TITANS of PROSTATE CANCER Ment Is for Men Who Are Diagnosed with High-Grade Prostate Cancers That Are Likely Following the Johns Hopkins Model, Leaders in to Recur

PROMISE& PROGRESS THE SIDNEY KIMMEL COMPREHENSIVE CANCER CENTE R AT JOHNS HOPKINS

TRANSFORMIN G PROS TA TE CANCER DETECTION, DIAGNOSIS, AND TREATMENT

2012/2013 PROMISE&PROGR ESS 2012/2013 VOLUME ONE

Promise & Progress is published by The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 06 Office of Public Affairs 901 South Bond Street Suite 573 Baltimore, Maryland 21231 (410) 955-1287 William G. Nelson, M.D., Ph.D. Director Amy Mone Director of Public Affairs Valerie Matthews Mehl Editor and Sr. Writer [email protected] Michelle Potter Production Manager and Editorial Assistant Vanessa Wasta Associate Director, Media Relations and Web Projects Keith Weller Feature Photography Peter Howard Cover Photography MSK Partners, Inc. Design and Production

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CONNECT WITH US 34 WWW.HOPKINSKIMMELCANCERCENTER.ORG 02 40 CANCER MATTERS , OUR BLOG FEATURING Headline Makers In The News Philanthropy TOPICS FROM CLINICIANS, RESEARCHERS, The latest research from Noteworthy progress, Gifts and donations that PATIENTS, AND STAFF. the Kimmel Cancer Center new appointments, and are funding our cancer including new discoveries other cancer news. research and advancing CANCER NEWS REVIEW , MONTHLY PODCAST in cancer treatments and clinical care. FROM DIRECTOR WILLIAM NELSON half-matched transplants MEDIA CENTER , VIDEO AND PODCAST GALLERY that may cure sickle cell disease. P&P PROMISE & PROGRESS WEB EXCLUSIVES

On the Cover: Former Temptations singer Damon Harris, at his Owings Mills home. @HOPKINSMEDNEWS

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REDEFINING CANCER

THE KIMMEL CANCER Center is an treatment is delivered with evidence-base d, incredible cancer discovery engine. Our personalized care that gets interventions laboratory scientists have made world- to patients who we know will benefit and class findings that have revolutionized moves them away from those we know cancer research. Still, what we are most will only be harmed. At the same time, we proud of is how we are using these break - are using the clinical characteristics that throughs to improve the experience and distinguish one group from the other to outcomes of patients. This only occurs develop novel prevention approaches, when scientists work side by side with better screening and diagnostic markers, clinicians, and this is the Kimmel Cancer and more effective treatments. Center model. A new clinical arm of our As a prostate cancer clinician-scientist, genetic and epigenetic sequencing labora - and a member of this team, I am so proud tories (see page 40) is focused on translat - of this work. As the Kimmel Cancer Cente r ing these revolutionary discoveries about Director, I am excited about the possibili - the unique molecular blueprints of cancers ties because I recognize that much of what into clinical tests that will help identify we learned about prostate cancer can be those people most at risk and guide applied to make similar advances against diagnosis and treatment. other cancer types. Johns Hopkins clinicians and scientists WE ARE NOT CONTENT WITH THE STATUS QUO. have a long history of pioneering advance s against prostate cancer. It was here that WITH DISCOVERY COMES THE OPPORTUNITY, AND the first radical prostatectomy was per - I BELIEVE THE OBLIGATION, TO RE-EVALUATE formed, and here that it was reinvented. Here, laboratory scientists developed the AND IMPROVE HOW WE DELIVER CANCER CARE. first animal models to characterize the We are not content with the status quo . Our ability to make these unprecedented properties and types of prostate cancer, With discovery comes the opportunity, gains is tied directly to the generosity of and here, current researchers and and I believe the obligation, to re-evaluate our donors. The National Cancer Institute , clinicians build upon this work to deliver and improve how we deliver cancer care. the Department of Defense, Sidney Kimme l, 21st century personalized cancer medici ne. In this issue, you will read about signifi - David H. Koch, the Commonwealth This bench-to-bedside tradition is what cant advances in how we detect, diagnose Foundation for Cancer Research, the sets Johns Hopkins apart and ensures and treat prostate cancer. We recognized Prostate Cancer Foundation, Safeway, continued progress against prostate that this is a disease that is too frequently Jones Day, AEGON, the Patrick C. Walsh cancer and all cancers. overdetected and overtreated but, at the Prostate Cancer Research Fund, the same time, is a leading killer of men. Wit h Maryland Cigarette Restitution Fund, the multidisciplinary expertise of some of and many dedicated individual donors the world’s best urologists, oncologists, are among the contributors who have William G. Nelson, M.D., Ph.D. radiation oncologists, pathologists, radiol - made the Johns Hopkins prostate cancer Marion I. Knott Professor and Director ogists, and cancer scientists we are trans - program one of the strongest and most The Sidney Kimmel Comprehensive forming how prostate cancer screening and productive in the world. Cancer Center at Johns Hopkins

2012/2013 PROMISE &PROGRESS 1 HEADLI NE MAKERS THE LATEST RESEARCH from the JOHNS HOPKINS KIMMEL CANCER CENTER

HALF-MATCHED TRANSPLANTS MAY CURE SICKLE CELL DISEASE Blood , September 6, 2012 Kimmel Cancer Center bone marrow transplant researcher Javier Bolanos- Meade, M.D. , and team have shown that half-matched (hap - loidentical) bone mar - row transplants can cure sickle cell anemia, a painful and debilitat - ing blood-forming dis - Bolanos-Meade ease in which red blood The crescent-shaped red blood cells are shaped like crescents instead of cells of sickle cell anemia discs and clog blood vessels, cutting off oxygen to tissues and organs. Bone marrow transplant replaces the “We’re trying to reformat the blood of lung cancer, known as small cell lung diseased marrow with the healthy marrow system and give patients new blood cells cancer (SCLC). “Small cell lung cancers of a donor. After an average of two years Brodsky to replace the diseased are very aggressive. Most are found late, of follow-up, eight of 14 patients treated ones, much like you when the cancer has spread, and typically with a half-identical transplant and would replace a com - survival is less than a year after diagno - another three who all received a fully puter’s circuitry with an sis,” says Charles Rudin, M.D., Ph.D. , matched bone marrow transplant remain entirely new hard professor of oncology and Director of the symptom free. Ten patients are believed drive,” says Robert Kimmel Cancer Center Lung Cancer to be cured of their sickle cell disease. Brodsky, M.D. , Therapeutics Program. “Our genomic Patients with severe sickle cell disease Director of Hematology and The Johns studies may help identify genetic pathways (SCD) face shortened life spans, intractab le Hopkins Famil y Professor of Medicine and responsible for the disease and give us pain and eventual organ damage as a Oncology. “Whil e bone marrow transplant s new ideas on developing drugs to treat it.” result of their disease. SCD primarily have long been known to cure sickle cell Among the genetic alterations identified affects African Americans. Most patients disease, only a small percentage of patient s by the investigators was an increase in t he die before age 50, and many suffer poor have fully matched, eligible donors.” number of copies (amplification) of a gene quality of life with frequent episodes of Six of the transplants were not suc - called SOX2. Normal cells should contain “off-the-charts” pain, and an increased cessful. The patients own diseased blood just two copies of the gene (one copy from risk for kidney failure, stroke, deep-vein cells eventually returned. Work to improve each parent), which is involved in embryo thrombosis, and lung disease. The ability the rate of bone marrow engraftment in development. In cancer, researchers sus - to safely use half-matching donors (parents, half-identical transplants for sickle cell is pect that amplification causes an overpro - most siblings, ongoing. duction of SOX2 proteins that, in turn, and all chil - Funding for the research was provided by reignites and sustains cell growth associ - dren of the the National Cancer Institute and National ated with tumor formation. “SOX2 is an patient) makes Institutes of Health grants P01CA15396 and important clue in finding new ways to bone marrow K23HL083089 and Sistema Nacional de treat small cell lung cancer,” says Rudin. transplant a n Investigadores (Mexico). • “We may be able to link a patient’s out - effective option come to this gene and develop a drug to EMBRYO GENE LINKED TO target it or other genes it regulates.” for the majori - Fuchs and Luznik ty of sickle cell LETHAL LUNG CANCER The research was funded by the Burroughs patients. Kimmel Cancer investigator s Nature Genetics , September 2, 2012 Wellcome Fund, the Flight Attendant Medical Ephraim Fuchs, M.D. , and Leo Luznik, Scientists from several institutions, led by Research Institute, the National Cancer M.D. , pioneered the haploidentical version researchers at the Kimmel Cancer Center, Institute grants P50CA058184, P50CA70907, of the therapy to help patients who do not completed a comprehensive map of the and P50CA058187, the CAPES Foundation, have matching donors. genetic mutations linked to a lethal type and the Ministry of Education of Brazil. •

2 PROMISE &PROGRESS 2012/2013 UPDATE: DETECTABLE LESIONS DRUG TREATMENT NOVEL TECHNIQUE WARN OF HEREDITARY REPROGRAMS CANCER REVERTS CELL TO PANCREAS CANCER CELLS EMBRYONIC STATE Gastroenterology , April 2012 Cancer Cell , March 20, 2012 Public Library of Science , August 8, 2012 A Johns Hopkins-led study of 216 adults Experimenting with cells in culture, The same scientist who last year trans - at high risk for hereditary pancreas cance r researchers obtained promising results formed human blood cells into beating found that more than four in 10 people with two drugs once considered too toxic heart cells has now developed a safe and have small lesions in their pancreas long for human cancer treatment. The drugs, super efficient method to turn the clock before they have any symptoms of the azacitidine (AZA) and decitabine (DAC), back on blood cells, reverting them to the deadly disease. The prevalence of the are epigenetic-targeted drugs and work to primitive state from which they derived. lesions increases with age, and are most correct cancer-causing biochemical alter - This form, known as the stem cell state, is common in people age 50 and older. ations to the environment of DNA. the point at which blood cells may develo p Ultrasound done by endoscopy was The researchers said the drugs also into any other type of cell in the body. better than MRI and significantly better were found to take aim at a small but The work by Elias Zambidis, M.D., than CT scans at finding these potential dangerous subpopulation of self-renew - Ph.D. , assistant professor of oncology precursors to pancreas cancer. ing cells, sometimes referred to as cancer

and pediatrics at the Canto Endoscopic ultrasound stem cells, which evade most cancer Institute for Cell detected lesions in drugs and cause recurrence and spread. Engineering and the 42.6 percent of study The study produced evidence that low doses Kimmel Cancer Center participants, versus 33 of the drugs could cause antitumor respons - is the latest work in his percent with MRI and es in breast, lung, and colon cancers . ongoing effort to effi - 11 percent with CT. In Conventional chemotherapy agents Zambidis ciently and consistently five patients, precancer - work by indiscriminately poisoning and convert adult blood cells into stem cells ous lesions that likely would have gone killing rapidly dividing cells, including that can be used for clinical research in undetected were identified and treated. ca ncer cells, by damaging cellular machin - place of human embryonic stem cells. About 10 to 15 percent of all pancreas ery and DNA. “In contrast, low doses of “Taking a cell from an adult and con - cancers are hereditary. This research, led AZA and DAC may verting it all the way back to the way it by Marcia Irene Canto, M.D., M.H.S. , re-activate genes that was when that person was a 6-day-old professor of gastroenterology and oncolo - stop cancer growth embryo creates a completely new gy, could help reduce the death rate from without causing imme - biology toward our understanding hereditary pancreas cancer, which is diate cell-killing or DNA of how cells age and what happens generally fatal once these lesions begin damage,” says Stephen when things go wrong, as in cancer to grow and symptoms appear. “We Baylin Baylin, M.D. , Ludwig development,” Zambidis says. now know that although these high-risk Professor of Oncology and Deputy More common methods use viruses patients often tend to develop pancreatic Director of the Kimmel Cancer Center. to convert cells to a stem cell state, and lesions, we can detect the lesions, track Baylin and his colleague Cynthia among hundreds of blood cells, they them over time and remove them before Zahnow, Ph.D. , assistant professor of typically obtain a successful conversion they become cancer,” says Canto. oncology and the Evelyn Grolman Glick in one to two cells. Zambidis chose not Not all pancreatic cysts become Scholar, decided to take another look at to use viruses because they can mutate pancreas cancer. Earlier research by Bert the drugs after they had genes and initiate cancers—the very Vogelstein, M.D., and his team in the showed benefit at low disease he is working to fight—in newly Ludwig Center for Cancer Genetics, are doses in patients with a transformed cells. Instead, he and his developing biomarkers that predict the pre-leukemic disorder team opted to use plasmids, rings of DNA malignant potential of cysts. Researchers called myelodysplastic that replicate briefly inside cells and then hope those findings used in conjunction syndrome (MDS). Their degrade, and umbilical cord blood treated with the results from this new study will Zahnow new work revealed that with growth factors to transform cells to help experts find and treat potentially the low-dose therapy reversed cancer cell the primitive stem cell state. This tech - lethal pancreas cancers while they are gene pathways, including those control - nique resulted in a successful conversion still curable. ling cell cycle, cell repair, cell maturation, of 50 to 60 percent of cells. The r esearch was supported by the cell differentiation, immune cell interac - The work was supported by the National National Cancer Institute Specialized Program s tion, and cell death. Effects varied among Institutes of Health National Heart, Lung, of Research Excellence (SPORE), The individual tumor cells, but the scientists and Blood Institute, grants 1U01HL099775 Lustgarten Foundation for Pancreatic Cancer generally saw that cancer cells reverted to and U01HL100397, the National Cancer Research, The Michael Rolfe Foundation, a more normal state and eventually died. Institute grant CA60441, and the Maryland Olympus Corporation, Cooke Medical, the The results of clinical trials in lung Stem Cell Research Fund grants2011-MSCRF Karp Family, H.H. & M. Metals Inc. Fund cancer, led by Charles Rudin, M.D., II-0008-00 and 2007-MSCRF II-0379-00. • for Cancer Research and ChiRhoClin, Inc. • Ph.D. , professor of oncology and Director

