WilliamREPORT Guy Forbeck Research Foundation VOLUME 18 / SPRING 2003

From The Chairman’s Desk SCIENTIFIC ADVISORY The most produc- Moritz Ziegler to address the topic of “The BOARD REPORT tive use of cancer New Biology of Enigmatic Neuroblastoma research dollars is the and Relevant Treatment Strategies.” Cell Death and reaction that you get An Appreciation Meeting was held in Edward A Frick when the William June to thank our many loyal Lake Cancer - an Guy Forbeck Cancer Research Geneva supporters. It was held at the Intimate Link. Foundation is discussed by leading scien- Lake Geneva CC with over 250 people in Several of our meet- tific researchers. This has been the attendance. Dr. John Kemshead from ings in Hilton Head emphasis of the Foundation since it was Baxter Labs, Dr. Bruce Chabner from have focused on cell founded in 1984. With over 1,000,000 Harvard and Dr. James Stewart from the death. This may people in the United States diagnosed University of Wisconsin participated in a seem rather strange John T. Kemshead, PhD with cancer each year, making cancer dol- stimulating and informative round table as cancer is the antithesis of this; it pri- lars more efficient is vital. discussion. At the meeting Bobby Smyth marily being thought of as resulting We are beginning to understand the caus- was presented with a Trustee Emeritus from uncontrolled cell growth. However, es of cancer and to initiate new methods Award for his many years of outstanding there are two reasons for our considered of prevention, diagnosis, and treatment. service to the Foundation. focus on this topic. The first is the hope The “war on cancer” is far from being There is a very special place in our that if we understand more about cell won, but some of the battles are begin- heart for Jim and Jennifer Buchanan, and control processes then we will under- ning to turn our way. their daughter Lindsay. Jim and Jennifer stand more about cancer. The second This past year’s forum addressed a started the Homefront Bike Tour and reason is that another way in which a key topic, “ and raised over $345,000 for the Foundation. malignancy may arise is through cells Cancer”, and was chaired by Dr. Ronald Lindsay had neuroblastoma and in spite not understanding when to die. This DePinho from Dana Farber Cancer of this, was a tremendously positive young results in a mass or tumour as cells are Institute in Boston and Dr. Charles Sherr girl. Everything possible was done world- not being eliminated from the body at from St. Jude Children’s Research wide to stop this terrible disease but the right time. Hospital in Memphis. It was one of the Lindsay passed away on May 25th. Her The reasons why we do not suffer best sessions ever. The 2003 Forum topic courageous spirit will always inspire the from more cancers than we do, is in my will focus on “DNA Damage and Cancer Foundation and not a day goes by that I view down to control processes. Cells Susceptibility Syndromes” and will be don’t say a prayer for her. ...Continued on page 9 chaired by Dr. Alan D’Andrea from Dana This is the time of the year when we Farber Cancer Institute in Boston and ask for your renewed support to maintain From the Chairman’s Desk...... 1 Prof. Dr. Jan Hoeijmakers from the the momentum that has been established. Scientific Advisory Board ...... 1 Erasmus University of Rotterdam It is through your generous help that con- Forum 2002: (Netherlands). tinuing progress will be made. Cellular Senescence and Cancer ...... 2 In 1999 the foundation established Thank you for your continuing assis- Awards and Grants...... 6 the “Focus on the Future” program tance to the Foundation. Forums 2003 and 2004 ...... 8 where grants are awarded to allow the Financial Report...... 9 recipients to hold meetings similar in con- Benefactor List ...... 10 tent and format to the very successful Objectives ...... 12 Board of Trustees & annual Hilton Head Forums. The 2003 Edward R. Frick In This Issue... Scientific Advisory Board ...... 12 Focus grant was been awarded to Dr. Chairman, Board of Trustees th 2002 Forbeck Forum: XVIII Annual Forum November 7–9, 2002 Hilton Head Island, South Carolina

“Each day, I Subject: Cellular Senescence and Cancer encounter patients and I: Biology in Human Cell Systems their families whose lives II: Tumor Suppressors / Senescence Pathways are touched by cancer. III: Modeling Cancer & Cancer Genomes It is heartening to see IV: Models / Methods to Probe Senescence such dedication on your part to eliminate this Chairmen modern black plague.” Ronald DePinho, MD Harvard Medical School Boston, MA Charles Sherr, MD, PhD St Jude Children’s Research Hospital Memphis, TN Ron DePinho, MD Ron DePinho, MD Participants Judith Campisi, PhD Lawrence Berkeley National Laboratory Berkeley, CA Titia de Lange, PhD New York, NY “I thought that the Steven Elledge, PhD Baylor College of Medicine Houston, TX meeting was a great Gerard Evan, PhD University of California San Francisco, CA success. I enjoyed William Hahn, MD Harvard Medical School Boston, MA everything — the sci- ence and the venue and Gregory Hannon Cold Spring Harbor Laboratory Cold Spring Harbor, NY the socializing.” Jacqueline A. Lees MIT Center for Cancer Research Cambridge, MA Scott Lowe, PhD Cold Spring Harbor Laboratory Cold Spring Harbor, NY Charles Sherr, MD, PhD Jerry W. Shay, PhD UT Southwestern Medical Center Dallas, TX Maarten van Lohuizen the Netherlands Cancer Institute Amsterdam, Netherlands

Karen H. Vousden, PhD National Cancer Institute Frederick, MD Charles Sherr, MD, PhD

2002by Ronald A. ConferenceDePinho, M.D. & Charles J. Report Sherr, M.D. Ph.D.

