diagnosis. $3.00 M ■ Fund behavioral and epidemiological studies that examine both negative and positive physiologic and psychosocial effects, and their correlates, of cancer on survivors who are post-treatment. $5.00 M ■ Identify the genetic and/or phenotypic markers of susceptibility to treatment-related adverse effects and gene-environment interactions, using molecular epidemiological research. (See page 50, Objective 1.) ■ Support efforts to synthesize the research, and its implications for future directions, with respect to the role of sociocultural, behavioral, emotional, and spiritual factors in survivor and family outcomes and their willingness to adopt appropriate surveillance and health maintenance behaviors post-treatment. $1.50 M ■ Ensure that efforts to expand our knowledge base, with respect to the impact of can- cer and its treatment on survivor’s outcomes, includes attention to diverse cancer sites and under-represented groups — e.g., certain ethnic groups, persons diagnosed at 65 or older, older survivors with competing health problems, rural populations, low- income groups, or those with limited education.

2. Accelerate the pace of intervention research in order to reduce $12.00 M cancer-related chronic and late morbidity and mortality. ■ Expand research on the most promising and cost effective medical, behavioral, educational, and psychosocial interventions to address cancer patient needs for improved quality of life — e.g., reducing cancer-related symptoms such as distress, pain, and nausea; minimizing post-treatment organ dysfunction; promoting healthy practices such as exercise, smoking cessation, diet change; and addressing individual needs. This research would include examination of the impact on the patient of type, intensity, and length of well characterized and controlled interventions on appropriate intermediate biomarkers — e.g., immune functioning, cortisol levels, PSA levels. $9.00 M ■ Support the development of interventions that involve family members and friends versus those directed only at the cancer survivors, as well as interventions that target minority and medically underserved populations. $3.00 M

3. Develop tools to assess the quality of life and care of post- $ 5.50 M treatment cancer survivors and their family members. ■ Promote the development of new instruments to assess health-related quality of life beyond the active treatment period and evaluate the validity of existing instruments.

90 The Nation’s Investment in Cancer Research .Esr h eeomn n ismnto fnwitretos $3.50M ■ Ensurethedevelopmentanddisseminationofnewinterventions 5. ■ 5.50M $ ■ ■ EnhanceNCI’s capacitytotrackoutcomesforcancersurvivors. 4. ■ ■ ■ aaeetadSpot$1.00M $ Management andSupport ■ $9.00M ■ Expandthescientificbaseforunderstandingbiologicand 6. ■ ■ immunologic effects ofcancerandtreatment.$6.00M delayed radiationinducedorgan fibrosis underlying cardiacsequelaeofdoxorubicintreatment; explorethemechanismsof examine chemotherapyinducedorgan dysfunction—e.g.,mechanisms therapy —e.g.,mechanismsunderlyingpost-chemotherapy cognitivedysfunction; Support researchthatseeksto:investigatetheneuropsychologic impactofcancer to modulatetreatment-relatedtoxicities.$3.00M ment (e.g.,fatigue,organ dysfunction, secondmalignancies)andtestnovelstrategies the incidenceofandmechanismsforcertainphysiologic lateeffects ofcancertreat- Fund pre-clinicalstudiesinclinicallyrelevanttissueand animalmodelstoexamine psychosocial andsupportivecareacrosstheillnesscontinuum.$0.75M Develop anddisseminatecurriculastandardsforthedeliveryofeffective care ofsurvivors.$1.50M Support studiestotesttheadoptionandimpactofbestpracticesinpost-treatment cancer treatment.$1.25M up care,surveillance,andmonitoringofcancersurvivorswhohavecompletedinitial Promote thedevelopmentanddisseminationofbestpracticeguidelinesforfollow- or cancer-related professional and non-profitorganizations. and bestpractices,incollaborationwithotherFederalhealth- clinical trialsnetwork.$2.50M Establish aseparateregistryforpediatriccancersurvivorsseenwithinthe long-term (upto5-10yearspost-treatment).$2.00M Develop andsupporttheinfrastructureforclinicaltrialsgroupstofollowpatients selected Surveillance,EpidemiologyandEndResultsregistries.$1.00M Pilot theexpansionofdatacollectiononhealth-relatedoutcomesforsurvivorsin evaluation ofco-morbiditiesthatarebothcancerandnon-cancerrelated.$1.00M the NationalHeart,Lung,andBloodInstitute),developmeasuresthatpermit In collaborationwithotherNIHinstitutes(e.g.,theNationalInstituteonAgingor vivors acrossthecontinuumofcare.$0.50M impairment —andexaminethevalueplacedonaspectsofqualityhealthbysur- ed toqualifyachangeinfunctionasclinicallysignificant—e.g.,improvement, Use appliedandtheoreticalstatisticsto:establishthecriteriaorcutoff scoresneed- assess theimpactofsuchscreeningonpatternsandoutcomescare.$2.00M who areathighriskforpoorphysical,psychosocial,orbehavioraloutcomesand Promote thedevelopmentandtestingofscreeningtoolsthatidentifyindividuals toxicity criteriaforlateeffects ofcancertreatment.$2.00M This shouldincludeefforts toacceleratethepaceofdevelopmentcommon and newcancertreatments. physiologic mechanismsintheadverselateeffectsofcurrent and dysfunction; explore long-term A Planand BudgetProposal for FiscalYear 2004 T tl$46.00 M otal

91 ADDRESSING AREAS OF PUBLIC HEALTH EMPHASIS Highlights of Recent Cancer Survivorship Related Research 3

Tool Enhances Studies on the Long-Term Consequences of Cancer Treatment. Among the critical issues for cancer survivors are the “late effects” of their illness and treatment that sometimes do not show up for a number of years. To better define these consequences, the NCI is funding a program to update the common toxicity scoring system to incorporate the LENT score, Late Effects of Normal Tissues. This scoring system enables investigators to: ■ Compare newer treatments with the current regimens for treating all cancers. ■ Relate laboratory research to the severity of effects experienced by patients when investigating molecular mechanisms for late tissue damage. ■ Facilitate the development, for use in clinical trials, of interventions to prevent, reduce, or possbly reverse “late effects” of cancer treatment.