2012/2013 PROMISE &PROGRESS 3 HEADLINE MAKERS of the Lung Cancer Therapeutics Progra m, BRAIN CANCER EXPERTS growing demand for nutrients. The blood and published in 2011 in Cancer Discovery , SET THE RECORD STRAIGHT vessels are formed when tumors pump also indicate that the drugs make tumors Oncotarget , January 2012 out growth factors that increase vessel more responsive to standard anticancer Laboratory findings from Kimmel Cancer production. Such studies opened the door drug treatment. This to treatment strategies that specifically Rudin Center brain cancer researchers refute means, they say, that outside studies that suggest blood vessels targeted blood-vessel growth and the the drugs could become that form within brain cancers are largely vessel cells themselves. More recently, part of a combined made up of cancer cells. “We don’t ques - scientists in Italy and at the Memorial treatment approach tion whether brain can - Sloan Kettering Cancer Center in New rather than a stand- cer cells have the poten - York published results of studies suggest - alone therapy and as tial to express blood ing that these tumor blood vessels are mad e part of personalized approaches in vessel markers and may by primitive types of brain cancer cells patients whose cancers fit specific occasionally find their and were more prone to drug resistance. epigenetic and genetic profiles. way into blood vessels, Eberhart teamed up with colleagues at The research was funded by a SPORE Eberhart but we do question the the Dana Farber Cancer Institute and grant for lung cancer from the National extent to which this happens,” says Harvard Medical School to examine the Institutes of Health, the Hodson Trust Charles Eberhart, M.D., Ph.D. , chief of molecular features of brain cancer cells Foundation, Entertainment Industry neuropathology and professor of patholo - from 100 patients and used biomarkers as Foundation, Lee Jeans, Samuel Waxman gy, ophthalmology, and oncology. “In well as known brain-cancer related gene Cancer Research Foundation, Department of general, we find no evidence in our study mutations to distinguish normal vascular Defense Breast Cancer Research Program, that these vessels contain substantial cells from cancer cells. They found that Huntsman Cancer Foundation, and the amounts of cancer cells.” only 10 percent of the samples contained Cindy Rosencrans Fund for Triple Negative Eberhart became aware of claims about vascular cells that had cancer gene muta - Breast Cancer Research. All of the studies the cancerous nature of tumor blood tions, and in those rare tumor samples, have been accelerated by funding from the vessels when students solicited his opinion only a few cells were affected. Stand Up to Cancer (SU2C) project in part - on journal articles on the topic. “My first These findings, that refute the preva - nership with the American Association of reaction to this research was ‘How could lence of cancer-like blood vessels, call into Cancer Research (AACR). • this be true?’” says Eberhart. “Our clinical question the use and value of anticancer experience examining tissue from brain drugs that target blood vessels in brain cancers does not support it.” cancer patients. Research has long demonstrated that Funding for the study was provided by the malignant brain tumors contain large National Institutes of Health grants numbers of blood vessels to feed their T32CA067751 and 5R01NS055089. •

ON THE WEB NEW FINDINGS ON BRCA1 SEQUENCING OUR PROVOKING AN IMMUNE PREDICTING WHICH BREAST CANCER GENE GENES: IS CANCER RESPONSE TO CANCER LUNG CANCER DRUGS Kimmel Cancer Center breast can - WRITTEN IN OUR DNA? Breakthrough discoveries have WILL WORK cer researchers have showed that Technology called next generation revealed an immune inhibitory Researchers showed that DNA the inactivation of a single copy of sequencing can be used to reveal checkpoint called PD-1 that is co- changes in a gene that drives the the breast cancer gene BRCA1 an individual’s complete and entire opted by tumors to shut down an growth of one type of lung cancer leaves breast cells vulnerable to DNA (whole genome). Right now, immune response to cancer cells. could make cancers cells resistant cancer by reducing their ability to it costs about $5000 to sequence Two clinical trials that used anti - to treatment. The findings indicate repair DNA damage, causing an individual’s whole genome, but bodies to block PD-1 and a related which classes of drugs won’t work genetic instability, the hallmark of the price tag is decreasing rapidly. resulted in significant and long and which ones may be the most cancer. An inherited mutation in With its increasing affordability, many lasting responses against effective. Learn more. BRCA1 is the leading risk factor for have suggested that it could be used melanoma skin cancer, renal cell hereditary breast cancer, prompting to identify individuals who were likely (kidney) cancer, and lung cancer. THE LIFE CLINIC preventive mastectomies or close Read the story on page 40. to develop cancer in the future as The Life Clinic at the Johns monitoring. Learn how these new well as those who would be safe Hopkins Kimmel Cancer Center findings may aid development of from the disease. But, will it? assesses and monitors cancer drugs to prevent hereditary breast survivors to help manage long term cancer and tools to identify women complications from previous cancer who benefit most from prophylactic treatments. treatments. WWW.HOPKINSKIMMELCANCERCENTER.ORG

4 PROMISE &PROGRESS 2012/2013 prevention to balance the need to take care of patients with established cancers with an effort to identify and help people at risk. There are tens of millions of Americans who are at permanent increased risk of developing lung cancer because of a prior or current history of smoking. Screening for early lung cancer using low-dose spiral CT scans save lives, and we plan to provide this screening for people with a history of smoking, but we are also taking it a step further and planning intervention s for people with premalignant nodules. Nodules (small abnormal spots on the lung) are identified in about 30 percent of heavy smokers who have spiral CT scans. Lung nodules are quite common, particu - larly in smokers, but they are not always cancer. We have developed a nodule clinic in collaboration with the Pulmonology Department to monitor and manage people with nodules discovered through spiral CT. We will develop protocols and test prevention strategies that we hope will keep nodules from progressing to lung cancer. The Kimmel Cancer Center Bayview team will be among the very first in the world to use screening as a research tool. With our Center’s depth of expertise in the genetic and epigenetic causes of can - cer, we can make inroads in prevention that are not being done anywhere else. We MEET PHIL DENNIS will take an at-risk population and person - THE KIMMEL CANCER CENTER AT BAYVIEW alize lung cancer risk assessment and pre - vention. People with precancerous lesions Phillip Dennis, M.D., Ph.D., is the new Director of the Bayview Campus of the will have the opportunity to participate in Kimmel Cancer Center where he is creating a Thoracic Cancer Center of intervention trials that target molecular Excellence. He is a seasoned clinician and investigator who, before coming to and cellular changes that this research the Kimmel Cancer Center, had served as director of the NCI/Navy Oncology shows can lead to lung cancer in future Clinic at the National Naval Medical Center and was a senior investigator at years with the aim of reversing the process. the National Cancer Institute, where he was the recipient of the Alton Ochsn er Award Relating Tobacco and Health. Dennis shared his vision for the Does this work increase our Bayview campus. understanding of lung cancer? When does the new Bayview clinic tors. We will have a multidisciplinary lung Smoking is the leading cause of lung can - open and what can patients expect? cancer clinic to bring together for patients, cer. By bringing these people in to the My plan is to take the Kimmel Cancer in one clinic, all of the specialties involved Hopkins system, we will be able to better Center’s Bayview program from a com - in the diagnosis and treatment of lung understand tobacco exposure and lung munity hospital to a fully participating aca - cancer. What makes our clinic particularly cancer risk, genetic features, and family demic arm of Johns Hopkins. We expect unique is its focus on cancer prevention in hi story. We can begin to make progress the clinical areas to open in the Spring of addition to cancer treatment. by studying and evaluating treatments 2013. They will include a medical oncology that target the very earliest, premalignant treatment area overlooking a beautiful What is your strategy for cancer changes that lead to lung cancer—take out garden with 22 infusion chairs and private prevention? a cancer before it actually is a cancer. I exam rooms, and a radiation oncology The Kimmel Cancer Center Bayview cam - think we have the opportunity to make treatment area with two linear accelera - pus will have a dedicated center for cancer unprecedented strides against lung cancer.

2012/2013 PROMISE &PROGRESS 5 [COVER STORY ] Transforming Prostate Cancer DETECTION, DIAGNOSIS AND TREATMENT

by Valerie Matthews Mehl

6 PROMISE &PROGRESS 2012/2013 2012/2013 PROMISE &PROGRESS 7 [COVER STORY ]

PROSTATE CANCER IS AN ICONOCLAST AMONG CANCERS . It is at odds with what experts know to be the optimal approach for most cancers: Find it early and treat it early. Prostate cancer is different. It may be one of the few cancers humans can live with. It is most often slow growing, and even late-stage cancers can many times be held in check for years. On the other hand, it is a cancer that kills many men. It is the second leading cause of cancer death for men. The challenge, then, is deciphering the “good” prostate cancer from the “bad.” As a result, it is a model for personalized cancer medicine as Johns Hopkins urologists and cancer scientists and clinicians lead the way, using the most advanced science and technology to redefine for the world who to screen, who to treat, and who to safely leave alone .

WHERE WE CAME FROM, Forward thinking, Walsh compiled an and around the world. Walsh, a clinician, WHERE WE ARE GOING extensive database of thousands of and Coffey, a basic scientist, embodied the The innovation that sets the Johns Hopkins patients and followed them for 30 years. bench-to-bedside collaborations that are prostate cancer program apart can be What he and others learned from these the hallmark of Johns Hopkins medicine traced , in part, to the inventive thinking of men became the laboratory fodder for the and provided strong roots for a prostate Patrick Walsh and Donald Coffey. They bespectacled inquisitor Donald Coffey cancer program. set the standard—challenging clinicians who began exploring the basic biology of This is, in many ways, the golden age. and investigators to think beyond the sta - prostate cancer and provided some of the Generations of clinicians and investigator s tus quo; beyond what is adequate to what first insights to the subtle and unique provide incredible depth to the prostate is extraordinary. Walsh developed an variations of cancer DNA. Like Walsh, cancer program much like grandparents anatomical, nerve-sparing approach to he shared what he learned. One of Johns do for a family. Today, under the leader - surgery that, for the first time, cut out and Hopkins School of Medicine’s first triple ship of Kimmel Cancer Center Director cured prostate cancer without causing professors, Coffee is the consummate William Nelson, Brady Urological devastating side effects for men. Patients teacher, inspiring generations of Institute Director Alan Partin, and the world over traveled to Johns Hopkin s researchers to not only look for answers Radiation Oncology and Molecular to have Walsh’s surgery, and urologists-in- but to ask questions that had never before Radiation Sciences Director Theodore training sought to come to Johns Hopkins been asked. DeWeese, Johns Hopkins experts, from a to learn the pioneering technique. Today, Those who studied under Walsh and wide range of disciplines, are on the fore - it remains the most common surgery Coffey became leaders in prostate cancer front poised to transform how prostate performed at Johns Hopkins. treatment and research at Johns Hopkins cancer is detected, diagnosed, and treated.

8 PROMISE &PROGRESS 2012/2013 Donald Coffey trainees have gone on to become titans in cancer discovery. (Left to right) Schaeffer, Partin Among them is Kimmel Cancer Center and Carter Director William Nelson, Brady Urological Institute Director Alan Partin, renowned cancer genetics pioneer Bert Vogelstein, and Prostate Cancer Foundation President Jonathan Simons.