This exciting and highly productive pathways influence the biological impact a permissive microenvironment for Forum focused on cellular senescence – a of oncogenic lesions such as Myc and epithelial carcinogenesis. Such senescent biological response governed by known can we forge a link to the core cell cycle microenvironment cells secrete proteases cancer-relevant pathways and thought to machinery? A discussion of these issues among other factors that have been be integral to the suppression of cancer generated more questions than answers linked to tumor progression. and the response to anti-cancer agents. and the level of discussion was so robust Dr. Titia de Lange of the Investigators from diverse areas discussed that most speakers found it challenging Rockefeller University discussed how the cellular senescence mechanism from to get past the first few slides of their abnormal telomere structure activates a the molecular, cellular and organismal talk. senescent response in mouse and human perspectives. Numerous outstanding Dr. Judith Campisi of Lawrence cells. She emphasized that, although questions were discussed including: Berkeley National Laboratory focused on there is general agreement on the involve- Does senescence represent an effective the issue of the cellular senescence is an ment of p53 in the senescence signaling mammalian tumor suppressor mecha- example of evolutionary antagonistic pathway, the data are less clear on the role nism on one hand yet drives the age- pleiotropy and presented evidence that of p16. Furthermore, the telomere dam- related pathologies on the other? Are cellular senescence in cultured cells is age signaling pathway appears to be dif- there species-specific differences in mice driven by a ferent in human and mouse cells as and humans or does this relate to exper- process linked to “This was one of the reflected in the response of these cultured imental design? What role do accumulated most stimulating and cells to alterations in telomere structure plays in suppressing or fueling chromo- oxidative stress. enjoyable meetings I’ve brought about by the expression of aber- ever attended. Many somal instability and how does this She also reviewed good ideas (and some rant telomere binding proteins. influence the initiation and progress of the evidence that collaborations) have Dr. Ron DePinho of the Dana- cancer in the organism? What are the strongly suggests already come out of it, Farber Cancer Institute and Harvard nature of the signals emanating from the that senescent and more will perco- Medical School presented his work on telomere and how is this signal mediated cells accumulate late through in the engineered mice harboring defective by damage signaling pathways in normal in normal tissues, future, I am sure.” tumor suppressor pathways and critically and neoplastic cells? How is telomerase and that these Judith Campisi, PhD shortened telomeres and how such alter- regulated? How do cellular senescence cells may provide ations impact on processing of aging and 2 cancer. He presented data showing that genes he recently identified in genetic protein in ß cells together with switch- advancing age, telomere attrition, and screens that repress telomerase expression able c-Myc. In this case, activation of c- accompanying genomic instability coop- in normal cells. Many of these were Myc triggers rapid, progressive and inex- erate to compromise the overall health linked to tumor suppressor pathways, orable ß cell neoplasia that is immediate- and well-being of mammals on the level furthering the link between telomerase ly accompanied by profound angiogene- of tissue stem cells. The telomerase and cancer. sis and local invasion. Similar oncogenic knockout mouse has provided a model to Dr. Gerard Evan of University of results are obtained upon activation of c- dissect the complex role of telomeres in California presented his elegant mouse Myc in ß cells lacking the tumor sup- cancer pathogenesis. Cancer, particular- models of cancer designed to understand pressors p19ARF or p53, although each ly epithelial carcinomas, is among the the immense complexity of the tumor type of anti-apoptotic lesion has its own most common aspects of aging in phenotype and the underlying genotype. distinct suite of attendant characteristics. humans and telomere erosion has been In particular, he delineated the issues sur- Thus, inhibition of c-Myc induced cited as a risk factor in the genesis of cer- rounding the concept of tumor establish- apoptosis, either through the mitochon- tain human tumor types. In line with ment and maintenance. He focused on drial or ARF/p53 pathway, is sufficient this view, late generation mTERC null the possibility that cancers require only a to enable Myc to induce a state resem- mice exhibit an age- and generation- very restricted complement of interlock- bling full malignancy. Subsequent de- dependent increase in cytogenetic abnor- ing mutations but which can only be activation of the switchable Myc onco- malities and a significant increase in the acquired by a circuitous and protracted protein triggers rapid and complete incidence of spontaneous cancers. To evolutionary process. A case in point is regression of all ß cell adenomas, indicat- examine the genetic interactions between the Myc oncoprotein. Deregulation of ing that Myc is required both to induce telomere dysfunction and key check- expression of the c-Myc protein repre- and to maintain the neoplastic state. He point pathways in relation to tumor for- sents an archetypical proliferation-dereg- concluded with an outline of the impli- mation, the cellular response to telomere ulating oncogenic lesion found in most cations of these data both for our under- dysfunction was examined against the human cancers. However, the potent standing of the evolution of tumors and backdrop of various tumor suppressor pro-apoptotic activity of c-Myc means for identification of useful therapeutic mutations. In p53-/- (but not Ink4a/Arf that its deregulation can only be accom- targets. or Atm-/-) mice, carcinomas emerged as modated in cells in which cell death is Dr. William Hahn of the Dana the largest class of clinically apparent being potently suppressed. They have Farber Cancer Institute presented a tumors, greatly exceeding sarcomas and explored the mechanisms by which c- provocative series of results showing that lymphomas. These epithelial cancers Myc induces apoptosis and identified a the rate limiting, telomerase catalytic emerged with complex cytogenetic pro- novel p53-independent pathway by subunit, hTERT, is expressed in primary, files similar to that seen in human carci- which c-Myc directly influences mito- pre-senescent human fibroblasts, previ- nomas, pointing to telomere dysfunction chondrial integrity. To explore the role ously believed to lack hTERT and telom- as a mechanism driving chromosomal of c-Myc-induced apoptosis in limiting erase expression, during transit through instability. Acquisition of fully malignant c-Myc oncogenesis in vivo, they con- the cell cycle. Disruption of this expres- phenotype including metastases may structed mice that harbor a switchable c- sion of telomerase inhibits cell prolifera- require telomerase-mediated telomere Myc protein targeted to specific tissues. tion, induces early entry into replicative maintenance as a late event in the evolu- These animals allow the direct examina- senescence and alters the maintenance of tion of these cancers. tion in vivo of both the immediate and the 3’ single-stranded telomeric over- Dr. Steve the delayed consequences of acute activa- hang. These observations support the Elledge of Baylor tion of the c-myc oncogene in different view that telomerase and telomere struc- College of somatic settings. Activation of c-Myc tar- ture is dynamically regulated in normal Medicine provided geted to pancreatic ß cells using the human cells and that telomere length an overview of the insulin promoter rapidly (16 hours) alone is unlikely to trigger entry into cellular response to induces ~100% sustained ß cell prolifer- replicative senescence. double strand ation in all islets, in the absence of any Dr. Gregory breaks in DNA. other growth-promoting lesion. Hannon of Cold He discussed the However, such ß cell proliferation is Spring Harbor relationship of this accompanied by overwhelming apoptosis Laboratory provid- response to the process of telomere ero- that rapidly leads to islet involution and ed exciting new sion that occurs when cells have under- concomitant acute diabetes. The clear insights on RNAi gone extensive proliferation, such as dur- implication is that ß cell neoplasia can- in mammalian cells ing the early stages of tumorigenesis. He not arise without early suppression of that build on the then discussed how cells can overcome apoptosis. To confirm the predicted use of biochemical the defects in telomere erosion by induc- oncogenic synergy between c-myc and systems from ing the catalytic subunit of human suppression of apoptosis in ß cells, we Drosophila and genetic studies in plants telomerase and described a number of co-expressed the anti-apoptotic Bcl-xL and invertebrates. ...Continued on page 4 3 2002 Forum Annual Report trols. They have identified additional Spring Harbor Laboratory presented the ...Continued from Page 3 changes in the E2F3-deficient cells that idea that the process of cellular senes- Together, these efforts have begun to are typically associated with cellular cence can be conceptualized much like reveal a mechanistic basis for RNA inter- stresses such as senescence and oncogenic apoptosis, in that both processes involve ference and related phenomena. The challenge. These include increased defined programs that can eliminate canonical model involves a two-step expression of p16INK4A, p21CIP1 and damaged cells following stress. With mechanism that includes an RNAseIII p19ARF. The increased expression of this analogy in mind, Dr. Lowe dis- family nuclease, Dicer, which initiates p19ARF is particularly surprising given the cussed several issues, including: (1) fac- RNAi by processing dsRNA silencing prevailing view that p19ARF is an E2F- tors that influence the decision to apop- triggers into small RNAs of ~22 nt in responsive gene. In addition, p53 tose or senesce; 2) how different stress length. These enter an effector complex appears to be activated in the E2F3-defi- signals are integrated into a common RISC, which seeks out and degrades cient cells, revealing significant cross-talk arrest program; and (3) the molecular homologous substrates. Genetic studies between the E2F and the p53 pathways. mechanisms that drive senescent cells of Dicer-null animals (i.e., C. elegans) We have generated E2f3:p19ARF, into an apparently irreversible cell cycle have suggested roles for the