Adjusting Chemotherapy Dosage Reduces Incidence of Congestive Heart Failure among Cancer Survivors. Treatment with the chemotherapy drug anthracycline, or more specifically its metabolic byproduct doxorubicin, places sur- vivors at risk for congestive heart failure following their cancer treatment. At greatest risk are women, African Americans, and younger patients. NCI-supported researchers have discovered that moderately reducing the overall cumulative dosage of anthracycline can reduce the incidence of congestive heart failure from seven to well under one percent.

Growth Hormone Replacement Helps Children Safely Achieve Normal Height following Treatment for Leukemia. Seventy to eighty percent of children with Acute Lymphoblastic Leukemia are cured with current treatments. However, because of treatment-related effects, many of these survivors are short in stature as adults. Some of these patients have been treated with growth hormone therapy over the years, although the medical community has not been in agreement about the effectiveness or the safety of such treatment. An NCI-sponsored team of investigators recently found that replac- ing growth hormones, in those survivors where it is low, effectively induces “catch-up growth” and most patients reach nor- mal, or near normal, adult heights. This study also examined safety issues, confirming that this treatment does not cause relapse or second cancers. Although further study is warranted, these results suggest that growth hormone therapy is a safe treatment choice that will benefit many adult survivors of this disease.

Lung Cancer Survivors Retain Quality of Life. Although lung cancer is one of the most common cancers in the United States, little is known about the quality of life of lung cancer survivors. NCI-supported scientists recently analyzed self- reported indicators from five-year survivors of non-small cell lung cancer for factors that have the most effect on quality of life, such as other diseases, pulmonary function, depression and anxiety, tobacco use, social and spiritual well-being, and demographics. Notably, half of the survivors said their cancer had made a positive change in their life and the majority were “very hopeful.” Risk factors for poorer quality of life are strongly linked to depression, suggesting potential interventions by health care providers. The number of comorbid conditions (other diseases) experienced by the survivors was a weak indica- tor of overall life quality, although those with higher income and with few comorbid conditions reported better physical well being. Nonwhite participants rated greater than whites for overall quality of life as well as for mental health. This study, for the first time, highlights the range of experiences for long-term survivors of this disease and provides insights for potential rehabilitation. The complex interactions of quality of life by race/ethnicity and socioeconomic status deserve further study.

Social Interventions Can Benefit Breast Cancer Survivors. An NCI-sponsored study of breast cancer survivors over a four-year follow-up period shows that health-related quality of life is influenced by the survivor’s availability of social networks. On average, socially isolated women were more adversely affected by breast cancer, scoring lower on “role function,” “vitality,” and “physical function,” compared to the most socially integrated women. The level of a patient’s social integration is an important factor and appears to explain more of this variance than differences in treatment or tumor type. The study results suggest that rehabilitation programs should incorporate interventions that address the availability of adequate social support among breast cancer survivors.

3 See also Highlights of Progress, pages 12-13.

92 The Nation’s Investment in Cancer Research People’s Story

I had leukemia as a kid. The treatment was rough, but my family and friends and all of the doctors and nurses really helped me keep a positive frame of mind — even when the cancer came back a few years later and I had to go through treatment all over again. I know I’m fortunate to be alive.

Adult Survivors of Childhood Cancers An estimated 8.9 million Americans with a history of cancer other than non-melanoma skin cancer or in situ diseases were alive in 1997. Of these, an estimated 270,000 were survivors of childhood cancers. Survival rates from childhood cancers have increased dramatically over the past few decades, due in large part to the fact that nearly 80 percent of children with cancer are treated in clinical trials by multi- specialty medical teams. For an increasing number of ing good care of myself will help keep treatment success (even in the patients of all ages, cancer is a me cancer free and help me have the face of a difficult prognosis), and chronic disease, not a fatal one. fullest possible life. what contributes to people’s Over many years of survival, ability to overcome side effects patients may find their cancer We recognize more and more that that impact their mobility, physi- journey marked by a series of surviving cancer involves factors cal comfort, or psychological well successes and failures that may related to the way our bodies and being. include the management of minds respond to the changes recurrences, physical and cogni- brought on by the disease. We I still check in from time to time with tive side effects, or even second need to better understand these the doctors who treated me, but since cancers. As treatments and sup- changes and how they influence I became an adult, most of my health portive care have improved, how- cancer progression, treatment, care is provided by my primary care ever, it has become possible to and life after treatment. For physician. reduce recurrences and minimize example, evidence is emerging or eliminate some of the delayed that psychosocial factors that Because the large and growing or long-term side effects com- influence immune or endocrine number of long-term survivors is monly experienced by patients processes may influence the a relatively recent phenomenon, treated with less advanced development or progression of no clearly defined system exists therapies. certain cancers. for monitoring and managing long-term and delayed side As I’ve gotten older, I’ve needed to NCI supports research on the effects or second cancers. keep that positive attitude. I’ve had relationship of particular treat- Research is needed to determine some side effects from my treatment ments to specific short- and long- the most appropriate roles of — I’m diabetic and my heart and term side effects. We also need to oncology specialists, primary lung functions are reduced somewhat. understand, for example, the bio- care providers, and survivors But I take my medicine, and pay logical basis of these side effects, themselves in their lifelong attention to my diet, my stress level, why some patients are able to be follow-up care. and things like that. I think that tak- more optimistic than others about PEOPLE’S STORY