FIRST DO NO HARM The purpose of early detection is to catch a cancer early so that it can be removed or destroyed before it causes harm. It makes sense for most cancers. The problem with detecting prostate cancer early, however, is that the diagnostic procedures and treatments can sometimes, particularly in older men, cause more harm than the dis - ease itself. PSA (Prostate Specific Antigen), the test that makes the early detection of caused by tumors, and it often left men prostate cancer possible, is at the center of incontinent and impotent. For a man with the dilemma. Recently, the United States prostate cancer, it seemed that if the Preventive Task Force recommended cancer did not claim his life, it certainly against routine PSA testing for early would claim his quality of life. PERSONALIZED detection claiming the harms outweighed It is no surprise, then, that when a CANCER SCREENING the benefits. Their announcement gained test was developed that could detect the The numbers are staggering. Each year widespread attention, but the truth is, cancer early, before there were any 20 million men get screened with PSA. experts at Johns Hopkins had been symptoms, it was going to be used. Many of them undergo unnecessary evaluating the test and changing prostate Imagine, Carter says, if such a test biopsies, suffer complications such as cancer screening and treatment long existed for pancreas or lung cancer. infection and bleeding, and still others before the U.S. Preventive Task Force Overdetection or not, people would be have surgery, radiation treatment, hor - weighed in. standing in line to get the test. monal therapies, and drug treatments that “We’ve known for a long time that With no science to guide when have unpleasant side effects. Out of all of there is a lot of harm that can potentially prostate cancer screening should begin these men, less than one-third of 1 percent come with PSA testing,” says, urologist and how often it should be done, howev - will die from the disease. “It’s clear that H. Ballentine Carter who has studied and er, the nation, overzealously embarked on for many men, the benefits may be small evaluated the test in large populations of a practice of overscreening, overdetecting, and the harms significant,” says health men for more than 20 years. Carter and and overtreating the cancer with free policy expert and Maryland Cigarette other Johns Hopkins prostate cancer screenings and “awareness” campaigns Restitution Fund supported investigator experts say that PSA is not inherently a that helped fuel the trend. Craig Pollack. The challenge is figuring bad test as it has been characterized in The result was a dramatic increase in out from among the masses, which men recent headlines. The problem, they say, prostate cancer incidence, and most will benefit from screening and which is not so much with the PSA test, but experts agreed that many of the cancers ones will not. instead how the test is used. detected would have never caused any Confusion abounds, says Pollack. Ask Before the Prostate Specific Antigen harm. Doctors were finding a lot of patients why they get screened, and they test, or PSA as it is now commonly prostate cancers, but many of them, Johns say it is because their doctor recommended known, hit the market in the late 1980s, Hopkins scientists found, would never be it. Ask doctors why they recommend prostate cancer was essentially an a problem. “Now,” Carter says, “we must screening, and they say their patients untreatable disease. There was no move to a more measured approach.” expect it. While Pollack finds that most method for finding the cancer, and men He and other Johns Hopkins prostate primary care providers he has surveyed went to the doctor only after they began cancer experts have put medical science recognize the issues surrounding routine experiencing symptoms, such as trouble back in the equation and using sound PSA screening, they are unsure about urinating or blood in their urine. By that research to determine how best to screen how to explain it to their patients. time, the cancer was already well for prostate cancer and how to tease out “There are clearly some mispercep - advanced, and it could not be cured. the prostate cancers that are likely to kill tions,” Pollack says, “and since the major - Surgery was used primarily to relieve from those less aggressive forms that may ity of screening occurs in the community, symptoms, such as bladder obstructions not require treatment. we need to provide them with a decision-

2012/2013 PROMISE &PROGRESS 9 making tool that can help them improve their practice.” Bill Nelson Such a tool, a novel computer-based system, which can be integrated with patients’ electronic medical records, was developed by Carter, Pollack, cancer prevention and control expert Elizabeth Platz, and other Johns Hopkins cancer and public health experts. It will be pilote d in Johns Hopkins Community Physicians offices throughout Maryland. They hope it will help primary care providers dis - cuss prostate cancer screening with their patients and direct PSA to men who will benefit and away from those who will not. The decision-making tool takes into IT’S INFLAMMATORY account age and personal medical history, THERE IS A compelling body of evidence that links inflamma - along with previous PSA test results and tion to prostate cancer. It’s not acute inflammation, the kind serves as an interactive guide for physi - that occurs briefly when tissue is injured, but chronic inflam - mation—an ongoing assault and stress to tissue that contin - cians to use when talking to patients ues day after day without end. Population studies by Elizabeth about prostate cancer screening. Pollack Platz and team have found that men with chronic inflammation and his colleagues found that while most have a higher risk of developing aggressive forms of prostate physicians said they took age and life cancer. William Nelson led a research team that found that expectancy into account when deciding to environmental exposures, such as eating charbroiled meat, order PSA screening, many also said they can cause inflammation inside the prostate gland and poten - had a hard time estimating life expectancy tially influence the early stages of prostate cancer. Now, in their patients and welcomed help in investigators are comparing normal prostate tissue and this area. prostate cancers to better understand the extent of prostate Screening is not one size fits all, says inflammation and how it influences cancer development and Carter. While Pollack acknowledges that progression. They will also identify the specific types of immune cells that are triggered by an inflamed prostate to making the shift from a population improve and develop immune-base d treatment approaches. • approach, in which everyone is screened, to an individualized approach, directed to only those who good research tells us will benefit, can be challenging. Men who are ing screening, doctors will instead be physical. This tool helps address misper - not recommended for screening, particu - prompted to discuss the potential benefits ceptions about screening and facilitates larly if they have been screened in the and risk of PSA with him. The tool discussions that will help doctors and past, may be concerned, and doctors may includes talking points to help guide doc - patients make more informed decisions. worry they could miss a cancer. However, tors to speak to their patients about the Carter has conducted large population Pollack says there is conclusive evidence potential risks and benefits of PSA studies involving thousands of men, and that annual screening is not necessary for screening. Doctors will also be prompted the data overwhelmingly show that men everyone. “An individualized approach to explain the potential harms and bene - over age 75 are more likely to die with prostate cancer than of it, particularly if THE GOAL IS TO REDUCE SCREENING, they have other more pressing health problems. As a result, these men will not AND ULTIMATELY TREATMENT, IN PEOPL E benefit from PSA, and Carter says doctors WE KNOW, WITH CERTAINTY, WILL NOT should explain that to them. Kimmel Cancer Center director and prostate BENEFIT, AND INCREASE IT AMONG cancer expert William Nelson frames it PEOPLE WHO WILL. this way, “I tell men who are over 75 and considering routine screening, ‘You don’t just makes sense,” he says. “Our goal is to fits of treatment. need it. You’ve won. Prostate cancer is demonstrate that a personalized approach “The goal is to reduce screening, and not going to be a problem for you.’” results in better care and fewer complica - ultimately treatment, in people we know, If the doctor and patient determine tions at a lower cost, and that is good for with certainty, will not benefit, and screening would be beneficial, the tool everyone,” says Pollack. “ increase it among people who will,” also provides recommendations for when If a man aged 40 to 75 comes in for an Carter says. Men have grown to expect and how often to rescreen. appointment, rather than routinely offer - PSA screening to be part of their annual With all of the confusion, clinician

10 PROMISE &PROGRESS 2012/2013 Michael Carducci wants to be sure that showed that many men with low-grade him and his loved ones. Cameron’s men who have prostate cancer under stand disease would never be harmed by their prostate cancer fit the parameters for that the PSA controversy only involves cancer but could be, and all too often are, active surveillance. He had a low Gleason screening. PSA, he says, remains a vital harmed by treatment. “The majority of score and his cancer was very slow grow - tool in monitoring men who have already men diagnosed with prostate cancer each ing. “Active surveillance sounded like a been diagnosed and in determining if year are over 65 and have a low risk of win-win good thing,” says Cameron. He there is a medical problem in men who dying of their disease if treatment is says regular biopsies done under local are experiencing symptoms. “If you are a deferred,” says Carter. “Yet, more than anesthesia to monitor his cancer were a guy who is up five times a night going to 90 percent of these men, including 80 per - minor inconvenience in exchange for his the bathroom, you have blood in your cent who are over age 75, are likely to ongoing and treatment-free health. He urine, or erectile dysfunction. This is no choose some form of treatment. Active says he was also comforted by the knowl - longer screening. This is diagnosis,” says surveillance addresses excessive treat - edge that five of the world’s best prostate Carducci. “It is important that men understand the difference.” “I TELL MEN WHO ARE OVER 75 AND

TO TREAT OR NOT TO TREAT CONSIDERING ROUTINE SCREENING, OME OF T he greatest potential ‘YOU DON’T NEED IT. YOU’VE WON. of personalized medicine is in using our new knowledge about PROSTATE CANCER IS NOT GOING TO Sthe biology of cancer to get the BE A PROBLEM FOR YOU.’” right treatments to the right patients. Sometimes the right treatment may be no ment of milder stages of prostate cancer, cancer pathologists were reviewing his treatment. especially in seniors.” biopsy samples. Today, at age 71, One important way to reduce harm to About 40 percent of men are diagnosed Cameron remains active and healthy and men is to individualize the management with low-risk disease, and for a signifi - confident that he made the right decision. of prostate cancer. PSA alone is not cant number of them, active surveillance “For any guy in my situation,” he says, responsible for the adverse affects men offers a way to very carefully monitor “active surveillance is the way to go.” have suffered; it has been what doctors their cancer and give them the option to Cameron is among the more than 1,000 have done with PSA—mainly overtreat - delay treatment as long as it does not men who have participated in active sur - ing the disease. When a man is diagnosed progress. Many of these men will never veillance since Johns Hopkins began with cancer, Carter says, it is important require treatment, but if they do, careful offering it 16 years ago, and there are for him to know that invasive treatments surveillance allows the growing cancer to currently about 600 men enrolled. The are not the only option. be spotted and treated while it is still cur - average participant is 67 or older. This Treatments for prostate cancer can able. A National Cancer Institute (NCI) option, Carter says, is for men who are include the surgical removal of the model that uses computer simulation to likely to live out their natural lives without prostate, radiation, hormonal therapies, determine patien t outcomes evaluated all being harmed by prostate cancer. In and chemotherapy. Each of these has the of Carter’s active surveillance data and other words, prostate cancer is not going potential to cause serious problems, such compared it to data from men who would to kill them. The men have a PSA test as erectile dysfunction, impotence, and have qualified for active surveillance but and rectal exam every six months as well urinary incontinence or bowel damage. chose surgery. In a worst-case scenario, as an annual biopsy to carefully monitor For many men, treatment is clearly the the NCI model found that over a 15-year their cancer. More recently, Carter has best option, and our prostate cancer clini - period, men who chose active surveillance added MRI (magnetic resonance imaging) cians are among the best in the world. stood to gain an average of seven addition - to surveillance. “We know that there is Johns Hopkins clinicians have pioneered al years of not being treated, and at the potential to underestimate the extent of surgical, radiation, and drug remedies for most, risked losing three months of life. disease in some men, and MRI helps us the disease, but they have also been on the Pennsylvania businessman Alex make sure we haven’t missed anything,” forefront of a nontreatment approach. It is Cameron was one of the first participants says Carter. “A recent study showed that called active surveillance—active being in active surveillance. Cameron was in when MRI found there was no cancer the key word. his late 50s in 1999 when he was diag - there, there was really no cancer there.” Carter, although one of the world’s nosed with prostate cancer and began For many years, Johns Hopkins was leading prostate cancer surgeons, believes exploring options including hormone the only cancer center to offer active sur - that putting the scalpel aside is sometimes therapy, brachytherapy, and surgery. In veillance. This is, in part, because med - the best tactic for men who are diagnosed his research, he also learned of Carter’s ical reimbursement is a fee-for-service with a low-grade form of the disease. The active surveillance approach and sched - system that favors procedures. Johns approach has been the focus of research uled an appointment. He admits that with Hopkins urologists, arguably the best in the Brady Urological Institute at Johns a wife, three daughters, and eight grand - FOR MORE ON PROSTATE CANCER Hopkins since 1995. Data gleaned from children to live for, the idea of leaving the several large studies unequivocally cancer alone was somewhat troubling to WWW.HOPKINSKIMMELCANCERCENTER.ORG

2012/2013 PROMISE &PROGRESS 11 trained in the world, were the only ones willing to explore the possibility of a bet - ter option for some patients. Endorsement of active surveillance by the Prostate Cancer Foundation and heightened concerns about overtreatment stemming from the U.S. Preventive Task Force’s recommendation, is now bringing this “no-treatment” treatment new consideration. The Prostate Cancer Foundation is working to provide patients more assur - ance and has established the National Proactive Surveillance Network, a Web- based system (NPSN.net) that provides education about active surveillance and helps patients find participating doctors. Soon, patients and physicians will be able to securely access the system to enter, review, and track their own data. Men participating in active surveillance would be able to enter all of their PSA data and track their personal results to see where they fall in respect to other participants.

MOLECULAR REASSURANCE Still, many men, upon learning they have prostate cancer, are uncomfortable leaving the cancer untreated. “They need stronger, quantifiable reassurance that their cancer won’t hurt them, a nd we don ’t have the ability to give them that right now,” says prostate cancer researcher Srinivasan Yegnasubramanian. He believes if physicians were able to remove any doubt, it might change minds and significantly improve outcomes for men. He is working to create an accurate test that could be applied to blood or urine and provide clear biological evidence to distinguish aggressive prostate cancers from the slow-growing type, which could be left alone. A Gleason score is an excellent barom - eter of aggressiveness, but it is only as good as the sample, he says. In men who have a prostatectomy, it is very telling because pathologists have the entire prostate to examine. When a tumor is sampled through a biopsy, though tech - Yegnasubramanian nology has greatly improved, it is still possible to miss critical areas of a tumor that could be the key to distinguishing occur without mutating DNA but can begin to increase, they can alert doctors to harmless cancers from dangerous ones. have the same effect as mutations and a growing cancer. Moreover, they are very Removing this uncertainty is at the core silence the function of important tumor common in prostate cancer. “Epigenetic of Yegnasubramanian’s research. suppressor genes. These changes, known alterations can occur more fre quently and His test is based on chemical alter - as epigenetic alterations, are a signature consistently than muta tions in prostate ations to specific regions of genes. They for cancer and when they are seen or cancer,” says Yegnasubramanian.