RNAi E2f3:p16INK4A and E2f3:p53 compound arrest. He also discussed how disruption machinery in the regulation of endoge- mutant mice to investigate how this of specific nodes in tumor suppressor nous genes. Specifically, Dicer and com- interplay is mediated and how it con- networks can influence cellular respons- ponents of the RISC complex have been tributes to both cell cycle control and es to cancer chemotherapy. In particular, implicated in processing of and in gene tumorigenesis. She presented consider- Lowe and colleagues have shown that a regulation by endogenously encoded able progress in establishing the proper- senescence program controlled by p53 small hairpin RNAs, known collectively ties of the double mutant MEFs (DKOs). and p16INK4a contributes to treatment as microRNAs (miRNAs). The Hannon The homozygous mutation of either outcome in vivo, and that these proteins group exploited these observations to test p19ARF or p16INK4A does not affect either act in a cooperative manner to engage the possibility that miRNAs might be the up-regulation of p21CIP1 or the pro- the cell-cycle arrest program. In parallel, remodeled to regulate genes of interest. liferation defect of the E2F3-deficient they have also identified an important They demonstrated that expression of cells. In contrast, the inactivation of p53 role for the Rb tumor suppressor in the shRNAs from RNA polymerase III or specifically suppresses the inappropriate process by which RNA polymerase II promoters results in expression of p21CIP1, but not p16INK4A senescent cells are silencing of homologous genes and have or p19ARF, indicating that the changes in maintained in a recently extended these findings to living p21 expression are predominantly p53- state that is non- animals. They continue to pursue parallel dependent. Surprisingly, the inactivation responsive to paths toward a deeper understanding of of p53 and resulting reduction in p21 mitogens. the underlying mechanism of RNAi and levels did not suppress the proliferation Dr. Jerry Shay toward expanding the applications of defect of the E2F3-deficient cells. of the UT RNAi as a tool for investigating gene Moreover, E2f3:p19ARF, E2f3:p16INK4A Southwestern function in mammals. and E2f3:p53 DKOs that have been Medical Center Dr. Jacqueline Lees of MIT Center transformed with rasV12 show similar used the example of neuroblastoma (IVS) for Cancer Research reviewed the com- impaired proliferation when tested in to discuss the relationship between plexity of the RB-E2F signaling network either focus formation or soft agar colony telomeres, senescence and telomerase. in normal and cancer cells. Through the assays. Importantly, however, E2F3-loss Two important concepts emerged, first analysis of various E2f mutant mouse did not affect the well-documented, telomerase is not needed for the initiation strains and the resultant E2F-deficient of cancer but a mechanism to maintain immortalized phenotypes of the p19ARF, mouse embryonic fibroblasts (MEFs) has telomeres is required for the long term p16INK4A and p53 mutant MEFs. She demonstrated that E2F3 as a key inducer progression of all human cancers. Other therefore concluded that p19ARF, of cellular proliferation. E2F3 acts in a topics covered by Dr. Shay included: 1. Is p16INK4A or p53 act upstream of E2F3 in dose-dependent manner to induce the progressive telomere shortening in the control of cellular proliferation but cell cycle dependent expression of almost human cells a mechanism to prevent can- downstream of E2F3 in the control of all known E2F-responsive genes. The cer or a cancer-initiating mechanism cellular senescence. Her program contin- reduced expression of one or more of leading to increased genomic instability? ues to investigate these E2F3-regulated genes delays pas- 2. What is the evidence that telomere how E2F3-loss sage through the G /S transition and sig- shortening is important in chronic 1 results in the acti- nificantly reduces the rate of DNA syn- human diseases leading to increased sus- vation of p53 and thesis. As a result, E2F3-deficient MEFs ceptibility to cancer? 3. What are the the induced expres- have a major defect in their ability to re- most promising approaches for inhibiting sion of p16INK4A enter the cell cycle in response to mitogen telomerase for use in cancer therapeutics? and p19ARF. stimulation and proliferate at a markedly 4. What is the evidence for alternatives to Dr. Scott telomerase for telomere-maintenance and reduced rate relative to wild-type con- Lowe of the Cold 4 how can we investigate these mecha- this activity), our unpublished results activity of p53 is nisms? In particular, he reviewed evi- reveal that Myc-induced apoptosis does key for tumor sup- dence that cell grown in typical culture not require E2F1 activity. pression, and is conditions are exposed to a continuous Dr. Maarten van Lohuizen of the likely to be an state of oxidative stress that may not be Netherlands Cancer Institute presented effective activity to representative of cells in vivo. This oxida- his studies on the regulation of target for restora- tive stress leads to increased ROS that INK4a/ARF tumor suppressor locus in tion by new thera- may be sensed by p16 leading to a growth normal and neoplastic cells. The pies. It is therefore arrest state that mimics replicative senes- INK4a/ARF tumor suppressors are now of interest to cence. Many “stressors” including well established as an important cancer- understand the mechanisms that deter- oligonucleotide-based cancer therapies, prevention mechanism by halting cell mine the outcome to p53 activation. A ectopic over-expression of genes, irradia- cycle progression upon different kinds of therapeutic approach in tumors that tion, as well as inadequate culture condi- stress signals, such as activation of onco- retain wild type p53 is to inhibit HDM2 tions can induced this premature senes- genes. The INK4a/ARF locus is under - the ubiquitin ligase for p53 - and so sta- cence (stasis, culture shock) state. He stringent control (strongly repressed in bilize p53. It remains unclear, however, emphasized that these effects have largely normal cells) and there is evidence for how tumor cells will respond to such been misinterpreted as fundamental bio- different ‘threshold levels’ for Arf in treatment. Small molecules with this logical mechanisms involved in regulat- mediating ‘stasis/senescence’ arrest and activity would, to some extent, mimic ing cellular senescence that are telomere suppression of oncogenic transforma- the function of HMD2-binding proteins length independent. He articulated the tion. Therefore, important questions to like ARF and L11. Interestingly, their view that the analysis of the mechanisms be answered further are how is the preliminary work has suggested that p53 of signal transduction, regulation of gene INK4a/ARF locus regulated and do we responses induced by ARF and L11 are expression, proliferation, senescence and know all the downstream effectors of not the same, and understanding the death may be compromised by the failure INK4a/ARF signaling? He and his col- basis for these differences will contribute to consider the environment in which the leagues approached these issues by gener- to the development of new therapeutics. cells are propagated. ating INK4a/Arf reporter constructs and In closing, the Forum resulted in an Dr. Charles Sherr of St Jude by developing genetic screens in primary extremely robust exchange among the Children’s Research Hospital discussed cells to bypass stasis/senescence. Another participants. Several attendees remarked the family of INK4 protein in cell cycle relatively unexplored issue of interest is a on how effective the Forum was in com- regulation and cancer suppression. He possible role for the INK4a/ARF fail-safe municating new unpublished informa- reported that, among the family of four during development. Such connections tion and ‘out-of-the-box’ thinking that INK4 proteins, only one (p16INK4a) are suggested by the transcriptional regu- will no doubt stimulate new lines of has been frequently linked to cellular lation of INK4a/ARF by developmental basic research and new opportunities for senescence and tumor suppression. In regulators such as Polycomb repressors cancer intervention. The regulation of mice, the four proteins are expressed in and TBX2/3. These connections are of telomeres and telomerase play a critical different patterns, with p18INK4c and special interest to cancer in light of the role in determining genomic stability p19INK4d being detected during devel- emerging role for Polycomb repressors in and replicative lifespan. opment in utero, and with p16INK4a controlling the balance between differen- The work discussed at the forum will the and p15INK4b being induced in cul- tiation and proliferation (self renewal) of participants to re-investigate some of the tured cells in response to stress, and in precursor cells/stem cells. paradigms that describe how telomere mice in haphazard patterns as they age. Dr. Karen H. Vousden reviewed the maintenance regulates replicative senes- The so-called “Rb pathway” (p16 — p53 response indicating that cell cycle cence. Further studies promise to incor- cyclin D/Cdks — Rb family) is not lin- arrest and apoptosis reflect separable porate observations not easily explained ear, because p27 and p21 are normally functions of p53 that can be controlled by prior models of telomere function sequestered into cyclin D/Cdk complex- independently. Several mechanisms that and to help define how this knowledge es and these Cdk inhibitors are “mobi- contribute to the choice of response can be exploited to better understand lized” by INK4 proteins to block cyclin induced by p53 have been identified, and treat cancer. E/Cdk2 and cyclin A/Cdk2 activity. including differential expression of cell Ronald DePinho Finally, both INK4a and ARF are active- cycle arrest and apoptotic target genes, ly suppressed during embryonic develop- and selective inhibition of expression of ment. Although ARF is an E2F-respon- cell cycle arrest targets. p53-mediated sive gene, it is not periodically expressed induction of proteins with anti-apoptot- 2002 Forum Chairmen: during the cell cycle, implying that its ic activity may also contribute to the Ronald DePinho, MD promoter is insulated from responding overall choice of response. The apoptotic Charles Sherr, MD, PhD to transient signals. Although some have “I go to a lot of scientific meetings and really this was one of the most useful suggested that Myc and E2F1 regulate and productive ones that I have attended. I think you are making a fabulous apoptosis by inducing ARF (and even contribution to cancer.” that Myc may depend upon E2F1 for Karen H. Vousden, PhD 5 GRANTS and AWARDS: “FOCUS on the FUTURE” PROGRAMS:

The William Guy Forbeck Research California. Jan was the first to Foundation is pleased to sponsor two show that it is p53 that responds programs to further the advance of can- to telomere dysfuction and also cer research. identified ATM as the upstream The “Scholar Award” recognizes prom- kinase responsible for p53 activa- ising young scientists working in this tion, and more recently, discov- ered that replicative senescence is field. “Focus meeting” grants are induced by a change in telomere designed to give other researchers an 2002 Scholars: Alison Bertuch, Jan Karlseder, Masashi Narita status, not complete loss of telom- opportunity to conduct their own meet- eric DNA as was previosly thought. Jan ing along the lines of the Foundation’s 2002 SCHOLAR AWARD was nominated by Titia de Lange, PhD annual Forum. More information can from the Rockefeller University. Dr. de be found on our web site at wgfrf.org. The Foundation received a number of Lange said Jan “has a strong intererst in very qualified applications for the 2002 pursuing similar problems for the future Forbeck Scholar Award. The Scientific The FORBECK SCHOLAR AWARD as an independent investigator. He is a Advisory Board selected three outstanding very interactive and outgoing contributor young scientists to attend the 2002 Forum The Foundation looks for outstand- at meetings and always initiates interesting and receive this award. discussion by asking probing questions.” ing clinician or post-doctoral fellows We were pleased to present this year’s with an interest in cancer research. Scholar Award to three candidates. “Interaction between the participants was Award recipients are invited to attend Alison Bertuch, MD, PhD is an impressive and constructive, and the surround- the Foundation Forum held in assistant professor in Pediatrics at Baylor ings were wonderful. I was deeply moved by the College of Medicine in Houston, Texas. way you converted something tragic into some- November in Hilton Head Island, thing so positive.” Jan Karlseder South Carolina. A $1,000 contribution She obtained her B.S. from MIT and her is made to each award recipient’s insti- M.D. and Ph.D. from the University of Masashi Narita, MD, PhD is a post Rochester. Alison was nominated for the tution. Nominations are made by letter doctoral fellow at Cold Spring Harbor Foundation Scholar Award by David Laboratory in New York. He received his of recommendation from the applicant’s Poplack, MD, who said “Dr. Bertuch is an director of studies, including a short M.D., and Ph.D. from Osaka University intelligent, highly motivated and driven School of Medicine in Japan. Masashi synopsis of the applicant’s research individual. She has demonstrated the was nominated by Scott Lowe, Ph.D. and interest and a brief explanation of why ability to approach medical problems with currently works in Dr. Lowe’s laboratory. this individual is recommended. scientific inquiry and has a strong inclina- His interest is in cellular senescence and tion to pursue problems that ultimately Nominations are due in the spring of he hypothesized that, as during apoptosis, relate to patient care. She has keen ana- each year. different stress-inducing stimuli might lytical abilities, and a single-minded inter- induce senescence through a common est in molecular aspects of oncology.” FOCUS MEETING GRANTS mechanism, leading to activation of a Alison’s research interest focuses on Ku, a ‘senescence machinery.’ In a series of cell protein shown previously to be critical for biology experiments, Masashi showed The activities of the Foundation DNA repair which, paradoxically, also that changes in heterochromatin accom- have been expanded by offering grants to functions at telomeres. Using yeast as a support small “Focus Meetings” to be model system, she has performed a pany senescence, including a redistribu- modeled on the annual Forum held in detailed mutagenesis of Ku, which has tion of HP1 proteins and K9methyl his- Hilton Head. The significant variation is enabled her to dissect its roles at the tone H3. Regarding certain studies in his lab, Dr. Lowe says “Masashi has been the that this forum is proposed and organ- telomere versus at DNA breaks. single driving ized outside the Foundation and is based “Attending the 2002 Forum was an extremely force behind gen- “It was scary experience, on a competative application process. valuable experience. Having the opportunity to erating these and so it was extremely The Foundation is interested in sponsor- meet such a distinguished group of scientists and results, and has precious experience for ing small interactive meetings which discuss my work and future goals with them was worked tirelessly me. I am learning and very special. I left with an even stronger deter- learning everyday (of focus on developing strategies which will mination than ever to extract from all of this for two years to course learning English improve our understanding of cancer great science its specific application to pediatric get to this stage.” too), and this forum and cancer therapeutics, and where there oncology with the hope that it will make the dif- Forum partic- was so inspiring, ference in the lives of children in the future.“ ipants have agreed encouraging, and big is a clear interchange of ideas between step for me. I really feel scientists and clinicians. Applicants Alison Bertuch these scholars add like I have changed a to the dynamic identify a topic, venue, date, and take little after the forum.” interaction of the Jan Karlseder, PhD is an assistant Masashi Narita responsibility for organizing the meeting. Forum. professor at the Salk Institute in La Jolla,