A Plan and Budget Proposal for Fiscal Year 2004 93 Extraordinary Opportunity for Investment GOAL

Understand the causes of tobacco use, addiction, and tobacco-related cancers and apply this knowledge to their pre- vention and treatment.

Research on Tobacco and Tobacco-Related Cancers

The Opportunity NCI also has a special concern for the health of former smokers who, despite quitting, now com- Lung cancer, the leading cause of cancer death, prise about half of those diagnosed with lung would be a rare disease in the absence of smoking. cancer. The development and marketing of new Smoking is the leading cause of cancers of the lung, tobacco products also is of great concern. Scientists mouth, larynx, esophagus, and bladder, and plays a must examine the toxicity of these products as well role in cancers of the pancreas, cervix, and kidney. as evaluate whether or not “harm reduction” is a The devastating impact of tobacco use and tobacco viable public health strategy. NCI’s commitment to smoke exposure on the incidence of cancer, heart research on tobacco and tobacco-related cancers is and lung disease, stroke, and other serious illnesses reflected in our investments both in basic biological is both compelling and conclusive. Tobacco use research on the effects of tobacco exposures and in causes more premature deaths (approximately community-based studies of smoking prevention 430,000 per year in the United States) than do all and cessation programs. drugs of abuse combined. In 2002, about 170,000 people will die of cancer because of their use of Progress in Pursuit of Our Goal tobacco products. A major challenge in the fight against tobacco-related cancers is that addiction to Defining Biological, Behavioral, and nicotine drives the continued use of tobacco even Social Bases of Tobacco Use and when the user is fully aware of increased risk of dis- Addiction ease and premature death. Some people will contin- NCI is advancing tobacco research to answer ques- ue to smoke even as they undergo treatment for a tions related to why people begin to use tobacco, life threatening disease. become addicted, and have difficulty stopping use of tobacco products, as well as genetic and environ- NCI’s commitment to preventing, diagnosing, and mental factors that influence tobacco use and addiction. treating tobacco-related cancers began more than 40 years ago. To remain at the leading edge of this Funding for Transdisciplinary Tobacco Use important area of research, NCI must devote addi- Research Centers (TTURCs), located within tional resources to address the complex challenges seven academic institutions, is approaching its of tobacco use. Research recommendations related fourth year of sponsorship by NCI, the National to tobacco use made by NCI’s Lung Cancer Institute on Drug Abuse (NIDA), and the Robert Progress Review Group echo many of the Wood Johnson Foundation. These centers are sup- Institute’s priorities, such as: porting a broad array of studies, including projects ■ Developing and expanding new approaches to evaluating new models of nicotine addiction, the the biology and treatment of nicotine addiction. role of genetic and environmental factors in smok- ■ Conducting basic biological research on the ing initiation and persistence, methods for prevent- effects of tobacco exposures including the differ- ing tobacco use across cultures, and determinants of ential toxicity of various tobacco products. relapse. TTURC sponsored research continues to ■ Continuing and evaluating current and planned inform us. population-based tobacco control efforts. ■ Certain genes regulating the activity of the neu- ■ Detecting and treating tobacco-related cancers rotransmitter dopamine help determine which and metastatic disease. smokers are able to quit. Although these genes do not appear to influence the effectiveness of