12 PROMISE &PROGRESS 2012/2013 Not only do these alterations serve as find in the laboratory and what will truly prostate cancer by shedding new light on signatures for cancer, they are also poten - benefit patients.” other mechanisms that could be targeted tial therapeutic targets. Unlike mutations, Yegnasubramanian also is collaboratin g in treatment. What the investigators in epigenetic alterations, affected genes with Kenneth Kinzler, one of the world’s uncover about the genetic and epigenetic are not missing. Instead, they are leading cancer genetics experts, Stephen basis of extremes of therapeutic response silenced by changes in the chemical envi - Baylin, a foremost epigenetics expert, in prostate cancer will likely reveal ronment, so researchers have the oppor - and nationally known prostate cancer similar information about other cancers. tunity to use drugs to revert genes back to investigators Michael Carducci and Mario normal function. Epigenetic signatures Eisenberger to better understand how PROVING A NEGATIVE could be used to distinguish indolent differences in the prostate cancer genome HE OLD ADAGE , “You can’t prove prostate cancers from aggressive ones, and epigenome have an impact on treat - a negative,” is a dilemma at the monitor cancers for progression and ment outcomes. His research will help T core of creating better screening recurrence, and to determine whether physicians make the right treatment and diagnostic tests for prostate cancer treatments are working. decisions for each individual prostate that limit the need for invasive procedur es. In recent years, the pace of these dis - cancer patient. How do we use scientific discoveries to coveries has greatly accelerated because of In prostate cancer that recurs and prove the absence of cancer with the a new technology known as next generatio n spreads after treatment, the first line of same certainty as we prove the existence sequencing. This powerful technolog y has approach is hormone (androgen) suppres - of cancer? the ability to rapidly and simultane ously sion therapy—in essence cutting off the Despite its problems, Brady Urological sequence millions to billions of DNA supply of hormones that are believed to Institute Director Alan Partin and other molecules. As a result, cancer research be fueling the cancer. At this stage, most prostate cancer experts say PSA is an that used to take decades can now be men will survive about four years. invaluable tool in helping monitor men completed in weeks. Yegnasubramanian However, our investigators have found who have already been diagnosed and, is the director of the Kimmel Cancer that there are extremes in patient survival even with its limitations, remains useful in Center’s Next Generation Sequencing that could provide important new clues the diagnosis of prostate cancer. With a lit - Center, located in the David H. Koch about the disease. Some men progress tle help, Partin says it could be even better. Cancer Research Building. rapidly and may die within the first year Throughout his career, Partin collected He and his team are using this technol - of their recurrence, but others appear to blood, urine and serum samples from ogy, in conjunction with new techniques be cured by the hormone suppression his patients and created the world’s they have developed, to profile prostate therapy, living for years without any sign largest prostate biorepository. It greatly cancers and identify a panel of epigenetic of cancer recurrence. Yegnasubramanian advanced the understanding of prostate markers unique to prostate cancers with and team believe the reasons for these dif - cancer and has been critical in his work high Gleason scores and another to charac - ferences are hidden within the genome to develop biomarker tests that could aug - terize cancers with low Gleason scores. and epigenome of prostate cancer, and ment PSA. The tests, he says, could help Once they identify the specific markers they are hoping to use the power of next diagnose prostate cancer without expos - that brand both aggressive cancers and generation sequencing to uncover the ing men to repeated biopsies. PSA detects slow growing ones, they can adapt the biological differences. cancer but it also detects a lot of other technology to find them in blood and urine. “If there is a question we can ask “IF THERE IS A QUESTION WE CAN ASK where genomic information can help inform who should get a particular treat - WHERE GENOMIC INFORMATION CAN HELP ment and who should be monitored, I INFORM WHO SHOULD GET A PARTICULAR think we can go after it,” says Yegnasubramanian. “The prostate cancer TREATMENT AND WHO SHOULD BE program has one of the best teams on MONITORED, I THINK WE CAN GO AFTER IT. earth to define and tackle these ques - tions.” Though many centers are think - What is different about the cancer things. “We need a test that when it’s ing about these problems, he says Johns DNA of long-term survivors versus those negative, we know the patient is OK. Hopkins is uniquely positioned because of men who have a very rapid progression? Whe n it’s positive, we want to be confi - its strength in translational medicine to The answer would allow clinicians to dent that it’s truly positive. We don’t make progress. “We have equal strength direct more intensive therapies to men want to continue doing four biopsies to in the clinic and the laboratory,” he says. whose cancer DNA predestines them to find the one cancer we’re looking for,” says “This is a major asset that is rarely found be less responsive to standard treatments Partin, who is the David Hall McConnell in other centers doing genome research. and give less therapy, or stop treatment Professor of Urology. Some have the research component but altogether, in men whose cancer DNA do not have the clinical strength we have points to long-term remission. What they SEE VIDEOS ON PROSTATE CANCER here. Having both, allows us to make learn about the extremes of treatment the critical connection between what we responses should also help all men with WWW.HOPKINSKIMMELCANCERCENTER.ORG

2012/2013 PROMISE &PROGRESS 13 A positive PSA means only that a man referred to as biochemical recurrence. could have prostate cancer. Currently, The test uses new nanotechnology TARGETED RADIATION the only way to know for sure is to biopsy approaches to measure PSA values 1,000 THERAPY the cancer, a process in which a needle is times lower than a standard PSA test. A A NEW FORM OF targeted radiation guided by ultrasound, and more recently rising PSA without any visual tumors is therapy, known as proton beam thera - MRI and other imaging technologies, considered a biochemical recurrence, and py, very precisely zeroes in on tumors, through the rectum into the tumor. warns clinicians that prostate cancer cells increasing the damage to cancer cells, While Johns Hopkins cancer researchers may remain in the prostate and increases while minimizing radiation exposure and engineers have led the way in devel - the likelihood that the cancer will ulti - to healthy tissue and organs. Its oping new technologies that make mately return and spread. precision and safety has improved prostate tumor biopsies remarkably pre - Partin and team studied blood samples Aradiation treatment and become the cise and safe, many men still undergo from 31 men who had undetectable PSA, standard of care for pediatric cancers, repeat biopsies to confirm or disprove a using the standard test, for five years after tumors of the brain, spine and eye, cancer. Each biopsy carries a risk of prostatectomy. One-third of the men later and cancers of the lung, head and bleeding and infection. Partin believes a began to have a rising PSA, and when neck, and bone (sarcoma). The new urine test based on a genetic discov - Partin used AccuPSA on the blood sam - Kimmel Cancer Center is currently ery by Brady Institute laboratory scientist ples, he found that the one-third of men developing plans for a proton beam William Isaacs may help dispel some of with biochemical recurrence had a small facility on its Washington, D.C., the uncertainty and alleviate the need for but measurable rise in their PSA just campus to provide care for patients multiple biopsies. three months after surgery. In the other with these types of cancers and also will be one of the few centers embark - IDENTIFYING WHICH MEN WILL HAVE ing on evidence-based research to determine other cancers best treated CANCERS THAT ARE LIKELY TO BE by proton beam therapy. CURED WITH STANDARD TREATMENTS There is growing concern among prostate cancer clinicians and scien - AND THOSE MEN WHO HAVE CANCERS tists because the most commonly pro - DESTINED TO RETURN AND SPREAD IS ton beam-treated cancer is prostate cancer, and there are currently no ESSENTIAL TO THE MANAGEMENT OF research studies or findings to support PROSTATE CANCER. it. Kimmel Cancer Center Director William Nelson and Radiation Unlike PSA, this new gene-based men, 75 percent had AccuPSA levels Oncology Director Ted DeWeese, both urine test, called PCA3, only detects lower than the men who recurred. The prostate cancer experts, are among the prostate cancer, but it too has its limita - small study allowed Partin and team to concerned, and they are committed to tions. While PCA3 outshines PSA in determine a threshold for AccuPSA that gathering the needed research-based terms of its specificity to prostate cancer, could help them distinguish, within a few evidence to prove, or disprove, its ben - it is not as sensitive, so it has the potential months after surgery, men whose cancer efit. One of the first research projects to miss cancers. PSA, on the other hand, has been entirely eliminated with surgery at the Kimmel Cancer Center proton is very sensitive—quite good at picking up from those who may have had some beam facility will be the important abnormalities in the prostate—including remaining cancers cells that could put basic science and clinical studies that (but not limited to) cancer. Combined, the them at risk for cancer recurrence in the will help resolve the scientific contro - two tests compensate for the other’s immediate years after surgery. versy surrounding the use of proton shortcomings and, as a result, have the Identifying which men will have can - beam therapy for prostate cancer. • potential to very accurately detect cancer. cers that are likely to be cured with stan - If a man has an elevated PSA, but a biop - dard treatments and those men who have sy did not reveal cancer, Partin says the cancers destined to return and spread is 1950s and later refined by Johns Hopkins PCA3 test could potentially serve as the essential to the management of prostate pathologist Jonathan Epstein, ranks the final word. “If a PCA3 is negative, you cancer, says Partin. nature of the prostate cancer on a scale can trust that the patient probably does of six to ten. Gleason six represents a not have prostate cancer. If it is positive, SEPARATING THE “GOOD” lower- risk cancer; seven through 10 then he probably does,” Partin explains. FROM THE “BAD” means the cancer is more dangerous. “It adds another piece of information to The complexities of managing prostate In short, the lower the number is, the help us better and more safely diagnose cancer go beyond the PSA controversy. better. Evaluated in conjunction with prostate cancer.” Prostate cancer experts have gotten PSA (Prostate Specific Antigen) tests, Partin also is working on a test called extremely adept at separating aggressive biopsy results, and the size of the tumor, AccuPSA to monitor prostate cancer cancers from nonaggressive cancers. The our experts say it does a good job guiding patients following surgery for what is Gleason score, first established in the treatment.

14 PROMISE &PROGRESS 2012/2013 As one of Hopkins busy prostate can - Schaeffer is now working to decipher who learned how to do prostatectomies cer surgeons at Johns Hopkins, Edward the specific mechanism that controls the by training under its pioneer Patrick Schaeffer has observed first hand that gene in hopes of developing a treatment Walsh, the undisputed paragon for how it while many of his patients are cured with that can reset SPARCL1 to normal and should be done—do not need the assis - surgery, some of them inexplicably have prevent cancers from returning. tance of da Vinci. On the other hand, their cancers return. In his laboratory, robots can be quite helpful and sometimes he is working on ways to identify these THE CASE FOR OPEN make it possible for surgeons who do not patients and to develop new treatments AND CLOSED have the skills to perform a Walsh-style to prevent the cancer’s return. HE DA VINCI robotic surgical sys - open procedure to perform prostatectomies. To decipher clues about the abnormal tem has made minimally invasive When it comes to prostate cancer, men cell growth that leads to prostate cancer T surgery a household word and has may have a difficult time distinguishing growth and spread, Schaeffer identified become a favorite marketing tool of com - good marketing from good medicine. and focuses on a group of genes that regu - munity hospitals around the country. Patients hear advertisements about one lates and controls normal prostate devel - The da Vinci system boasts smaller machine or another, and they think if opment. He postulated and subsequently incisions, less pain, shorter hospital stays, their doctor does not use it, he is not showed that genes that control the move - and shorter recovery time for patients. practicing good medicine, warns John ment and invasion of prostate cells during In certain instances, this is true. For Wong, a Kimmel Cancer Center medical normal prostate development, become prostatectomy, however, not everyone physicist who has invented several reactivated in prostate cancers. agrees. Prostate surgeons—like Alan cancer-related devices. Many claims, he Schaeffer’s work has not yet revealed the Partin, H. Ballentine Carter, Edward says, are made with no scientific evidence triggers to turn these invasive genes back Schaeffer, and the many other urologists to back them up. on, but he has found that the molecular process is linked to the most aggressive prostate cancers. This promising finding allows him to not only pinpoint those Tran patients whose cancers are destined to return after surgery, but it also reveals a potential new target for treatment. Schaeffer’s laboratory team, led by Paula Hurley, is particularly interested in a gene known as SPARCL1, which can accurately predict whether a seemingly localized tumor will return and spread within a few years after surgery. The nor - mal prostate has high levels of SPARCL1 expression, which holds cells in check, preventing them from migrating and moving around. Low levels of SPARCL1 allow cells to move well, serving as a bio - logical red flag that the cancer will return with a vengeance. Currently, Gleason Score is used to identify more aggressive prostate cancers. For example 30 percent or more of patients with a Gleason Score of seven or CHOLESTEROL DRUGS higher are at highest risk of having their GOOD FOR HEART DISEASE AND PROSTATE CANCER cancers return. Unfortunately, there is POPULATION STUDIES AT JOHNS HOPKINS have shown that men on choles - currently no way to differentiate the terol-lowering drugs known as statins have a greatly decreased risk of developing patients who are cured with surgery from advanced prostate cancer. Physician and scientist Phuoc Tran has gone back to the those whose cancer will recur. Measuring laboratory to figure out why. He suspects that these drugs block the activity of an SPARCL1 expression at the time of sur - important cancer-growth-promoting gene known as c-myc, and he proved in laboratory gery seems to provide the answer. In studies that high-dose statins, in fact, reduce c-myc activity. Now Tran, a radiation addition, Schaeffer’s research indicates oncologist and expert on the c-myc oncogene, has initiated a clinical trial in collabora - that SPARCL1 could also play a role in tion with urologist Edward Schaeffer to verify in prostate cancer patients what he predicting tumor recurrence in a number observed in the laboratory. If he confirms his findings, it could open the door to treat - ment strategies that could improve surgery or radiation therapy outcomes. Similarly, of other tumors, including bladder, statin-based prevention approaches could lock prostate cancer in a nonthreatening breast, colon, rectum, tongue, lung, skin, stage and potentially stop it from occurring at all. • and ovarian cancers.