6 2003 FOCUS on the FUTURE GRANT AWARD

In the 5th year of the Focus program, the Foundation Scientific Advisory Board reviewed grant applications and awarded the grant to Moritz M. Zeigler, MD, Children’s Hospital, Boston.

The New Biology of Enigmatic Neuroblastoma And Relevant Treatment Strategies March, 2003 Neuroblastoma remains the most frequent solid abdom- tasizing malignancy to a mature and benign ganglioneuroma. inal and thoracic malignancy of childhood, a tumor charac- Second, it has the potential to undergo spontaneous regres- terized by an aggressive behavior and a dismal outcome. sion, and even frank disappearance, despite an original large Therapeutic strategies have historically emphasized aggres- and even disseminated tumor burden. sive multimodal therapy, and the marginal improved prog- As investigators have sought to understand this biologi- nosis seen in the last several years has depended on the accel- cal behavior, a series of specific areas of investigation have eration and further intensification of such treatment. Such a evolved that will serve as the focus for this meeting. They strategy is contradictory to the observation that the diagno- include a delineation of the immunobiology of neuroblas- sis of low stage neuroblastoma is possible by mass population toma, a definition of signaling mediators, receptors, and screening, and low stage patients have a worse outcome in their mechanisms, the study of angiogenesis, angiogenic the face of more aggressive therapy. Furthermore, despite its inhibitors, and their potential linkage to signaling as well as poor prognosis, neuroblastoma is that tumor characterized the immune response, and the investigation of the genetic by two uniquely enigmatic, yet favorable, behaviors. First, it analysis of neuroblastoma as well as the putative application can spontaneously or by exogenous manipulation be stimu- of gene therapy as an effector for these various treatment lated to change its phenotype from an aggressive and metas- strategies.

2002 FOCUS SUMMARY REPORT Tumor specific immunological memory as a tool in cancer treatment Chairmen: the workshop, issues such as differentiation, homeostasis and Prof. Volker Schirrmacher and Dr. Philipp Beckhove functional characteristics, migration, homing to tumors and German Cancer Research Ctr, Heidelberg, Germany lymphoid tissues and redistribution of such memory T cells, April 24-27, 2002 - Deidesheim, Germany as well as their interactions with B cells and dendritic cells were discussed lively and controversy. The underlying expert The meeting intended to introduce a new field of cancer presentations provided the basis for these discussions and the immunology to an interdisciplinary group of outstanding consecutive lectures on issues related with clinical applications experts, both basic scientists and clinicians who cover all of such cells. The meeting enlarged profoundly the experts major aspects of the topic from basic immunology to prob- knowledge and understanding of the subject and led to a vari- lems related to the clinical application of new immunother- ety of scientific and clinical cooperations. apeutic approaches. The meeting was focused on the inter- disciplinary exchange of expertise in order to accelerate sci- Summary entific progress and to draw up future clinical applications. I. Memory T lymphocytes, dendritic cells, chemokines and T cell trafficking In the past, a number of tumor-associated-antigens II. Lymphocyte recirculation and homing in lymphoid and peripheral tissues III. Systemic role of homeostatic chemokines in adaptive immunity (TAAs) have been characterised to be capable of initiating IV. TCR-Repertoire-analysis of tumor-reactive T cells in cancer patients autologous and allogeneic T-lymphocyte responses against the V. Autologous B-lymphocyte responses to solid tumors; Serex-method respective tumors. Thus, TAA-reactive T cells may be potent VI. Tumor-associated antigens of solid tumors; autologous T cell immunity agents for cancer treatment. It has been recently demonstrat- VII. T cell monitoring in infectious and malignant diseases ed that cancer patients are able to generate high frequencies of VIII. Adoptive T cell therapies tumor-reactive T cells. Isolated and re-activated in vitro, these IX. Clinical application and monitoring of specific cellular immunotherapies cells exert potent anti-tumor functions in vitro and in vivo. Thus, clinical application of memory lymphocytes may For additional information, contact become potent a potent tool in cancer treatment. Throughout the meeting chairmen or the Foundation.

7 FORUM PLANNING

2003 Forum: DNA Damage and Cancer 2004 Forum: Targeted Therapies in Pediatric Susceptibility Syndromes Malignancies The Forbeck Foundation Forum in 2003 will be The Forbeck Foundation Forum in the year 2004 will chaired by Dr. Alan D’Andrea of the Dana Farber be co-chaired by Drs. Charles Sawyer from University Cancer Institute in Boston and Dr. Jan Hoeijmakers of of California at Los Angeles, and Gary Gilliland, the Erasmus University in Rotterdam. The topic for Howard Hughes Medical Institute and Brigham & the forum will be “ DNA Damage and Cancer Women’s Hospital, Harvard Medical School. The Susceptibility Syndromes”. The important role that theme for the forum will be “Targeted therapies in DNA damage plays in cancer development is illustrat- Pediatric Malignancies.” This topic pertains to the new ed by the clear connections between exposures to cer- quest of utilizing molecular and genetic information tain types of DNA damaging agents in the environ- about cancer to specifically design treatments which ment and the development of cancer, such as the links target functionally important molecular lesions. In the between cigarette smoking and lung cancer or sunlight past several decades enormous quantities of informa- exposure and skin cancer. In addition, the majority of tion have accumulated regarding the precise mutations inherited syndromes characterized to date that lead to which either activate or disrupt genes in many human increased cancer development in families result from cancers. In some cases this information has permitted inherited mutations in genes that are important for new classification of cancers, and the molecular abnor- DNA damage responses. For example, inherited muta- malities have become central to the diagnosis of specif- tions in either the Brca1 or p53 genes results in a very ic tumors. While large strides have been made in the high risk of developing breast cancer and both of these identification of gene abnormalities in cancer, thera- gene products are important for helping cells respond peutic advances have not been as forthcoming. This to various types of DNA damage. The genes mutated stems largely from the fact that traditional cancer ther- in certain rare diseases that affect children, such as apies have been employed prior to a complete under- Fanconi’s Anemia, Ataxia-telangiectasia, and standing of the mechanisms through which they work Xeroderma Pigmentosum, all play roles in cellular or the cellular targets which they attack. The “Targeted responses to DNA damage and children with these dis- Therapy” concept stems from the goal of developing eases have very high incidences of certain cancers. cancer treatments which specifically focus on disrupt- Studies of the genes mutated in these diseases have led ing molecules within cancer cells which are known to to a much better understanding of how all cells respond be central to the malignant behavior of the cell. Such to DNA damage and even more importantly to insights targets have included activated oncogenes such as Abl, about how cancers develop. In addition, since radia- a factor whose inhibition by the drug Gleevec has pro- tion therapy and most chemotherapies used to treat duced dramatic remissions in certain forms of cancer cause DNA damage, understanding how these leukemia. The discussion at this Forum will focus both gene products operate provides new ways to approach on the identification of targets as well as in strategies to the treatment of cancer. The discussions at the forum design drugs capable of inhibiting them in order to will focus on how these gene products function, how convert the information learned about cancer into ther- they contribute to cancer development, and how they apeutic advances. can be manipulated to improve cancer therapies. WEB SITE - www.wgfrf.org FOUNDATION VIDEO (DVD) AVAILABLE The Foundation web site contains general informa- A video presentation “showing” the history, purpose tion, a summary article on each of the Forums organ- and activity of the Foundation is available by con- ized by the Foundation, information about “Focus on tacting the Foundation. Please specify VHS video the Future” awards and grants, and several web site or DVD format. “pointers” for more information on cancer.