94 The Nation’s Investment in Cancer Research ent abarriertoquitting.Theirworkresultedinthe the physicalorpsychologicaleffects ofnicotinepres- dependence. Lossofautonomyoccurswheneither ory wherebylossofautonomysignalsonset significant. Theauthorsofthisstudyoffered athe- chological determinantsofdependenceareequally dependence inyouthisphysiological,butthatpsy- published studyshowedthatnotalltobacco within onemonthofsmokinginitiation.Arecently cent smokerscanexperiencewithdrawalsymptoms children andyouth prevention andcessationoftobaccouseby NCI supports50researchprojectsrelatedtothe ■ ■ ■ ■ ■ ■ Examples ofNCIsupportglobaltobaccoresearch include: 2030, with70percentofthosedeathsoccurringin thedevelopingworld. tobacco-related illness,andifcurrenttrendscontinue, thisfigurewillrisetoabout10millionperyearby The World HealthOrganization(WHO)estimatesthatfourmillion peopledieeachyearworldwidefrom International Activities a reductioninyouthsmoking. efforts toencompass thesefactorscouldleadto believe thattailoringpreventionandintervention at higherrisk. highly receptivetotobaccoadvertisingarealso ing. Moreover, depressedadolescentswhoare teristics areatanelevatedriskforcigarettesmok- combination ofaggressiveanddepressivecharac- and earlyinitiationofsmoking.Teenagers witha There arelinksbetweenspecificpersonalitytraits tion programsforhigh-riskadolescents. This informationisbeingusedtodevelopcessa- hood thatasmokerwillprogresstoregularuse. natal exposuretonicotineincreasesthelikeli- sion inyouth.Investigatorsalsofoundthatpre- use arefactorsthatinfluencesmokingprogres- availability, depression,delinquency, andalcohol Older adolescence,peersmoking,cigarette therapeutic responsetotreatment. involved indrugmetabolismdidpredict the medicationbupropion,anothergene Milan, Italy. Thisstudyof4,500subjectsinvestigatesthegenetics ofnicotineaddictionandlungcancer. Initiating amulti-institutional, population-based,case-controlstudyoflungcancer andsmokingin Capacity Buildingprogram, ledbytheNIHFogartyInternationalCenter. related illnessinthedeveloping world,throughtheInternationalTobacco andHealth Researchand U.S. andcollaboratingforeign scientistsandinstitutionstocombatthegrowing incidenceoftobacco- Providing $1.7millionoverthenextseveralyearsto extendandenhancetheresearchinterestsof Centers forDiseaseControlandPreventionthe SwedenCentreforTobacco Prevention. Co-hosting theThirdInternationalConferenceonSmokeless Tobacco, inSeptember2002,withthe molecular, epidemiology, behavioral, cancercontrol,andclinicalaspectsofthesecancers. Promotion ofScience,inFebruary2002,tobringtogether internationalresearcherstoaddress Jointly sponsoringtheSymposiumonTobacco-Related CancerswiththeJapanSocietyfor These findingsleadresearchersto . Studiesrevealthatadoles- ethnicity, educationalattainment,andmaritalstatus. smokers, currentandex-smokersbysex, and thereweresignificantdifferences amongnever users. Menweremorelikelythanwomentosmoke, history oftobaccouseand29.6percentwerecurrent and foundthat40.2percentofrespondentshada the DelawareValley RegionoftheUnitedStates Korean, Vietnamese, andCambodianrespondentsin tions. Investigatorscollecteddataon1174Chinese, lored prevention,cessation,andtreatmentinterven- Americans predictors oftobaccouseamongAsian Results fromarecent tobacco dependence. a validated,theoreticallybasedtoolthatmeasures ing signsofnicotineaddiction.Thismeasureoffers questionnaire thathelpssmokersidentifytenwarn- “Hooked onNicotineChecklist,”aself-administered and Tobacco-Related Cancers Preventing andTreating Tobacco Use In 2002,NCIopenedthedoorsto as NCI’s experienceindrugdevelopment. upon NIDA’s expertiseinaddictionresearchaswell Nicotine Addiction Group onMedicationDevelopmentfor these efforts, NCIandNIDAinitiateda and addictioninyouthadults.To complement ioral, andgeneticfactorsthatinfluencetobaccouse insights andknowledgeaboutthesocial,biobehav- research projectsisproducingimportantnew tiative, andseveraloftheyouthtobacco and CommunityTobacco ControlInterventionini- Research supportedthroughTTURCs,theState highlights theneedforculturallytai- A Planand BudgetProposal for FiscalYear 2004 that exploreswaystodraw study ofprevalenceand T obacco W orking

95 ADDRESSING AREAS OF PUBLIC HEALTH EMPHASIS The Plan

Research On Tobacco and Tobacco-Related Cancers

GOAL

Understand the causes of tobacco use, addiction, and tobacco-related cancers and apply this knowledge to their prevention and treatment.

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004

1. Expand the infrastructure needed to conduct a vigorous research and $25.50 M public health effort consistent with the enormous burden of tobacco-related disease. ■ Initiate prospective observational studies of the quitting and relapse processes, including the effectiveness of medications. $4.00 M ■ Continue support for including tobacco use in the Current Population Survey and increasing the number of non-English language translations. $2.50 M ■ Along with other government and non-government institutions, support the use of national, state, and regional tobacco surveillance data and the development of analytical tools, resources, and a network to track and evaluate progress in cancer control. $2.00 M ■ Expand the Cancer Intervention and Surveillance Modeling Network (CISNET) to develop models of tobacco use, dependence, relapse, and disease development. $2.00 M ■ Renew and expand support for the Transdisciplinary Tobacco Use Research Centers program, in collaboration with relevant public and private organizations. $15.00 M ■ Adopt and apply integrated study design models such as BEGIN (Behavior, Exposure, Genetics, Intermediate biomarkers, and Neoplastic markers) to support an interdisciplinary integrated approach to tobacco-related research.

2. Support innovative, integrated investigations to understand and $ 19.00 M treat tobacco use and addiction. ■ Capitalize on the breadth of expertise across NIH Institutes by supporting collaborative projects at NCI’s new tobacco use research clinic. $1.00 M ■ Accelerate the identification of new treatments for nicotine addiction through the implementation of a drug development and clinical trials collaborative group by NCI and other NIH institutes. $4.00 M ■ Support research on smoking cessation and relapse prevention in cancer patients and survivors. $2.00 M

Intervention Research Clinic, a state-of-the-sci- Translating Research Into Improved Outcomes ence center for tobacco use research by NCI scien- is an initiative that offers funding opportunities to tists and collaborators, including those in the NCI current NCI-funded investigators to support critical and other NIH intramural programs. The clinic will dissemination of promising interventions in the be a resource for NIH scientists conducting a range field of tobacco use and other cancer control areas. of genetic, epidemiological, basic science, and NCI is also actively involved in a public-private col- behavioral research studies and could provide laborative effort to develop a National Blueprint for research-based tobacco cessation services to patients Disseminating and Implementing Evidenced-Based from the NIH community. Clinical and Community Strategies to Promote Tobacco-Use Cessation.