2012/2013 PROMISE &PROGRESS 15 Partin agrees, saying that Johns Training is key. Patients need to Hopkins always evaluates new approaches understand that that the robot is not as NO SMOKE from an evidence-based scientific stand - important as who is operating the robot, A GOOD REASON TO QUIT; point. “We were using the da Vinci robot says Schaeffer. Johns Hopkins urologists A GOOD REASON TO DIET long before it was famous,” says Partin. are probably the best in the world at both CORINNE JOSHU , the Martin D. Abelof f “But, we take marketing and profits out open procedures and robot-assisted sur - Cancer Prevention and Control Scholar- of the equation and look at what really gery, he says. Patient demand supports in Training, was looking for straightfor - works the best for patients.” this contention. Johns Hopkins urologists ward lifestyle remedies that could Investigators in the Johns Hopkins are the most sought after, performing decrease the risk of recurrence in men Center for Computer-Integrated Surgical hundreds more prostatectomies than any Joshu who had surgery for Systems helped develop some of the tech - other hospital in the world. Their record prostate cancer and nology used in the da Vinci system, which is stellar, getting all of the visible cancer whose cancer had not employs robotics, sensors, imaging 90 percent of time while also preserving spread. She found that devices, and guidance systems to interface sexual and urinary function. Schaeffer men who were smoking and assist surgeons when operating. says he finds that some men prefer the one year after surgery Brady Urologist and biomedical engineer minimally-invasive prostate surgery doubled their risk of Mohamad Allaf works with these scien - approach, so unless the tumor is large and their prostate cancer coming back. tists and is director of minimally invasive bulky or has other characteristics that Former smokers and nonsmokers had and urological robotic surgery. Johns demand an open procedure be performed, no increased risk. Joshu says that smok - Hopkins was one of the first medical he usually leaves the choice up to the ing causes cell damage that triggers the institutions to integrate robotics into uro - patient. This is where the skill of the Johns growth of new cells to replace damaged logic surgery, and Allaf is considered one Hopkins urologists, experts at both types cells. It’s possible that this process sets of the world’s leading experts. He travels of surgery, makes a difference. They are in motion genetic changes that facilitate around the globe demonstrating and train - not limited to one or the other, so they can the return of the prostate cancer. ing other surgeons in robotic prostatectom y, select the approach that is best suited to Joshu also looked at weight change nephrectomy (kidney) and other urologica l each patient’s individual cancer. from five years before surgery to one operations. Like the other Brady surgeons, year after. She found men who gained Allaf is as skilled at open proce dures as HELPING PATIENTS five or more pounds (10 to 11 pounds on he is at robotic approaches, but with the MAKE THE RIGHT DECISION average), after surgery also doubled continuing demand from patients for Johns Hopkins prostate cancer experts their risk of cancer recurrence when minimally invasive procedures and his have pioneered therapies, diagnostic tests, compared to men who maintained their work innovating the next generation of imaging te chniques and basic science dis - weight. It didn’t matter if they were robotics in medicine, it is his focus. coveries. However, what Schaeffer and his normal weight or overweight to begin In terms of prostatectomy, Partin says fellow Johns Hopkins urologists and oncol - with. It was the act of gaining weight it’s a draw. Studies show that open ogists take the most pride in is providing that seemed problematic. Joshu is procedures and robotic procedures, personalized treatment plans for each working with researchers to figure out when performed by trained surgeons, patient, whether it is surgery, radiation why. “If you’re gaining weight, you are are equally good and there is really not treatment, hormone therapy, active surveil - in the process of active growing. much difference in pain or recovery. lance or a combination of these approaches. Perhaps this growth-promoting envi - ronment allows evasive tumor cells to set up shop and cause a cancer recur - rence down the road,” she says. With support from the Abeloff Scholars program and the Maryland Cigarette Restitution Fund, Joshu is investigating precisely how these lifestyle factors contribute to prostate cancer progression. “On a day-to-day basis, our bodies are trying to fight the outside world,” explains investigator Michael Carducci, who is collaborating with Joshu on the study. “Internally things are getting turned on to combat these exposures. The more you can limit these forces by not smoking and maintaining a healthy weight and diet, the easier you make it Drake on your body.” •

16 PROMISE &PROGRESS 2012/2013 Platz SCIENCE, POPULATIONS AND PROSTATE CANCER LIZABETH PLATZ IS a population scientist. She uses questionanaires, E records, and biospecimens to observe men—what they do and what they do not do—and applies what she sees to prostate cancer. For example, her land - mark study of nearly 5,600 men aged 55 and over, found those with normal or low serum cholesterol had a 60 percent lower risk of developing aggressive (high-grade) prostate cancer than men who had borderline and elevated levels. In an earlier study she observed that men who used cholesterol-lowering drugs known as statins had a decreased risk of develop - ing aggressive prostate cancer. There seemed to be a link—men with lower cholesterol and men who used cholesterol-lowering drugs, improved there prognosis, decreasing their risk of developing a more aggressive form of prostate cancer. To determine why she finds the things she finds, Platz, the Martin D. Abeloff Scholar in Cancer Prevention and Control, turns to her laboratory and clinical science colleagues to unearth answers, and vice versa. Marion I. Knott Professor and Director of the Kimmel Cancer Center William Nelson and investigator Srinivasan Schaeffer, medical oncologist Charles treatment best suited to each patient,” Yegnasubramanian worked with Drake, and radiation oncologist Danny says Schaeffer. “People come to our clinic researcher Jun Liu, who has constructed a Song co-direct a clinic where patients from after being told they need surgery and are repository of more than 3,000 FDA- around the world come to relieved to find out we can offer them an approved medicines, in hopes of identify - have their prostate cancer alternative to surgery. By the same token, ing some commonly used noncancer scrutinized by leaders in we have men who come to our clinic drugs that might work against prostate the field. Some men have because they have been told they cannot cancer. When they screened human localized disease and are have surgery, and we cure them,” he says. prostate cancer cells against the drug uncertain about what is He recalls one patient, in particular. He library, two of the top 15 hits were statin Song the best treatment for was 47 years old and had been told his drugs. One was digoxin, an older drug them. Others have more aggressive can - cancer was incurable. He came to the that, in the past, was commonly used to cers they have been told are not treatable. prostate cancer clinic, where Schaefer treat congestive heart failure. About- one quarter of the patients who and team worked out a plan that included Scientists are looking for new ways to come to the clinic have a change in the surgery and radiation therapy. That contain the cost of drug discovery, an grade or stage of the cancer, once examined patient continues to do well today. ente rprise in which a billion dollars can be by the Johns Hopkins team, which include Why can Johns Hopkins experts offer spent to bring one drug to market. The radiologists and pathologists, like Jonathan patients treatments that other hospitals promise of most drugs, or lack thereof, is Epstein, the world’s most sought after cannot? “The technical experience is usually only realized after years of costly prostate cancer pathology expert. Most of better here than anywhere else in the research. As director of a cancer center, the time, patients get better news than world,” says Schaeffer. “But just as Nelson understands cancer researchers what they were initially told. By the end of important, we know how, when, and to have to do better. He envisioned a two-stage the day, the crack team will have laid out whom to employ this expertise. This approach to see if what he, Yegnas ubramanian, for them treatment options and plans . personalized approach is the essence of and Liu found in the laboratory studies of “We offer a service based on our the Prostate Multi-D Clinic, and we do it prostate cancer cells would be supported extensive experience that delivers the better than just about anyone.” or refuted by what Platz observed in men. (continues on page 22)

2012/2013 PROMISE &PROGRESS 17 18 PROMISE &PROGRESS 2012/2013 d r a w o H

r e t e P

: y h p a r g o t o h P

[ TRANSFORMING PROS TA TE CANCER ] Damon Sings

Former Temptations membe r DAMON HARRIS reflects on his 14-year battle with prostate cancer.

by Valerie Matthews Mehl

2012/2013 PROMISE &PROGRESS 19 TODAY, WHEN DAMON HARRIS LOOKS AT OLD 1970 s PHOTOGRAPH S of himself performing as a member of the vocal group the Temptations, he does not simply reminisce about his twenties and the heyday of his career. Instead he reflects at what the camera lens does not reveal. Beyond the spotlight and celebrity , he marks the beginning of his battle with prostate cancer.

AMON WAS DIAGNOSED unmistakable. Damon did not just have turned up a patient-led advocacy group with advanced prostate can - prostate cancer; he had bad prostate can - called the National Prostate Cancer cer in 1998 at just 47 years cer. His biopsy and other tests revealed Coalition (NPCC). The urologist Damon old, but he has since learned that the cancer had already spread. saw in Nevada did not offer much hope, Dfrom his doctors that this but a contact he made while attending the slow growing cancer had probably started group’s annual meeting in Washington, forming 20 years earlier. At the time the D.C., did. Damon became friends with photos were taken, there were no symp - Judge Ralph Burnett, himself a newly toms to alert him to the invisible genetic diagnosed prostate cancer patient and the miscues occurring within his body and organization’s chairman at the time. The giving rise to the cancer cells. He was judge was a champion of increased unaware that as an African- American research funding and education for men man with a family history of prostate can - diagnosed with the disease. “He was gen - cer, he was at increased risk for the dis - uinely concerned for me and told me I ease and at risk for developing it at a needed to see his doctor, Dr. Bill Nelson at younger age. His father died when Damon Johns Hopkins,” says Damon was just 25. However, Damon did not Damon followed Judge Burnett’s realize until he read the death certificate advice and made an appointment to see that his father died from prostate cancer. Dr. Nelson. Damon’s prostate cancer was “I saw my Dad die. I saw him suffer, but too advanced to be cured with surgery, he never talked about it,” says Damon. It but hormone drug therapy could—and was indicative of the time. “Black men did—keep it in check. The treatments didn’t talk ab out prostate cancer,” he says. As a young man, he had dreamed of have not been without their side effects, Flash forward 15 years, and perhaps living in Reno. His plans did not include but he has been well enough to continue things are not that different. Damon a diagnosis of prostate cancer. Within performing. A highlight for him was per - recalls living with symptoms for five days of his diagnosis, he went to the Reno formances last year at the Kimmel Cancer years before going to the doctor. Like his chapter of the American Caner Society Center’s Cancer Survivor’s Day celebra - father before him, he suffered in silence. (ACS) for what he calls his “crash course tion and Art of Healing Program. He He convinced himself that the pain he in Cancer 101.” The local ACS director sang “We Shall Overcome,” and was was experiencing was just a normal part asked Damon to be a coordinator and joined by patients in a moving and spon - of middle age. “I was stretching and put - facilitator for its Man-to-Man program, an taneous display of courage and solidarity ting cold compresses on my pelvis trying education and support program for men that, while emotional for all who wit - to relieve the pain.” with prostate cancer. He spoke to many nessed it, was probably only fully appre - He was living in Philadelphia at the groups. The black population in Reno ciated by those fighting cancer. “I was time. He had spent the last decade touring was very small, so he was the only black moved to ask patients to come stand with internationally as a solo artist and had man in the room. “It was an eye-opening me because I could identify with what decided to relocate to Nevada to work with experience for them and for me,” recalls they were going through,” says Damon. a singing group who was performing at a Damon. “It was an unusual encounter for “Though we all have different experiences hotel in Reno. He enrolled at the Reno us all, but despite the obvious differences, in fighting our cancer, we are also joined campus of the University of Nevada to we were brothers. The disease brought us together by a similar experience. I was the continue his studies in music education. together.” one on the stage singing, but my voice A few years later, the pain returned, The ACS sent Damon around the was speaking for all of us.” and now it was intolerable. Dr. Carol country to attend national conferences For the first time, Damon has written, Scott at the University’s Health Center and other prostate cancer events. His arranged, and produced his own music. convinced him that he needed a PSA test “crash course” also led him to another He recorded “You are My Woman” last and prostate exam. The results were prostate cancer group. An internet search spring at Johns Hopkins Peabody