8 ...ContinuedScientific Advisoryfrom Page 1 Board Report 2002 FINANCIAL REPORT must have multiple ways of controlling their growth and function and The accounting firm of Cherry, Bekaert and there must a great deal of redundancy built into the overall control Holland audits the Foundation’s financial records process. When these control processes fail then a tumour may arise. annually. The above reasoning is why so many of our Foundation meetings The Foundation has established a very sound finan- have focussed on and cell death. In the past we have held a cial position. Steady growth in income has allowed meeting on programmed cell death or apoptosis. This is a particular cell the Foundation to expand its program, primarily process leading to cell’s death, and it often occurs as a result of cellular through the funding of “Focus” grants. The damage. However, this topic is not necessarily relevant to cells dying of Trustees continue to aim at a very high mark - that old age. Cells, like our bodies, age and then die. Each cell type within us 90% of the total expense goes directly to support appears to have a finite life and this differs from cell to cell. For example scientific programs. red blood cells have a half-life of about 120 days, the cells lining of our BASIS OF SUPPORT intestines turn over very quickly whereas our nerve cells live for many The William Guy Forbeck Research Foundation years. Understanding, natural cell senescence or cell aging, the topic of desires and has a broad base of support. Of major our 2002 meeting, can hopefully give important clues as to what goes significance to the Foundation are the contribu- wrong when cells do not die at the right time in the right way. tions from many individuals and their families. Over the last two decades we have made phenomenal progress in Many people have chosen to use the Foundation as understanding the process of cell death. We know that there are mecha- a fitting memorial gift. A number of corporations nisms that protect our chromosomes from damage throughout the life of and other foundations have also supported the the cell. In addition, year by year we are learning about the complexities Foundation with contributions, some having very of the pathways that function to tell our cells to either divide, remain rigorous qualifications for grants. active and functional or die. These topics were reviewed in depth, during A significant increase in income 1997-2001 was the 2002 meeting along with discussions as to how one might interfere due to the 5-year pledge of support of the with these pathways. For those of you who want a little more detail a Homefront Bike Tour. report of the meeting is included in this newsletter. EXPENSES 2002 It is hard to imagine the complexity surrounding our bodies. These Historically, 85%-90% of the total expenses go are made up of not just millions but trillions of cells. Each of these cells directly to supporting the annual Forum and appears to understand that it has a function and it normally undertakes Foundation projects. Membership information this until the time comes when it is eliminated. When one considers that costs include the annual newsletter, member mail- cancers are though to arise from errors in just one cell it is remarkable ings, and the video. that the disease is not more prevalent. The Foundation has no paid employees, and the The pharmaceutical companies are ploughing ahead, trying to iden- trustees participate at their own expense. tify targets for drugs within the cell that can control cancer. One good Administration expenses include auditing costs, as example of this is Glevac, a drug that has been developed that works in well as printing and postage expense. chronic myeloid leukaemia. This recognises a particular target within the Members of the Scientific Advisory Board attend cancer cells and blocks their ability to divide. The incredible thing about the Forum meeting in Hilton Head and hold their Glevac is that is appears to have little effect on normal cells within our annual meeting at that time. The SAB provides the bodies. Clearly, now that proof of principle has been demonstrated, a technical direction for the Forum and the massive effort is being made, by the drug companies, to identify other Foundation. molecules that can block the division of different cancer types. However, Projects funded during 2002 include the Scholar as indicated above the complexity of the machinery of the cell is Award and funding one Focus meeting grant. immense. This is the prime reason for continuing to encourage research by academics, clinicians, biotechnology companies and the pharmaceuti- S cal industry. Bringing individuals from these disciplines together is just as AdministrativeForum Forum important as it was when the Foundation was formed nearly two decades 7% 54% 54% ago. So much progress is being made but more remains before we can say we have cancer under control. Scientific Advisory A Board 8% MembershipM Funded John T. Kemshead, PhD Projects Chairman, Scientific Advisory Board Information 16% 15% 9 Founding Sponsors Mr. Richard Barnes Mr. and Mrs. Robert P. Evans Mr. and Mrs. John T. Geldermann Mr. and Mrs. William J. McGinley Chicago Children’s Charities Mr. and Mrs. A. George Forbeck Mr. and Mrs. Thomas A. Geldermann Mr. and Mrs. Michael O’Brien Mr. Thomas H. Dittmer The Traders Foundation Mr. and Mrs. Hayden Leason Mr. and Mrs. Richard Pfeil In the early years of the Foundation, each of the Founding Sponsors made a committment for $5,000 per year for five years. These pledges provided a stable financial basis for the Foundation and allowed efforts to be concentrated on establishing the Foundation and organizing programs.