96 The Nation’s Investment in Cancer Research 2 1 A surrogatebiomarker isameasurablemolecularfeature(for example,abloodprotein)thatcanbeused tomonitorthecourseo ■ ■ $31.00M ■ ■ Applycutting-edgeresearchtobetterunderstandandtreat 3. ■ ■ ■ ■ Management andSupport ■ See page69. markers clinical studiesfocusonvalidatingsurrogatebio- prevent cancersinformersmokers identify newer, morepotentagentsthatmay NCI isfunding initiative issupportingfour clinicaltrialsevaluating susceptible organ systems.Theclinicalresearch prioritize agentsthatprevent cancersintobacco- high-risk smoker. Thesestudieswillidentifyand els underexperimentalprotocolsthatmimicthe of treatmentinplace ofmorelong-termoutcomemeasures, such astimetotumorprogression,remission, ordeath. infrastructure toimprovetreatmentoftobaccouse.$2.00M Enhance theCancerInformationService’s smokingcessationservicesandresearch based lungcancertreatments.$10.00M Support interdisciplinarystudiestoacceleratedevelopmentofnew, molecularly $3.00 M Provide supplementstoaddressdisparitiesinclinicalcareoftobacco-relatedcancers. harm. $10.00M understand thenatureandimplicationsoftobaccoproductsintendedtoreduce Support studiesofthemechanismssusceptibilitytotobacco-relatedcancers vulnerability tosmokingdependenceandtobacco-relatedcancer. $6.00M resources toinvestigatethegenetic,biological,andbehavioralfactorsinfluencing Support clinicalandpopulationstudiesthatincludetissuebiospecimen tobacco-related cancers. centers. $5.00M elucidate thegeneticsofsmoking,incollaborationwithotherNIHinstitutesand Support innovative,population-basedstudiesinvolvingawholegenomeapproachto efforts focusedontobaccouseandcessation,includingInternetstrategies.$1.00M public andprivateorganizations todevelop integratedandcoordinatedcommunication C co use,cessation,andrelapse.$3.00M Provide supplementstofurtherourunderstandingofdisparitiesinpatternstobac- prevention, andcessationinterventionstounderservedpopulations.$3.00M Support theidentification,development,anddisseminationofeffective tobaccouse, ollaborate withtheCentersforDiseaseControlandPreventionotherrelevant 1 for tobacco-relatedcancersinanimalmod- preclinical andclinicalstudiesto . Thepre- CT todetectearlylungcancers. Screening Study NCI isalsosupportingthe chemopreventive studies. examined withregardtotheirpotentialutilityin spiral computedtomography(CT)scan,arebeing the as markers aswellimagingmodalities,such cohorts offormersmokers.Avarietynovelbio- the efficacy ofchemopreventiveagentsinspecified A Planand BudgetProposal for FiscalYear 2004 to assessthefeasibilityofspiral T tl$76.00M otal f adiseaseortheeffects National LungCancer 2 $ 0.50M

97 ADDRESSING AREAS OF PUBLIC HEALTH EMPHASIS Public and Private Partnerships and Collaborations In support of tobacco research collaborative efforts, NCI is: ■ Supporting seven Transdisciplinary Tobacco Use Research Centers in partnership with the National Institute on Drug Abuse (NIDA) and the Robert Wood Johnson (RWJ) Foundation to integrate tobacco-related research on genetic susceptibility, sociocultural factors, innovative treatments, and healthcare policy. ■ Facilitating an NCI/NIDA Working Group on Medication Development for Nicotine Addiction to develop targeted new treatments. ■ Partnering with 10 other public and private organizations to develop a “National Blueprint for Disseminating and Implementing Evidence-Based Clinical and Community Strategies to Promote Tobacco-Use Cessation.” ■ Organizing and sponsoring a Women, Tobacco, and Cancer Conference with the NIH Office of Research on Women’s Health, the DHHS Office of Women’s Health, the American Cancer Society, the American Legacy Foundation, and others. ■ Sponsoring a National Tobacco Monitoring Research and Evaluation Workshop, in November 2002, along with the Centers for Disease Control and Prevention, RWJ Foundation, and American Legacy Foundation, to improve the utility of tobacco use surveillance systems. ■ Participating in NOTURF (National Organization for Tobacco Use Research Funders), a consortium of research funding organizations in the United States and Canada dedicated to fostering commu- nication and action around tobacco research.