20 PROMISE &PROGRESS 2012/2013 Institute accompanied by Peabody musi - when he began experiencing symptoms, are reluctant to talk about it, we are never cians. “People I have met through this he still would not have gone to the doctor. going to get this problem under control.” battle and all that I have gone through “Sadly, the thought of having a DRE [digi - While he hopes for a greater impact, with treatment, thinking I would never tal rectal exam] is scarier for many men Damon says if his work gets just one man sing again, inspired me to record this than dying,” he says. “I’ve heard men to talk to his doctor about prostate cancer, song,” says Damon. “Those experiences say, ‘I’ll die before I do that,’ and I want to he feels he’s made a difference. gave me hope and purpose and a belief do anything I can to make sure that does - Sharing his journey and his experience that my life was not over.” n’t happen.” at Johns Hopkins is one way he hopes to Damon says he also has drawn To help get his message out and pro - accomplish that goal. “Johns Hopkins is inspiration from his old friend Judge vide support to African-American men, the greatest hospital in the world,” says Burnett, who passed away in 2007, but Damon has formed the Damon Harris Damon. “I’m not a wealthy man as many not before leaving a lasting mark. Under Cancer Foundation and is developing an would expect or imagine, so it’s not my his leadership, first as chairman and later associated website that links African- celebrity that has earned me the best as a board member, the National Prostate American men to African-American urol - treatment. In my experience, it’s repre - Cancer Coalition tripled its membership, ogists. It was an idea that came to him sentative of what Johns Hopkins delivers and federal funding for prostate cancer while attending a conference through the to each and every patient,” says Damon. research doubled. He was a staunch and American Cancer Society. A chance Dr. Nelson points out that Damon vocal supporter of Johns Hopkins, lever - meeting with acclaimed black urologist Harris is a perfect example of someone aging support from the Department of Janice Arnold made him think, “Maybe who may have benefitted from screening. Defense for the Johns Hopkins prostate some black men would be more willing to With so much attention focused on over - cancer program and advocating for the get screening examinations if they could screening men, Dr. Nelson wants men to Kimmel Cancer Center’s National Cancer go to an African-American doctor. The understand that screening is not bad; Institute SPORE (Specialized Programs of history of black people in America is such screening the wrong people is bad. He Research Excellence) grant for prostate that some black men are understandably says, “What we need to do is target cancer. Judge Burnett participated in reluctant to listen to white doctors. The prostate cancer screening to the right studies that helped Johns Hopkins scien - trust is missing,” he says. “But, we can’t men, those who will benefit, and away tists begin to unravel the complex genetic quit trying to get the message out.” His from those who will not.” changes associated with prostate cancer. goal is to make sure every man has an Even though Damon missed the Judge Burnett asked Damon to help option that works for him. If going to a opportunity for early detection and a the group reach out to black men who, as black doctor is more comfortable, he cure, he still considers himself a prostate Damon now understood all too well, were wants them to know where to find one. cancer success story. At 62, he has lived more likely to develop prostate cancer at a “Information is key,” says Damon. with advanced prostate cancer for 14 younger age but less likely to get “People need to make their own decisions. years. He attributes his survival to a com - screened. “Judge Burnett thought black The decision I made may not be the right bination of “his doctors’ work and God’s men might feel more comfortable hearing one for someone else, but I try to help grace.” He says, “The Kimmel Cancer is a from and talking to another black man,” make sure people at least have the facts, second home to me. I feel certain that if I says Damon. A deeply spiritual man, like ACS and the NPCC did for me.” had not come to Johns Hopkins, I would Damon began to find a Godly purpose in not be alive now.” his diagnosis. “Maybe I was being called “TO HAVE CANCER Recently, the cancer has started to to do this. If I could use my experience grow again, and he is beginning radiation with the Tempts and Motown as a plat - IS NOT TO DIE. treatment to knock down some painful form to promote awareness, then I feel TO HAVE CANCER tumors pressing on the nerves in his hips like something good came from my and spine. He also is eager to begin treat - struggle,” he says. IS TO LEARN HOW ment with a new FDA-approved drug Some black men have not been recep - TO LIVE.” called MDV-3100. He continues to be tive, he admits, but he refuses to give up. impressed with the combination of “My experience is not everyone’s experi - First and foremost, he hopes that shar - approaches his doctors have used to keep ence. Some people are intimidated. Some ing his story and providing connections to his cancer under control. When drug just get tired of fighting the obstacles. I doctors will encourage men to discuss treatments have failed, he says, radiation want to educate and arm all men, so they prostate cancer with a doctor before they therapy has stabilized the cancer. will at least have the information they have symptoms. “Race is a sensitive Despite it all, Damon feels blessed. He need to make decisions,” says Damon. “I issue. The media are afraid to talk about does not ask why or wonder what if. “I especially want young African-American the problems of prostate cancer in was given the gift of voice, and I am being men and the nation to understand that African-American men. There is a hesi - allowed to use that voice and to be heard this is not just an ‘old man’s disease.’ I’m tance to emphasize race, but we can’t be through my music and my experience wit h living proof of that,” he says. Damon afraid to say that in America prostate can - cancer to help other people,” says Damon. admits that even if he knew there was a cer is different in African-American “To have cancer is not to die,” he says. “To prostate cancer screening test or exam men,” says Damon. “It’s a fact, and if we have cancer is to learn how to live.” •

2012/2013 PROMISE &PROGRESS 21 could develop treatments that would ben - efit all men. In this new age of molecular medicine, was there something else beyond currently used pathology indica - PRO ANTIANGIOGENESIS tors—stage, Gleason grade, and PSA— ANTIANGIOGENESIS: IT’S A LONG word to describe cancer treatments that work hidden within the cancer cell that could by cutting off the blood supply that tumors need for nourishment and growth. determine prognosis? Hammers Clinician-scientist Hans Hammers is hoping to take what he’s It was 2004, four years before Johns learned from success using antiangiogenesis therapies for kidney Hopkins researcher Carol Greider would cancer to better treat prostate cancer, where antiangiogenesis win a Nobel Prize for her research on has not worked so well. chromosome ends known as telomeres. Traditional chemotherapy does not work at all in kidney cancer. Similar to the plastic coverings that shield The kidney, adept at flushing out toxins, gets rid of anticancer the ends of shoelaces from damage, one drugs before they can go to work. Antiangiogenesis discoveries can think of telomeres as the protective end totally changed the way kidney cancer is treated, Hammers says, and every antian - caps of chromosomes. Building upon giogenesis agent they use targets a single pathway, known as VEGF Greider’s growing body of work, Meeker VEGF helps tumors develop the blood vessels they need to grow and spread. and De Marzo received a Maryland Targeting the pathway with treatment tears down vessels that have already formed, Cigarette Restitution Fund grant to study and blocks the development of new ones, and shrinks kidney cancers by half. telomere length and its potential link to Hammers believed he should be able to achieve the same response in prostate can - cancer. As normal cells age and divide, cer, but theses cancers were inexplicably resistant to the treatment. Animal studies some of the telomere DNA is lost and funded by the Maryland Cigarette Restitution Fund allowed him to trace the resist - telomeres get shorter and shorter. Normal ance to very primitive cells that march away from the tumor and begin growing else - cells monitor the length of their telomeres where in the body, in a process known as EMT. Hammers examined stable, treat - and initiate cell death if they get too short. ment-responsive kidney and prostate cancers. When he altered tumor cells to initi - It was already well recognized that telom - ate EMT, the cells became resistant to antiangiogenesis treatment. “What we see in eres were shorter in cancer cells than nor - a high Gleason grade, which represents the most aggressive prostate cancer, is mal cells. They wondered whether this essentially EMT occurring,” says Hammers. “Gleason rating is a depiction of EMT.” monitoring system breaks down in cancer Hammers is working to decipher the specific cellular mechanisms involved in EMT cells and whether assessing telomere length and identify targets for treatment. He believes targeting EMT could make could be a marker for prostate cancer aggres - antiangiogenesis treatments effective against prostate cancer and potentially siveness. In preliminary studies, the investi - many other cancers as well. • gators examined precancerous prostate lesion s and found much shorter telomeres. Platz and her epidemiology colleagues fol - researchers are now working to figure out This finding was the focus of their con - lowed nearly 50,000 men and compared exactly how it works in prostate cancer . versation as they sat huddled on the train digoxin users to nondigoxin users and Digoxin has a number of side effects, outlining the next step in their research. found men who took the drug had a 25 but Nelson says if they figure out how Their excitement about studying telomere percent lower risk of developing prostate it works, they can develop or identify length to see if it could tell them somethin g cancer than those who did not. Now, the another drug that can safely treat or new about prostate cancer aggressiveness team had laboratory evidence that digoxin even prevent prostate cancer. and prognosis did not go unnoticed by halted prostate cancer cell growth and a their fellow passengers in the “quiet car.” population study that found a significantly A TRAIN RIDE AND Unaware of their cancer discovery and decreased risk of prostate cancer among TELOMERES unappreciative of the chatter, Meeker, men who took the drug. Riding the train together on the way back De Marzo, and Platz were soon asked to It was unlikely a fluke. Getting the from a prostate cancer meeting in 2004, find different seats on the train. same findings twice, once in the laborato - researchers Alan Meeker, Angelo De Marzo, With funding from the Department ry study and then in the population study, and Elizabeth Platz enthusiastically of Defense, they began to study the ideas removed the likelihood that that the Rplanned the next phase of their break - they discussed on the train ride. They results they were finding occurred by through prostate cancer study. examined telomere length in the chromo - chance. Prostate cancer experts at Johns De Marzo is among the world’s best somes of human prostate cancer cells and Hopkins and around the world deemed prostate cancer pathologists, but what he nearby cells from the stromal or connective Nelson and team’s laboratory/population couldn’t figure out was why men with tissue surrounding the prostate that had approach quite smart. Combining the two seemingly similar cancers under the been preserved in a special specimen bank types of research helped ensure that the microscope often had very different at Johns Hopkins. Cell by individual cell, investigators were not wasting time or outcomes in the clinic. a research fellow painstakingly circled limited resources pursuing a dead end. What was different about their cancers , every relevant cell on digital images of With good evidence that the heart drug De Marzo, Meeker, and Platz wondered. tissue that were stained with a fluorescent truly has anticancer properties, the If they could figure it out, perhaps they dye to mark the telomeres. A computer -

22 PROMISE &PROGRESS 2012/2013 ized method quantified telomere length, treatment and determine precisely what properties. Kimmel wanted his cancer the number of short telomeres, long telom - treatments will work for each patient,” center to figure out if it was true, and eres, and mix of both. Meeker and De Platz says. Examination of telomere Center Director William Nelson thought Marzo developed the approach to complete length could also be used to help identify Carducci was just the person to sort it such a thorough and comprehensive exami - men whose cancer is likely to progress all out. nation. No research team had ever looked and would not be good candidates for Carducci, the AEGON Professor in cell by cell, opting instead to study bulk tis - active surveillance. Conversely, it could Prostate Cancer Research, decided not to sue, primarily because it was a simpler and be used to provide more evidence of limit his work to pomegranates. There are less labor-intensive process. Meeker recog - low-risk disease and give reassurance to a range of natural products marketed for nized they could miss something doing it men who are enrolled in active surveil - prostate health, and Carducci decided to that way. In fact, what they found could lance. “Treatment has side effects. We follow Kimmel’s lead and conduct studies only be deciphered by a method like the don’t want to give it to a man who does to look for real, scientific evidence that one Meeker and De Marzo developed. not need it or when we know it will not these natural ingredients had an effect on The research team was surprised to learn help,” says Platz. “Telomeres may be a prostate cancer cells through clinical that it was not short telomeres in the can - marker we can use to individualize our studies. He has recently completed studies cer cells that seemed to matter but rather prostate cancer therapy to maximize of pomegranate and is now beginning to the variability in the length of telomeres benefit and minimize risks and adverse look at Vitamin D and soy protein as well from cancer cell to cancer cell that influ - affects for each patient.” as muscadine grapes skins. enced the outcome of men with prostate The UCLA study found that pome - cancer. The unconventional approach WONDERING ABOUT granate juice slowed PSA doubling time was dead on. “If we had done it the way THE WONDER FRUIT in men who had prostate cancer, an everyone else does it, we would have HE IDEA for Michael Carducci’s indication that pomegranates could be never found this,” says Platz. “Some were clinical research of the pomegran - slowing the progression of the disease. shorter. Some were longer, but it was the T ate fruit actually came from the Carducci wanted to see if he could repli - variability from cell to cell that predicted Kimmel Cancer Center’s benefactor and cate these results and also determine if lethal prostate cancer, and it could be namesake Sidney Kimmel. A pomegranat e the amount a person consumes makes a found only by looking at each cell.” product manufacturer was widely touting difference. For his studies he used POM Variable telomere length in prostate a UCLA study that seemed to indicate Wonderful pomegranate extract capsules cancer cells and short telomere length in that the fruit had prostate cancer-fighting because the product is 100 percent pome - the nearby stromal cells translated to a much higher risk of dying from prostate Carducci cancer. Prostate cancer cells with less variability in telomere length and longer telomeres in the stromal cells marked a less aggressive form of prostate cancer. When they separated the samples based on these characteristics and referenced back to the actual patients from whom they were obtained, the investigators found that only one man in the lower-vari - ability/longer telomeres group died from his cancer compared to 20 in the higher- variability/shorter telomeres group. “The marker gives us information and de tects high-risk disease independent of other screening and staging tests,” says Platz. With support from the Department of Defense, the National Cancer Institute Prostate Cancer SPORE grant, and the Johns Hopkins Prostate Advisory Council, the research team is now working to develop an automated approach to speed up the burdensome process of measuring telomere length in individual cells. The team sees many potential applica - tions for their discovery. “Maybe there are subsets of men in whom we can use telomere length to predict response to

2012/2013 PROMISE &PROGRESS 23 The Co ffey Way DONALD COFFEY WAS RAISED IN THE HILLS OF BRISTOL, TENNES SEE IN THE 1930 s. His father ran a service station. Neither of his parents finished high school. He struggled in school himself—repeated grades, was asked to leave his first college, and was rejected by 20 graduate schools. He never heard of Johns Hopkins or Baltimore, and never knew a doctor or anyone with cancer, but after praying and medi - tating, he had what he describes as an overwhelming desire to study cancer. The unlikely journey that brought him to Johns Hopkins was far from easy, but as Johns Hopkins leadership would soon recognize, one of academia’s worst students was an astute learner and even better teacher. Coffey became one of Johns Hopkins foremost experts in prostate cancer and one of its most sought after professors.