In grateful acknowledgement of our donors... (from January, 2002 thru February, 2003) Benefactors Affinity Services Corporation Nancy & Nicholas Debenedictis Mr. Charles R. Horsburgh Kindergarten Class Mr. & Mrs. Robert S. Agnello Antoinette, Barbara and Mr. & Mrs. John W Hough, Jr Manchester Memorial School Mr. and Mrs. Mark G. Allen Angela De Frank Jim and Ann Howard Wendy A. Manninen Barbara H. Almy Jeffery & Joanne Dickinson Judith A. Howe Sandra M. Kirby Amsterdam Financial L.L.C Mr & Mrs Ralph J DiDomenico Mr. and Mrs. Daniel R. Huber Mr. & Mrs. Robert A. Marks Bill and Margaret Anderson Mr James S Dimare & Mr. and Mrs. John P. Huber Judy and Michael Mason Mr. and Mrs. Robert Arrix Mrs Lorraine Graham Mortimer G & Susan V Huber Mr. &Mrs. Mark C. McCloy Elena and Steve Arthur Mr. & Mrs. Charles H. Drawdy Ms. Julie Huska Mrs. William J. McGinley Martha (Marnie) Atkinson, Jr Mr. & Mrs. Thomas H. Durkin ICON Jim and Clare McGovern Rotchy and Julie Barker Dr. David R. Elmaleh J. P. Ieronimo Ginny McIlvaine Christina Barrett Ira K. and Susan C. Evans Sam and Charlee Irmen Mr. & Mrs. Christopher McKeown Alexandra Barrett Excell Marketing Terry and Tonia Irmen Mr & Mrs “Bud” Mechling Francine Clarke-Bartels Caroline B. Fabyan Mr. & Mrs. William Jackson Dr & Mrs Jeffrey S. Melamed Bill Bartholomay Foundation Mary Jane & George Farnsworth D. Elaine Jacobsen John V. Meredith Julie C. Bartlett Stanley H & Theodora L Feldberg Jerome &Kathleen Jacobson Merrill Lynch & Co Randolph P. Barton Ms. Catherine Felton Vance Jensen & Missy Hanahan Tracy & Andy Miller Mr. and Mrs. William Barton Dr. and Mrs. William Fischer Jesser and Farber, LLP Lawrence & Colleen Moelmann Alben & Clara Bates Fndatn Mr. and Mrs. John H. Fisher Bill and Helen Johnson Robert & Patricia Moore Fritz and Pauline Becker Mrs. Phyllis H. Fisher Nick and Jeanne Kampton Alice J. Morava Mr. & Mrs. Robert A. Bennett Jennifer and George Forbeck Robert and Mary Kasten Mr. Jim & Kris Moroney Ed and Jill Bessey Kevin Forbeck & Cindy Maher Ann and Bill Kasten Mr. and Mrs. John J. Morton Bierhaus Foundation, Inc Tricia Forbeck Michael Keefe Betsy and Hardy Nalley Raymond and Judith Biggs Dr & Mrs William Frackelton Mr & Mrs Fred Kees & Cheryl and Martin Nally Raymond J. Biggs Wm H Frackelton II & Paulina Feit Ms. Lee Nameche-Strong Jeffery & Theresa Bistrong Mary A Connelly, MD Robert E. Kelly, Jr. Gary and JoAnne Needham Howard P. Blatchford, Jr. Mr. & Mrs. Edward R. Frick Ruth and Matt Kerger Richard and Marianne Neidow Charles and Beth Boehland Mr & Mrs Harvey C Fruehauf Mr & Mrs Nicholas H. Kimball Mr. John J. Neuhauser Sarah and Ralpha Bogan The Furst Foundation John and Margaret Kinzer Mr. and Mrs. John Ogden Mr & Mrs John A. Bollero, Jr Bill and Maggie Gage William M. Kinzer Michael and Kay O’Halleran Jay and Kathy Bothwick Mr. and Mrs. Steven Gajdalo Jim & Sherry Kirchschlager Otzen Family Foundation Mr. and Mrs. David Bouchard Frank and Kathleen Gazzolo Mr. G. F. Kirkendall Mr. and Mrs. Brian D. Owen Mr. & Mrs. Grover Bowers, Jr Bartlett R. Geer Ms. Mabel A. Konadu Irene and Eric Pagh Mr. & Mrs. Peter T. Brastrom Mr. and Mrs. John C. Gehrig Mr & Mrs Peter Kostantacos Palmetto State Bank Nancy and Bob Breckinridge John T & Jane F Geldermann Brian H. Kushner, MD Scott and Ellen Paseltiner Maud F. Brennan Mr & Mrs Robert Geldermann Bridgid and Michael Kyle Mr. and Mrs. Werner W. Paster Staff of Brightwood School Mr & Mrs Stephen Geldermann Mr & Mrs Montague T Laffitte Bill and Debbie Terlato Connie Brown Tom and Joan Geldermann Mr. and Mrs. R. M. Laffitte Mr. and Mrs. Richard C. Paugh Mr & Mrs Michael L. Brown Eric and Diane Geschke Ms. Jennifer LaGrassa Michael Pavlov & Deborah Zelen Mr. and Mrs. Robert B. Bruce Ray Geschke Lake Geneva Country Club Mary Jo and Dick Pfeil Sally A. Buchanan the Philip Gillette Family Mary Theresa “Ted” Lane Philip Morris Andy Buck L. Kirk Glenn, CPA Tobey and Dennis Lannert Mr. & Mrs. William Philipbar Mr. and Mrs. John D. Cantrell Ms. Ruth S. Goldstein Mr. & Mrs. G Curtis Lansbery John and Susan Phillips Captain Dusty’s, Inc Mr & Mrs Andrew W. Greene the David Lawson Family Kenneth & Mariann Podmokly Charles P. Carey Ginger and Hollis J. Griffin Mr. and Mrs. Hayden Leason Stella and Bill Poggensee Joseph Casady The Griffith Family Foundation the Leavitt Family James and Patricia Poitras Mr & Mrs Thomas Cashman An Grosshuesch & Quentin Ables Ann M. Lehman Jerry and Samantha Polek Chicago Board of Trade John and Leslie Gurley the Peter Leone Family Myrna and Stuart Porter Carol A. Chicane Babbie and Don Guscio Leslee Sports Importing Mrs. Lois L. Pratt Catherine B. Cleary Mr. & Mrs. Albert J. Hagan, Jr John Lindsay Joseph and Tami Pringle Mr. and Mrs. Gerhard Cless the Hammond family Mr. and Mrs. Barton Love Ross and Sally Prio Chris and Lisa Collins Gregory Hannon Joan, Joe and Deven Lovejoy Hank and Sally Proesel Mr. and Mrs. Patrick Conley Heidi and Vaughn Harring Marianne and James Lowrey Peter and Patricia Ream Mr & Mrs Dwight B Corning Mr. and Mrs. John R. Hatch Mr. & Mrs. George Ludington Fred and Mary Reed Joe and Joella Cramblit Joyce S. Heathwood Marcia J Luxton Thomas Q. Reed Mr. & Mrs. Martin P. Crofton Mr. and Mrs. Don Hedberg Lunch Automotive Group Jane Letherman Reilly William and Ellen Cross Mrs. Katherine Dudley Helms Donald & Nancy Lee MacDonald Ms. Alice E. Rice Mr & Mrs J Richard Crowley Jr Margaret Hennessy Janet MacLean Mr. &Mrs. James E. Rich, Jr Mr. & Mrs. Patrick J. Curran Mr. & Mrs. Paul J. Hennigan the MacMillan Family Ms. Molly Ring Arlene Dahm Jay and MaryBeth Hicks James and Martha Maddock Dr. & Mrs. Edward Rogalski Terry and Debi Daniels Edra E. Hollon Buck and Carol Maher Ms. Ivy Ross