Understanding the Interplay Among of lung adenocarcinoma; lung cancer in young peo- Tobacco, Other Exposures, and Cancer ple, non-smokers, and families; and rarer tobacco- NCI is pursuing research opportunities to better related tumors such as pancreas and nasal sinuses. understand the interplay among tobacco and other Efforts are underway to collect tissue from a exposures such as alcohol and radon, and a person’s broader group of PLCO participants to allow high cancer risk. This work involves resource intensive, throughput analysis of new markers of patients longitudinal, screening, and cohort studies that may with specific cancers. involve genetic and biomarker components from tissue, blood, urine, sputum, and other body fluids. Additional relevant studies are yielding information on cancer risk related to the interplay among Several studies within the Prostate, Lung, tobacco and other exposures. In a case-control Colorectal, and Ovarian (PLCO) screening trials interview study on patients with esophageal cancer, are specifically focusing on tobacco exposure and researchers found a three-fold excess risk for the cancer. These studies are examining the relation- disease among those in the highest quartile of body ship between tobacco and colon adenomas, a com- mass index, a predisposition of obese individuals to parison of patients with emphysema, and a control gastroesophageal reflux disease, and an association group (persons without cancer or related symptoms) between esophageal cancer and cigarette smoking, to identify genetic factors that may influence sus- with little reduction in risk until 30 years after ceptibility to this condition. Another investigation smoking cessation. A large case-control study will target current and former smokers to identify of bladder cancer is ongoing in the New England candidate genes thought to influence smoking. region of the United States and Spain to identify occupational bladder carcinogens and to evaluate The Cohort Consortium,3 a group of investigators cigarette smoking (black vs. blond tobacco in Spain) involved in separate prospective studies of large as well as phenacetin-containing analgesics, dietary population groups, will expand their investigation factors, urination frequency, and pH. Genetic suscep- beyond looking at breast and prostate cancer to tibility markers will be evaluated in relation to identifying and studying tobacco-related cancers. bladder cancer risk as well as their interaction with These researchers will investigate a rare subtype environmental, occupational, and tobacco risk factors.

3 See page 49.

98 The Nation’s Investment in Cancer Research * SeealsoTable ofContentson page2formajortopicscoveredinthis document. genitourinary cancers,20,32. gene expressionarray, 54 gastrointestinal stromaltumors,37,68 gastrointestinal cancers,32,35,36,37,68. exercise andcancer, 8,53,90 Ewing tumors,45 esophageal cancer, 19,23,53,94,98 endometrial cancer, 53 diet andcancer, 8,16,21,23,40,52,53,64,72,73,75,76, colorectal cancers,8,9-10,11,16,17,19,35,36,37,40,49, childhood cancers,12,13,21,37,44,45,61,88,91,92,93, chemotherapy, preventionandtreatment,11,15,37,64, cervical cancer, 8,11,13,17,53,64,68,82,84,85,86,94 breast cancer, 8,9,10,11,12,15,16,19,20,22,32,37,49, brain tumors,15,19,20,21,32,35,68,69,88 blood systemcancers,20. bladder cancer, 19,22,53,63,94,98 alcohol andcancer, 23,49,53,95,98 aging andcancer, 8,12,21,46-47,77,79,88,90 head andneckcancer, 20,33,35,63. gynecologic cancers,18,19,20. genomics, 15,17,18,42,43,49,51,53,61,64 immune systemandcancer, 10,56,60,64,70,86,90,91, lung cancer, 8,10,11,13,18-19,20,33,35,50,53, 54,59, liver cancer, 53 leukemia, 10,13,17,19,20,21,35,36-37,44,54,64,71, laryngeal cancer, 53,94 kidney cancer, 11,17,19,22,53,71,94 Index ofSelectedTopics* cer. tal cancers,gastrointestinalstromaltumors,stomachcan- 83, 85,90,93,98 51, 52,53,59,63,66,68,69,79,82,85,98 95 69, 73,82,88,91,92,97. 81, 82,85,86,88,92,98 50, 51,52,53,54,59,61,63,64,66,69,71,72,74,76,79, myeloma. endometrial cancer, ovariancancer. 93. supraglottic cancer. cer, mouthcancer, oralcancers,pharyngealcancer, cancer. 63, 67,68,69,71,79,85,92,94-98. 92, 93 See also vaccines andcancer. e also See e also See e also See e also See leukemia, lymphoma, targeted therapy. e also See prostate cancer. e also See cervical cancer, e also See laryngeal can- tobacco and colorec- melanoma, 10,17,53,63,71. lymphoma, 10,12,15,17,19,20,21,33,35,44,45,52,54, vaccines andcancer, 17,61,63,64. tumor microenvironment,5,12,14,19,20,30,46,48,56-59 tobacco andcancer, 8-9,17,19,21,22,23,33,35, 49,53, testicular cancer, 52 targeted interventions,5,9-11,13,15,17,20,22,30,33, surgery, 10,13,15, 22,36,47,59,65,69,82 supraglottic cancer, 68 stomach cancer, 13,19,20,23,53 socioeconomic statusandcancer, 13,79,85,86,92 skin cancers,20,33,35. sarcomas, 20,71. rhabdomyosarcoma, 45 radiation therapy, 13,21,36,47,61,63,64,65,67,69,73, proteomics, 14,15,17,18,22,28,45,54,57,58,59,62,64. prostate cancer, 9-13,15,19,20,22,33,35,40,50,51,52, progress reviewgroups,16,18-23,27,29,30,60,68,94 pharyngeal cancer, 53 pancreatic cancer, 9,11,12,19,20,21,32,51,52,61,63, ovarian cancer, 9,10,15,20,33,35,45,52,54,59,69,79, oral cancers,59 neuroendocrine cancers,71 neuroblastoma, 45,61,71 nervous systemcancers,20 nanotechnology, 15,56,65,69 myeloma, 19,20,21,63,71 mouth cancer, 53,94 molecular targets. molecular profilingofgenesandproteins,9,20,49,52,54, minorities andcancer, 4,8-9,12-13,16-17,22,23,31,33, microenvironment. mesothelioma, 11 63, 70-71,88 and cancer. 69, 72,73,77,83,85,90,92,94-98 36-41, 44,47,48,54,57,58,59,60-64,91 79, 85,91 also See 53, 54,58,59,61,63,66,68,71,79,82,85,98 94, 98 82, 98 56, 59,60. 39, 75,76,77,79,81,83,84-87,90,92,95,97 molecular profilingofgenesandproteins. e also See e also See See See A Planand BudgetProposal for FiscalYear 2004 gene expressionarray, proteomics. targeted interventions. tumor microenvironment. e also See rhabdomyosarcoma. e also See melanoma. e also See skin cancers. immune system