Coffey's most recent research focuses on temperature and how it can be used to treat cancer 24 PROMISE &PROGRESS 2012/2013 {THE COFFEY WAY} “DON’T ASSUME ANYTHING YOU CAN’T PROVE.” Coffey

n more than 50 years at Johns look at the core of the nucleus. It was a cancer research, Drew Pardoll, an M.D.- Hopkins, Coffey has racked up a revolutionary idea. Most scientists Ph.D. student, and Bert Vogelstein, who long list of accomplishments. Many believed there was nothing inside the core. Coffey calls the only true genius he’s Iof the accolades are as unconven - Popular thought was that there was no ever met. tional as the man. He served as acting single place in the cell where DNA was Pardoll theorized that rather than chair of the Department of Pharmacology copied. Instead, scientists hypothesized using one mobile recording head, the without ever taking a course in pharma - that DNA was like a tape and was repli - DNA tape was instead copied at thou - cology. With no medical degree, he helped cated by a moving recording head, of sands of fixed sites along what they found the Cancer Center in 1973 with its sorts, which ran along the stationary tape. dubbed the nuclear matrix. Coffey first director Albert Owens and then ran it Coffey disagreed. He believed the core of explains, “The nucleus has a skeleton to in 1987, and served as President of the the nucleus was where DNA was copied it. That’s the nuclear matrix. Attached to American Association of Cancer Research and that the tape-like DNA strands, a that skeleton are recording heads, the from 1997 to 1998. The jovial, spectacled, yard long, were coiled tightly inside the machinery that replicates DNA. The DNA southern-speaking Ben Franklin look cell nucleus. is organized in thousands of loops moving alike is a one-of-a-kind, and his story is as For those born in the digital era, the through these heads.” Vogelstein used a much about cancer research as it is about tape cassette and recorder analogy seems series of calculations, which Coffey the human spirit. outdated, but one has to remember this describes as too complex to translate, and The early research of Donald Coffey research was occurring in the 1970s. showed that Pardoll’s model could work. was in many ways the bedrock on which modern genetic and epigenetic discoveries {THE COFFEY WAY} at Johns Hopkins were built. In 1974, he “THE EXPERIMENT THAT DOESN’T COME turned the research world upside down challenging the popular thought on how OUT THE WAY YOU THINK IT SHOULD IS DNA was copied. At the time, little was THE ONLY EXPERIMENT THAT IS REALLY understood about DNA and genes. Most researchers were interested in under - GOING TO TEACH YOU SOMETHING NEW.” standing what it was and what was recorded on it. Not surprising, Coffey had With a $500,000 no-strings-attached Coffey recognized that a doubting scientif - a different idea. He was interested in the cancer research grant from Bristol Myers, ic community would not believe it unless st ructure of the tape and how it was Coffey brought together two young up- they could see it, so they showed what all organized in the nucleus. He decided to and-coming unknowns in the field of of it looked like through pictures and

2012/2013 PROMISE &PROGRESS 25 scale models. Coffey recalls, “Ken Pienta Baylin and William Nelson showed that Company, and his boss there, a Johns and I went to Sears and bought a jigsaw, the coils and loops touch and interact Hopkins alumnus, inspired him to go to and we built an award-winning scale with many gene sites, creating a structure Baltimore. He boss told Coffey, “You’ll model 175 feet long of a relaxed single loop that turns off tumor suppressor genes. have to work your way in, but they’ll take of DNA magnified 25 million times.” Still, at the time of their discovery, care of you. When you hit the ball they Another scale model, this one just four the notion of a matrix was met with don’t care who you are.” feet long, was constructed to illustrate the skepticism. “It was amazing how these “I was a C student from East Tennessee super-coiled loops of DNA. young people here could prove this stuff State University, and now I was planning What does all of this have to do with against the greatest labs in the world,” to go to Johns Hopkins,” says Coffey. cancer? For that, Coffey, the professor says Coffey. Suddenly scientists at (Before Tennessee State, he attended known for using Slinkys, soap bubbles, MIT and Princeton were doing Kings College. The college president sug - soda cans, and a 175-foot long replica of a similar experiments. gested he leave after hiring a plane to drop DNA loop to illustrate a point, turns to Coffey was not blindly enamored of the political leaflets, some of which got wet the cassette recorder. He pops an work that came from more prestigious and dangerously fell to the earth like a cin - audiocassette tape into a tape player and academic institutions nor was he disre - der block. Years later, Kings College gave pleasing sounds of Johann Strauss’ Blue garding of the observations of everyday him an honorary doctorate .) Danube waltz begin to play. Without folks who learned their trade on the job Coffey discussed it with his wife Eula, warning, it is interrupted by the Rolling and not in the classroom. He was as com - and they agreed they should move to Stones singing Get Off of My Cloud. fortable conversing with the janitor as he Baltimore. By day, Coffey worked at Unexpectedly, the tape begins once again was with the CEO. This not only made Westinghouse designing radar antennas. to play Blue Danube. “This is cancer,” him a fine human being but also a stellar In the evening, he took classes and got says Coffey. “Cancer is like your body’s scientist. Coffey was interested in solving his foot in the laboratory door by wash - genetic tape playing the wrong song at the problems, and he was not someone moti - ing glassware for graduate students. wrong time,” explains Coffey. “The tape vated by notoriety or celebrity. After receiving a glowing reference from is all mixed up and contains errors. He tells of a job he had when he was in his former employer at North American Cancer is a problem of uncontrolled cell college working as a chemist for the North Rayon, the School of Medicine hired him growth and differentiation, and I want to American Rayon Company in Tennessee. to work evenings in the urology lab. A know what tape is played and when. They were having a problem with lines year later, in 1959, with no graduate Pieces of the tape are in wrong place, and that carried acid used in the production of degree , he was named the acting director there are errors in what is playing. Songs rayon. The acid would back up and spill of the Brady Urological Research are played at the wrong time. Embryonic all over the floor. Coffey was charged Laboratory. “The starting salary was songs are played when they should have with finding out what was causing the $5,000. I was making $18,000 at been turned off.” problem. He talked to everyone he could Westinghouse, but I knew I wanted to do cancer research.” After a year of running {THE COFFEY WAY} the lab, he was accepted to the School of “IF YOU FIND SOMETHING TO BE Medicine’s graduate program in Physiological Chemistry . TRUE, WHAT DOES IT IMPLY? OFTEN Coffey earned his Ph.D. at 33. By then, WE DON’T NEED MORE EXPERIMENTS. he had already been a chemist, an engi - neer, a laboratory director, and prostate WE NEED MORE CRITICAL THINKING cancer researcher. Everybody wanted ABOUT THE RESULTS.” him, and Professor Paul Talalay hired him to the Pharmacology Department fac - ulty. Soon thereafter, Professor William Of course, understanding what is on think of, including Big John, a laborer Scott invited him to join the faculty of the the tape and how it is played has been one who worked in the basement of the build - Urology Department. Coffey’s meteoric of the greatest scientific contributions of ing. Big John tipped him off to a vibration rise from his self-described role as “chief Johns Hopkins. Coffey’s students in a machine that started about 20 min - bottle washer” to become the Catherine Vogelstein and Pardoll became world- utes before the breakdowns occurred. Iola and J. Smith Michael Distinguished renowned scientists in their fields; This observation led Coffey to the cause of Professor of Urology; professor of Vogelstein as the most frequently cited the problem. Oncology, Pharmacology and Molecular researcher in all of medicine for his work Coffey believed that to find answers, Sciences, and Pathology; and a member of revealing the genetic blueprint for cancer one first had to ask the right questions. “He the professional staff of the Applied and Pardoll for his work in figuring out liked to gather everyone’s ideas. He made Physics Laboratory seemed right out of a how cancer cells evade the immune sys - people feel like no idea would ever be Hollywood movie. tem. As for the tightly coiled loops of looked at as being stupid,” recalls Pardoll. In fact, despite his academic struggles, DNA, Kimmel Cancer Center investigator Coffey and Big John became instant Coffey was a perfect fit for Johns Hopkin s. and leading epigenetics experts Stephen legends at the North American Rayon He believed that much could be learned if

26 PROMISE &PROGRESS 2012/2013 people from different disciplines would Urology Director Alan Partin, Radiation to other parts of the body could be reined just get together and talk about a problem. Oncology and Molecular Radiation Science in with heat. To develop it clinically, “People like to visualize a disease as one Director Ted DeWeese, and Prostate Coffey, Radiation Oncology Director Ted thing wrong. Like, there’s a wire loose in Cancer Foundation Presiden t and CEO DeWeese, and scientists Robert Ivkof, car, but it’s never just one wire in a car. Jonathan Simons, to name just a few. Shawn Lupold, and Prakash Kulkarni are By the same reasoning, it takes multiple Coffey continues to patrol the hallways using small antibodies that attach to iron steps to form a cancer cell. There’s an of Johns Hopkins in search of new talent. particles which, in turn, naturally attach aging phenomenon associated with it, a He has a simple formula for finding the to cancer cells throughout the body. genetic phenomenon, and a whole bunch best and brightest. He asks people. It When exposed to alternating magnetic of environmental and epigenetic factors. could be other professors or students, or fields, the iron particles vibrate enough to Man, I hate to tell you how often people even patients. He asks them, who is the heat up the cancer cells so they become from all those different fields don’t get smartest? Who is the best? Then, he more vulnerable to therapies. together in science,” says Coffey. recruits these rising stars to the fight Coffey says these discoveries have led to a new fascination with temperature. In {THE COFFEY WAY} terms of personalized medicine, Coffey points out, temperature, as fever, is one “GENERATE MORE THAN ONE CONCEPT the of primary measurements used to TO EXPLAIN YOUR DATA, THEN GIVE AL L determine whether someone is sick—and he ticks off a multitude of questions: “I am THE POSSIBILITIES YOUR EQUAL ATTEN - trying to understand temperature and the TION AND EFFORT. YOUR PET IDEA WILL scientific and evolutionary reason for the precise body temperature of 98.6°. Why is USUALLY TURN OUT TO BE JUST THAT.” it not 87° or 103°, and why does a chicken egg hatch at approximately 100°? Why is a For Coffey, neither the classroom nor against cancer. As the list of his recruits hurricane caused by only a few degrees the laboratory ever closed. In the hall - attests, the formula is one that works. change in ocean surface temperature? Why ways of the Brady, in his office over high Coffey turned 80 on October 10, 2012, does a flame form in a precise structure on tea, or in a conference room, Coffey could but age has done little to quell his quest a candle? And why does a woman's tem - be found fostering collaborations and for knowledge. His most recent research perature go up a few degrees when she inspiring innovative ideas about cancer. examines the shared traits between bacte - ovulates? Why is the sex of an alligator and It was not unusual for these discussions ria and cancer cells. Coffey and his col - turtle decided at precisely 100°? And why to last long after business hours. The next laborators believe that cancer cells, like does a man's sperm not survive body tem - morning, equations and notes jotted bacteria, rely on communication and perature? Why do snowflakes form such across blackboards were evidence to the “social networking” to survive and thrive interesting patterns? How does life form lively discussions that had occurred the within the body. Cancer cells and bacte - against the second law of thermodynamics night before. ria use chemicals and gene pathways to of increased entropy and heat? How can Coffey, who suffers from dyslexia, pro - override controls that tell cells how to this heat and temperature be used to cure foundly understands that everyone learns behave, he says. He hopes that better infections and to treat cancer and to germi - differently. The disorder that caused him understanding the social behavior of nate acorns and to form the precise tree to struggle as a student helped make him cancer cells—intricate cell-to-cell commu - line on the mountain?” one of the world’s greatest teachers. nication they use to grow, spread, and While the answers to these questions Among his many revered lessons is evade treatments—will inspire new may, for the time being, remain a mystery, what he calls the “Real Final Exam.” In it, therapeutic approaches. one thing is certain. In the inquisitive he extols several time-tested principles. In fact, the last one is a favorite of {THE COFFEY WAY} Coffey’s who sometimes seems to espouse cred it for everyone but himself. Back at “WHEN DISCOVERIES ARE MADE, GIVE North American Rayon Company, though EVERYONE CREDIT. YOU WERE PROBA - he put all of the pieces together to solve the acid line problem, he quickly redirected BLY NOT THE FIRST ONE TO STUDY THE credit to Big John and secured him a size - PROBLEM, NOR WILL YOU BE THE LAST.” able raise. He talks willingly and with pride about the accomplished researchers Coffey was also part of a team that mind of Donald Coffey, nothing changes and clinicians who have come through his used a testicular cancer model to prove but the birthday. His enthusiastic and laboratory. Rightfully so, as the list reads that cancer cells that are exposed to heat continuing quest for knowledge promises like a who’s who in cancer. In addition to are easier to kill with anticancer drugs to bring Johns Hopkins and the world Vogelstein and Pardoll, it includes Kimmel and radiation therapy. They showed that more unexpected discoveries, unusual Cancer Center Director William Nelson, even advanced cancers that have spread props, and riveting lectures. •