10 BobHonoraria and Maria Bradley Mr. & Mrs. Wendy Lawrence Mary Kay Ring Jennifer Buchanan Abigail Tamara Ms. Shirley Anne Roeger Jennifer & George Forbeck Mr. and Mrs. Bill Nachtrab Logan Joseph Rosengard Tyler Grant Horberg Mr. and Mrs. Dave Noe Mrs. Elyce Turba Mr. James Irmen Mary Reed Dr. & Mrs. William Wiersma the Birth of Jackson Philleo In Memorium Andrew Allen Dorothy Hamill Tom Menozzi Paula Barry Peter Hannon, Sr Robert T. Morava, Sr. Lindsay Noble Buchanan Elizabeth Lewis Helms Edward Neukirch Phil Carlucci Vicki S. Hershinow Sally Forster O’Neill Benefactors continued… Lawrence A. Chez Jean Hicks Julie O’Neill Eleanor R. Daley Mary Agnes Huber Arthur Otten Eileen De Marr Eva Hirshinow Johnson Carl Poticha Ms. Elizabeth H. Russ Marilyn Feinberg Dov Judlo Ronald E. Pratt Patrick and Shirley Ryan Lorrie Foley Yoshiko Kamo Jim and Rose Proesel Mr. & Mrs. Robert J. Ryan, Jr William Guy Forbeck Paul Kilgore Edward V. Quinn Melanie A. Sabo Bradley Dr. Charles W. Foster III Richard A. Kinzer Betty Reuland Will and Barbara Sander Marilyn Fox Edward J. Konicki Penny Sansone Michael and Cassie Sanders Jane MacMillan Frackelton Allene Lawrence Gladyce Schroeder Stuart Scantlebury & William H. Frackelton, MD John E. Lehman, Jr. Irene Schultz Lecia Turcotte Elinor S. Golson James Lehman Patrick Sreenan Florence Scott Emanuel Gordon Bert Leobmann Sidney J. Taylor Mr. and Mrs. Dan Shamai Zev Gordon Hugh-Blair Grigsby Long Chris Thayer Donna and Major Short David Greenberg Lottie Magged Dr. John Weisenberger James and Cindy Skarda Martha Guth Jane McGinley Carl Wellard Skelly Insurance Agency, Inc Cecile Smith Several people, very close to the Foundation, passed away in 2002. Mr. & Mrs. Robert W. Smyth Robert and Dru Anne Smyth Lindsay Noble Buchanan died May 25th at the age of 10. For seven years, Lindsay battled neuroblastoma, Sheldon Snyder one of the most virulent of childhood cancers. She was a little girl, bravely fighting a very large disease. Mr & Mrs Harvey M. Soldan Glenn and Carol Solheim Lindsay taught her friends and family many things, in particular, that it is not neces- Mr. & Mrs. Vincent F. Sorren sary to be an adult to be a warrior. Over the seven years of her treatment for cancer, Robert Spingler, DMD she participated in six experimental clinical trials at four cancer centers around the Kristen and Daniel Sreenan Ray and Candy Stecker globe, including Dana Farber in Boston, Memorial Sloan-Kettering in New York, City E. C. Styberg Foundation, Inc of Hope in California and the Children’s Hospital in the Netherlands. Lindsay knew Bob and Janet Swett that her treatment might help her. She also knew that it could help pave the way for Luis E. & Elizabeth A. Taveras thousands of adults and children living with this terrible disease and navigating Dr. and Mrs. Jack L. Teasley through its treatment. She worked very hard to make a difference. Anthony and JoJo Terlato John and Diana Terlato In their efforts to fight her disease, Lindsay’s parents, Jennifer and Jim Buchanan, became involved with the Mr. and Mrs. Edward R. Tobin Foundation in 1996. They organized the “Homefront Tour - A Ride for a Cure,” and set a goal of raising Tim and Wendy Tobin $250,000 over five years with the proceeds going to the Foundation to Thomas and Suzanne Tolpin “The 4th annual Home Front Tour was Ms Laura Tomasetti help find a cure for cancer. Every August for five years, the Buchanans more difficult than we could have imag- Bill and Barbara Turner and others biked 140 miles from Manchester, Massachusetts to ined. A week prior to the ride and Unilever United States Foundn Harrison,Maine. Their determination resulted in the significant sup- almost five years to thre day, our daughter Dr. and Mrs. Miller Upton port, involvement and awareness of the many people who supported Lindsay relapsed. We were stunned. John P. Vaile Jim and Jennifer, and $350,000 in contributions over the five-years. Words can’t describe the feeling. We Nan B. Vaile thought about canceling but felt it was Mr & Mrs Howard Vaughan, Jr Jim and Jennifer continue to work with the Foundation in their fight necessary to stay with our commitment to Ms. Marjorie C. Veit against cancer. Jim continues to participate as a member of the help battle cancer, cancer that attacks Mr. and Mrs. Arthur P. Venditti kids. After all, a committment is what Mr. and Mrs. Jeffrey D. Vivian Foundation’s Board of Trustees. Recently, Jennifer represented the changes a promise to reality.” Mr. & Mrs. John M. Volkhardt Foundation at a Focus meeting which addressed the subject of Mr & Mrs Ernst Von Metzsch Neuroblastoma. Jim Buchanan, Aug-2001 William M. Walsh Carpentry Mr & Mrs Robert S. Watterson The Buchanan family, Lindsay and her parents, personify Jim Buchanan’s words “a committment is what Ms. Kimberly E. Weeks changes a promise to reality.” Dr. and Mrs. George Wilding Abra Prentice Wilkin Dr. William H Frackelton died in Hilton Head on December 4that the age Judy A. Willis of 91. “Dr. Bill” was one of the original trustees of the William Guy Forbeck Ken and Sharon Wilson Research Foundation, involved in the creation of the Foundation in 1984, Robert and Joan Wogan William & Francis Wolf and was actively involved for many years, contributing his sincere interest, Susan and David Wright wisdom, insight into the medical world, and his own brand of humor. Mr. and Mrs. Howard R Wright Dr. Frackelton was predeceased by his wife, Jane McMillan Frackelton, who Mr & Mrs William Wrigley, Jr. rd ZAKS died on November 3 . She was the grandmother of William Guy Forbeck. Susan and Don Zick Before retiring to Hilton Head Island, the Frackeltons lived in Milwaukee, Mr & Mrs Brian Zimmermann Wisconsin, where Dr. Frackelton practised reconstructive surgery.

11 Board of Trustees In Appreciation David R. Barry, Jr. Thomas A. Geldermann Joseph Laver, MD Chicago, IL Lake Geneva, WI Charleston, SC

Hon. Sol Blatt, Jr. Hon. Ernest F. Hollings Hayden Leason Charleston, SC Washington, DC Humacao, PR

James A. Buchanan Terence J. Irmen William Terlato Manchester, MA Sylvania, OH Lake Forest, IL

Charles H. Drawdy T. L. Sam Irmen Henry Wagner, Jr. MD Hampton, SC Maumee, OH Tampa, FL

Jamie Forbeck Charles H. Jesser, CPA Nancy Wellard Chicago, IL Chicago, IL Hilton Head Island, SC Our heartfelt thanks go to all the people who have worked to make the activities of Jennifer K. Forbeck Emeritus Trustees Ann Huber Kasten the Foundation a success. Hilton Head Island, SC Winnetka, IL Joseph W. Black, MD Richard H. Goodemote We are grateful to the Scientific Advisory Edward R. Frick Montague T. Laffitte Robert W. Smyth Board and the Forum participants, the New Canaan, CT Bluffton, SC Howard Wright scientists and clinicians whose leadership and effort are the front line in the war against Cancer. Our special appreciation goes to the Scientific Advisory Board Foundation trustees and volunteers whose thoughtfulness, time and energy have Bruce A. Chabner, MD Emeritus Members: done so much for the success of the Massachusetts General Hospital Garrett M. Brodeur, MD Boston, Massachusetts Children’s Hospital of Philadelphia Foundation and the Forums. Most importantly, our thanks go to the David E. Fisher, MD, PhD Webster K. Cavenee, PhD hundreds of donors, individuals, busi- Dana Farber Cancer Institute Ludwig Inst for Cancer Research nesses and foundations, whose financial Boston, Massachusetts Isaiah Fidler, DVM, PhD support assures our continued work in Arnold I. Freeman, MD MD Anderson Hospital Cancer research. Hadassah Hospital & Hebrew Univ Jerusalem, Israel Ed Harlow, PhD Sincere Thanks, Massachusetts General Hospital Michael B. Kasten, MD, PhD St Jude Children’s Hospital Laurence Helson, MD Memphis, Tennessee New York Medical College

John T. Kemshead, PhD Philip A. Pizzo, MD Baxter Healthcare Ltd., Chicago, IL Children’s Hospital of Boston University of Manchester, England George and Jennifer Forbeck John D. Minna, MD University of Texas Dallas, Texas

Objectives • The objective of the William Guy Forbeck Research Foundation is to promote advances in the field of oncology, particularly pediatric oncology. • While the foundation may provide grants for pilot research studies and educational efforts, its centerpiece activity will be an annual scientific roundtable held at Hilton Head Island, South Carolina. • Attending each year will be up to twelve physicians and scientists who will meet in a completely private “think tank” environment, where they can exchange ideas freely in the hope of building on each other’s ideas, knowledge, and experience. • The objective is not to discuss published research, but rather to provide a forum for the cross fertilization of ideas, concepts, and observations. The hope is to shorten the cancer research timetable. • Participants will be invited on the recommendation of the Foundation’s Scientific Advisory Board, a distinguished panel of medical scientists. It is through your generous support that continuing research in the field of childhood cancer can be ensured. Contributions are tax deductible for federal IRS purposes. The IRS file number is 580063499. For additional information please write: William Guy Forbeck Research Foundation, 23 Peninsula Drive, Hilton Head Island, South Carolina 29926 or fax: (843) 837-3088 or visit our web site

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