99 INDEX OF SELECTED TOPICS Acknowledgments

The following people at NCI deserve special recognition The following people and organizations outside of NCI for their contributions to the development of this document. reviewed and provided input to the draft document in the summer of 2002. ■ In the Office of Science Planning and Assessment: Cherie Nichols, Kathie Reed, Jane Lockmuller, ■ NCI Advisory Groups: National Cancer Advisory Kathy Sorrow, Marianne Kost, Bernard Glassman, Board member Ralph S. Freedman; Board of Scientific Anne Tatem, Lisa Stevens, Samir Sauma, and D. J. Joya Advisors member Nancy Mueller; Board of Scientific Counselors members Elizabeth Fontham, Laurence N. ■ NCI Priority Area Champions: Jeff Abrams, Rachel Kolonel, and Alice Pentland; Director’s Consumer Liaison Ballard-Barbash, J. Carl Barrett, Martin Brown, Kenneth Group members Kathy Giusti, Paula Kim, Barbara Buetow, Neil Caporaso, Michaele Christian, Norman LeStage, Karen Packer, Christopher G. Pablo, Henry Coleman, Robert Croyle, Brenda Edwards, Ellen Porterfield, Nyrvah Richard, and Doug Ulman; Feigal, Harold Freeman, Robert Hiatt, Robert Hoover, and Progress Review Group leaders Scott Kern and Marvin Kalt, Jon Kerner, Brian Kimes, Gary Kreps, Nicole Urban Scott Leischow, Joseph Lipscomb, Mary McCabe, Lori Minasian, Ed Monachino, Barbara Rimer, Julia ■ Cancer Centers and SPOREs: H. Shelton Earp, Rowland, Edward Sausville, Dinah Singer, John Sogn, Jane Ehrke, Stephen P. Goff, Lynn Matrisian, Edward Robert Strausberg, and Daniel Sullivan Partridge, and Kent Lloyd

■ In the Office of Budget and Financial ■ Professional and Advocacy Organizations: Management: Jim Dickens and Ngan Nguyen Alliance for Prostate Cancer Prevention, American Association for Cancer Research, American Public ■ In other NCI Offices and Programs: Jill Johnson, Health Association, American Society for Clinical John Hartinger, Donna Bonner, Donna Kerrigan, Oncology, American Society for Therapeutic Radiology Jim Mathews, and Paul LaMasters and Oncology, The Children’s Cause, Lymphoma Research Foundation, National Coalition for Cancer Other contributors at NCI included Alan Rabson, Survivorship, North American Brain Tumor Coalition, Joseph Fraumeni, Peter Greenwald, Kelly Blake, Oncology Nursing Society, Robert Wood Johnson Kevin Callahan, Buddy Clark, Larry Clark, Jim Corrigan, Foundation, and Susan G. Komen Breast Cancer Barbara Croft, Andrea Denicoff, Marilyn Duncan, Kay Foundation Flemming, Leslie Ford, Barbara Galen, Louise Grochow, Ernie Hawk, John Hoffman, Jim Jacobson, Gary Kelloff, ■ Other Reviewers: Martin Hauer-Jensen, Deborah Elaine Lee, Allison Linden, Lance Liotta, Cheryl Marks, Mayer, Stephen Taplin, and Clare MC Tempany Susan McCarthy, Anne Menkens, Julie Schneider, Kara Smigel-Croker, Sudhir Srivastava, Tracy Thompson, ■ HHS Agencies: National Institute on Aging and the Stacey Vandor, and Paula Zeller. Centers for Disease Control and Prevention

And special thank you’s go to Suzanne Reuben of Progressive Health Systems, Sharyn Horowitz of Analytical Sciences, Inc., Rosemary Yancik of the National Institute on Aging, and Lynne Komai of The Watermark Design Office.

100 The Nation’s Investment in Cancer Research The Nation’s Investment in Cancer Research

. . . valuable rewards in cancer signatures research.

By establishing the “Signatures of Cancer” as a major priority area six years ago, NCI recog- nized that the cancer field faced an “extraordinary opportunity” that could revolutionize cancer detection and diagnosis. Studies of the molecular underpinnings of cancer revealed that every cell has a molecular signature — a unique biological characteristic that is related to the cell’s function in the body. Even more intriguing was the discovery that as a cell transforms from normal to malignant, its signature changes, and this change is a signal of the presence of cancer. We realized that by accurately “reading” the changes that distinguish a cancer cell from its normal counterpart, we could create tools to detect the earliest signature changes of cancer; enhance diagnosis by identifying a tumor according to its molecular features; and advance prevention and treatment by developing interventions that target the molecular features of a tumor. By committing the exceptional resources and developing the innovative new research programs needed to enable creative and high quality signatures research, we are able, today, to demonstrate how our Nation’s investment in cancer research is rendering dramatic changes in cancer prevention and care.

Through several ambitious initiatives, investigators are making striking progress in:

Defining the Signatures of Cancer Cells. Since 1997, Cancer Genome Anatomy Project (CGAP) scientists have worked to uncover all of the molecular information in a cancer cell and its components, including proteins. Today, they have successfully built a nearly complete tumor gene index by identifying over a million genes in more than 40 tissues. Building on this effort, researchers are annotating the types of cells and cancer that express these genes, developing catalogues of chromosomal changes in cancer, and identifying common genetic variations that influence cancer risk in various populations.

Identifying Biomarkers for Early Detection. Launched in 1999, the Early Detection Research Network (EDRN) aims to use the wealth of information coming from CGAP in the development of cancer biomarkers. Through this national research forum, scientists are working to discover, develop, and validate early markers of cancer. EDRN scientists already have successfully discovered a number of biomarkers that allow for the earlier detection of breast, prostate, colon, lung, and other cancers. NCI and EDRN scientists also have effectively applied proteomics to develop a potential screening test that uses patterns of proteins (see picture) to detect ovarian cancer.

Better Distinguishing Different Types of Cancer. The Director’s Challenge: Toward a Molecular Classification of Tumors was established in 1999 to support investiga- tors in their efforts to apply gene- and protein-based strategies in the development of new molecular classification schemes for human cancers. This information will improve our ability to accurately classify and diagnose cancer, predict prognosis, and select targeted treatments. Already, these studies are revealing new types and subtypes of cancer that appear to predict which patients will respond to particular therapies. Microarrays (see picture) are helping scientists identify tumor subtypes based on differences in gene expression.

For more information on NCI’s cancer signatures research, go to plan.cancer.gov. Valuable World Wide Web Locations Cancer Information Service (CIS)

National Cancer Institute cancer.gov By phone National Institutes of Health www.nih.gov 1-800-4-CANCER (1-800-422-6237) Department of Health and Human Services hhs.gov For deaf and hard of hearing 1-800-332-8615 Cancer News newscenter.cancer.gov Cancer Science newscenter.cancer.gov/sciencebehind On the Web From cancer.gov, click on LiveHelp.

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Access expanded content for this Plan and Budget Proposal, including links to key Websites, at plan.cancer.gov. Online links related to the chapters in this book include the following.

National Agendas for Disease-Specific Research Molecular Targets ■ Progress Review Groups prg.cancer.gov ■ Developmental Therapeutics dtp.nci.nih.gov ■ Research Initiatives cri.cancer.gov ■ Intramural Initiatives ccr.cancer.gov/initiatives

Investigator-Initiated Research Cancer Imaging and Molecular Sensing ■ Research Portfolio researchportfolio.cancer.gov ■ Biomedical Imaging cancer.gov/bip and cancer.gov/clinicaltri- ■ Research Resources resresources.nci.nih.gov als/understanding/science-explained-imaging ■ Funding cancer.gov/researchfunding Cancer Communications Centers, Networks, and Consortia ■ Extraordinary Opportunity cancercontrol.cancer.gov/eocc ■ Cancer Centers cancer.gov/cancercenters ■ SPOREs spores.nci.nih.gov Quality of Cancer Care ■ Applied Research appliedresearch.cancer.gov National Clinical Trials Program ■ Cancer Clinical Trials cancer.gov/clinicaltrials and Cancer-Related Health Disparities cancer.gov/clinicaltrials/understanding ■ NCI Center crchd.nci.nih.gov

Bioinformatics for Cancer Research Cancer Survivorship ■ Center for Bioinformatics ncicb.nci.nih.gov ■ Survivorship Research survivorship.cancer.gov

Genes and the Environment Tobacco and Tobacco-Related Cancers ■ Family Registry epi.grants.cancer.gov/CFR ■ Tobacco Research tobaccocontrol.cancer.gov ■ Genetics Network epi.grants.cancer.gov/CGN Research Training and Career Development Signatures and Microenvironment ■ Opportunities cancertraining.nci.nih.gov ■ CGAP cgap.nci.nih.gov ■ EDRN cancer.gov/prevention/cbrg/edrn Emerging Trends in Cancer ■ Director’s Challenge dc.nci.nih.gov ■ Progress Report progressreport.cancer.gov ■ Mortality Maps cancer.gov/atlasplus ■ SEER seer.cancer.gov

Ordering this document Telephone Assistance for Smoking Cessation By email [email protected] By Internet cancer.gov/publications Through the Cancer Information Service (CIS) at 1-800-4-CANCER, By phone 1-800-4-cancer NCI provides telephone-based assistance for smokers who want to By fax 1-301-330-7968 quit. Callers in the United States, Puerto Rico, the U.S. Virgin Islands, and territories in Guam and Saipan can speak with someone in English or Spanish.

Smoking cessation service representatives: ■ Assess the caller’s individual smoking behavior. ■ Provide brief educational messages. ■ Help callers develop a personalized action plan for quitting. NATIONAL INSTITUTES OF HEALTH ■ U. S. Department of Health and Human Services Reinforce the information with written materials.

NIH Publication No. 03-4373 October 2002 T290