2012/2013 PROMISE &PROGRESS 27 granate. Regarding the pomegranate two antioxidants, resveratrol, which is industry, he cautions buyer beware, as common to grapes, and ellagic acid, the JOHNS HOPKINS PROSTATE the demand for the fruit is 15 times greater same antioxidant in pomegranates. CANCER MILESTONES than production. Many products on the Carducci hopes that their studies will • Performed the first prostatectomy market contain a very small amount of lead them to alternative therapies for men in 1904 and later pioneered the pomegranate juice mixed with blueberry, whose PSA begins to rise after surgery, anatomical nerve-sparing approach grape, acai or other juices. Carducci says an event called biochemical recurrence. • Developed some of the first therapeutic pomegranate is of interest to cancer One option for these men is hormonal approaches and clinical models for researchers because it is the highest in therapy, but these therapies have annoy - prostate cancer, including the earliest antioxidants, chemicals known to have ing side affects such as weight gain and form of brachytherapy, and were the cancer-fighting properties. hot flashes and, even more of a concern, first to culture human prostate cancer Carducci and his team, which includes they may accelerate heart disease. “If cells to study therapeutic targets Emmanuel Antonarakis and Channing there is a more natural approach that • Developed the first animal models to Paller, are still sorting through their find - would allow these patients to avoid characterize the properties and types o f ings. They confirmed the findings of the adverse affects, it would be very exciting,” prostate cancer; the models were sent UCLA study, also finding that PSA dou - says Carducci. • Discovered the first human gene bling time slowed, an indication, but not mutation in prostate cancer proof, that it has an impact on the pro - TRACING THE MUDDLED • Deciphered the mechanisms for gression of the disease. Moreover, they GENEALOGY OF PROSTATE prostate cancer metastasis resolved the “how much is enough” issue, CANCER • Provided the first description of the and showed that low doses of the extract T TOOK 20 years of work, but a basic cellular and molecular properties had the same effects as higher doses. “We research team led by prostate cancer of prostate cancer have to verify that the affect we’re seeing I laboratory scientist William Isaacs has • Were the first to describe the impor - is caused by the pomegranate and not just uncovered the genetic driver for a heredi - tance of stem cells in prostate cancer a natural process we’re picking up tary form of prostate cancer that tends to because we’re watching more closely,” strike younger men. It is the first major • Deciphered how prostate cancer says Carducci. “We think that slowing gene finding associated with inherited growth is regulated PSA is good thing, but we have to prove prostate cancer. • Defined hereditary prostate cancer that it actually makes a difference in “It’s long been clear that prostate cancer • Performed the first DNA methylation patient outcomes,” he says. can run in families, but pinpointing the studies in prostate cancer Another similar study in partnership underlying genetic basis has been challeng - • Developed an animal model of prostat e with Howard University is exploring the ing and earlier studies have provided inflammation and defined PIA (prolifera - benefits of muscadine grapes. The skin of inconsistent results,” says Isaacs, the tive inflammatory atrophy), a new model these large, dark-purple grapes contains William Thomas Gerrard, Mario Anthony for what causes prostate cancer • Pioneered quantitative pathology to refine staging and prognostic markers • Developed the Partin Tables, Pound Isaacs Tables and Han Tables to predict localized cancers, relapse time, metastasis and survival • Used PSA velocity to define lethal types of prostate cancer • Developed and clinically tested the first prostate-specific adenovirus to treat recurrent and metastatic prostate cancer • Performed the first protein analysis of normal prostate and prostate cancer • Developed new biomarker tests for prostate cancer • Led the work in robotics for prostate cancer treatment • Pioneered tumor immunology studies and developed GVAX, the first therapeutic vaccine for prostate cancer • Identified new drug targets, PSA- activated prodrugs, and other agents

28 PROMISE &PROGRESS 2012/2013 Duhon and Jennifer and John Chalsty Walsh take their prostates out because he the problem. It did. “In six years, we went Professor of Urology. was the only guy in the world that could do from having no genetic risk factors for Isaacs’s work was inspired two decades it without leaving them impotent and prostate cancer to as many as 70,” says ago by the pioneering work of Bert incontinent. Over a five-year period, Isaacs. “For the first time we could deter - Vogelstein and team that uncovered genetic prostatectomy went from a surgery rarely mine increased genetic risk, but the effect alterations linked to hereditary forms of done to the most common surgery per - was small, increasing risk by 10 to 20 per - colon cancer. These findings led to cancer formed at Johns Hopkins. Walsh was ask - cent, so there really was no clinical implica - being defined as a genetic disease and ulti - ing his patients about family history, and tion,” says Isaacs. mately revealed the complex landscape of some of them were telling him that their At Johns Hopkins, with the mission of colon and other cancers among the general grandfather, father, brothers all had using science to improve patient care, the population. Unlike colon cancer, which prostate cancer. Influenced by the late findings were disappointing for an addi - provided inherited syndromes and early Barton Childs, a legendary Johns Hopkins tional reason. “It didn’t tell us what type onset of disease as clues, in prostate cancer pediatrician and geneticist that shaped the of prostate cancer men were at risk for or “there were no syndromes families where understanding of inherited disease, Walsh if it should be treated,” says Isaacs. “Again, 25-year-olds were getting the disease, and began cataloging prostate tumors to charac - we were running into the same wall.” we could study them,” says Isaacs. terize a hereditary form of the cancer. “Here’s the dilemma. We know statisti - It was frustrating for Isaacs because ear - Bob Carter, a young medical student cally that most prostate cancers are not lier studies seemed to indicate that prostate working with Isaacs and Bloomberg School going to progress to a point where quality cancer had a strong hereditary susceptibili - of Public Health investigator Terri Beatty, of life is affected. Most men will be fine, ty, higher than colon and breast. Where asked Walsh if he could look at his first 600 so we say we are overdiagnosing and was it? Why couldn’t they find it? patients, and using their wives as controls overtreating men,” says Isaacs. “But, It turns out that techniques that worked determined that if a man has prostate prostate cancer is the second leading cause so well in defining the genetic culprits for cancer or one of his brother’s has prostate of cancer death in men. We’re not over - colon and breast cancer did not work so cancer, the other brothers were at risk. diagnosing and overtreating these men. well with prostate cancer. “It’s a disease This 1990 finding reignited the search for To the contrary, I’d say these men are that most men get,” says Isaacs. He points an inherited form of prostate cancer and underdiagnosed and undertreated.” to volumes of books on his shelf that con - the gene or genes behind it. Isaacs was So, in the United States, we have erred tain pedigrees of families where three or intrigued. toward caution, Isaacs says, because we four families had prostate cancer. “It is the The group put an ad in Parade Magazine have not yet been able to unearth the genet - most common cancer in men. We are going seeking volunteers with a family history of ic factors that will definitively separate the to find families with multiple members who prostate cancer. Within two weeks, they slow growing cancers from the aggressive have the disease, even without a genetic had 2,500 men who responded and were ones. In some countries in Europe, the component, just because it is so common.” eager to help decipher the disease. Public opposite approach is taken and prostate Tweezing out which ones were genetically announcements by General Norman cancer is rarely treated because of the finan - linked and which ones were not turned out Schwarzkopf, Senator Robert Dole, and fin - cial burden it would place on its socialized to be a monumental task. ancier Michael Milken about their own medical system. With other cancers, early age at diagno - diagnoses with prostate cancer all con - “Prostate cancer is tailor-made for sis is a red flag for a hereditary link. In spired to bring attention and interest to the personalized medicine, but we need to prostate cancer, the best determinant of disease. “Research ticked up, but when the figure out what predicts aggressive early age of diagnosis relates directly to smoke cleared 15 years later, we still didn’t disease,” says Isaacs. how early a person is screened. “If you have anything particularly useful,” says In the meantime, Isaacs heads an inter - have a 20 year old with a lump in her Isaacs. “A few genes turned up, but their national consortium for prostate cancer breast, you know it’s early onset,” says effects turned out to be small.” genetics funded by the National Cancer Isaacs. “With prostate cancer, you could Then, in the mid 2000s a new idea was Institute. Investigators at the University have a guy diagnosed at 75 who may have being explored. Adopting the premise that of Michigan, one of the participant groups, had the tumor since he was 45 or younger.” humans are really all one big happy family were getting a reproducible hits in their It is well known that prostate cancer is a extending from a small number of original researched that pointed them to a region on slow-growing cancer and autopsy studies founders, there should be a limited number chromosome 17. An examination of this done at Johns Hopkins have revealed early of founder chromosomes in the population. region in the prostate cancer families col - cancers in men in their twenties and thir - Bert Vogelstein’s research revealed founder lected at Hopkins revealed the same but ties. “We wouldn’t know if a man had gene mutations associated with cancer in weaker signal. Some of the most interesting prostate cancer at 25 because no one the Ashkenazi population. “The same genes in this region were members of the screens for it at that age, and he probably thing occurs with everyone on the planet. HOX gene family. The earliest information wouldn’t have any symptoms that would It’s just harder to find,” says Isaacs. The on these genes evolved from fruit fly stud ies. cause him to see a doctor,” says Isaacs. HapMap Project, an international endeavor Enter PSA. Now men were being diag - to describe the common patterns of human VISIT OUR BLOG nosed in their 40s and 50s, and they wanted genetic variations, was beginning and their to come to Johns Hopkins to have Patrick work had the potential to shed new light on WWW.HOPKINSKIMMELCANCERCENTER.ORG

2012/2013 PROMISE &PROGRESS 29 Isaacs recalls a prominent jour - Eisenberger and Antonarakis nal that had displayed a photo of a fruit fly on its cover. The fly had legs coming out of its head where its antennae should be due to a HOX mutation. “The legs were perfectly nor - mal, except they were growing in the wrong place,” says Isaacs. Kimmel Cancer Center breast cancer researcher and Barbara Rubenstein Professor of Oncology Saraswati Sukumar was an expert on HOX proteins and had associat - ed them with breast cancer development and resistance to chemotherapy. “We knew from previous work that specific HOX genes were very impor - tant in normal prostate devel - opment in mice. What if it was somehow linked to the growth of prostate cells in humans,” he wondered. Isaacs was interested in a partic - ments: early onset of disease and family figure out how to get to these men when it ular gene in the HOX family, HOXB13. In history; and he had zeroed in on the cause. will work,” says Isaacs. There are some mice, this gene is turned on just at the time The mutation was rare in men diagnosed men, he suspects who could benefit from the prostate is developing. over age 65 with no family history. much earlier PSA screening, perhaps start - Working with the University of Michiga n It was a textbook case. On one hand, ing as young as 25 or 30. Prostate cancer group, Isaacs focused his research on fami - Isaacs was incredibly excited, on the other, clinician-scientist Michael Carducci agrees. lies with alterations on chromosome 17. he was not finding the indisputable link to “Research finds that it is the 50-year-old One of these families had nine members aggressive disease he had hoped for, or, for guy who is more likely now to present with with prostate cancer, and he had DNA from that matter, one that conclusively pointed metastatic disease than the guy who is 65 or seven of them. The University of Michigan to an indolent form of the disease. “Right 75,” says Carducci. “Maybe there should be team had three families where all of the now, it doesn’t help us with that critical an early check to find these guys. We’re members with prostate cancer had the question of who to treat and who not to trying to figure that out, so together, our same HOXB13 mutation. Isaacs had to treat, but we feel like we’re on the right research group is evaluating limited but make sure it wasn’t simply a result of the track,” says Isaacs. early screening for men at highest risk.” mutation being common in the population, The mutation was most prevalent in In the end, Isaacs says, “It’s a mixed bag. so he started genotyping everyone he could families of European descent. Isaacs found I’m very excited about this discovery, but find, regardless of family history, and a different HOXB13 mutation in men of I also realize that this is a tough cancer to including men without prostate cancer. African descent, and another team of figure out, and there is still much work to He looked at 5,000 samples and found the investigators found yet another mutation be done. The good news, Isaacs says, is that mutation was extremely rare in the general in Han Chinese men. “It appears there are at Johns Hopkins, the experts have known population, but in the men who had it, it different founder mutations for different this, so we’re ahead of the curve. The translated to a ten times greater risk of ethnicities,” says Isaacs. It could be useful prognostic question—which cancers will developing prostate cancer. Finally, they for families where a member had an progress and kill and which ones will not— also had the significant link to early onset aggressive prostate cancer associated with is the single most important question in that Barton Childs had pointed to so many the mutation. “We could potentially test prostate cancer.” years earlier. The mutation was most the other men in the family to see if they prevalent among men diagnosed early, have mutation so that those who carried it UNPRECEDENTED STRIDES under age 55, and many of them had a it could be monitored more closely and at The last few years have seen unprece - father or brother who had prostate cancer. an earlier time,” says Isaacs. dented strides in drug discovery for Now he had met both of Child’s require - He continues to delve deeper into the prostate cancer. Six new drugs have been causes of prostate cancer in African- approved and prostate cancer clinician American men where incidence and death Mario Eisenberger, the R. Dale Hughes LISTEN TO PODCASTS rates are double those of white men. Professor of Oncology, is working with WWW.HOPKINSKIMMELCANCERCENTER.ORG “Treatment is effective, and so we have to fellow clinical investigators Michael

30 PROMISE &PROGRESS 2012/2013 DEATH CARROT A MOLECULAR GRENADE FOR CANCER

Thapsia garganica is a 3-foot tall weed that grows wild and abun - into mice, their engineered drug looked promising. A three-day dantly in the Mediterranean. It is abundant because of its not so course of the drug shrunk tumors in half and outperformed other favorable reputation. Ancient Greek writ - standard cancer drugs. ings refer to it as the “plant of death” and With critical funding from David H. Koch, investigators Isaacs Arabs named the weed the “death carrot” and Denmeade worked with Michael Carducci, Angelo De Marzo, when they witnessed that camels who ate it and other Kimmel Cancer Center prostate cancer experts and quickly died. In the late 1970s, a Danish colleagues to take their discovery to patients. Denmeade likened chemist isolated its toxin, calling it thapsi - their chemically modified form of thapsigargin to a medicinal gargin. Kimmel Cancer Center researcher grenade. When the drug comes in contact with PSMA-secreting John Isaacs began collaborating with the cells, it pulls the pin killing all prostate cancer cells in its vicinity. chemist in hopes of harnessing its killing Delivered by injection, the drug, now called G202, works by power to treat prostate cancer. blocking the function of an essential protein that keeps calcium Thapsigargin, Isaacs found, indeed killed levels in cells at the correct level. In essence, it causes tumor cells prostate cancer cells, but unfortunately it to overdose on calcium and die. It also shuts down the blood also killed heart cells and brain cells. “We gave it to mice, and they vessels that feed prostate tumors. were dead within minutes,” he recalls. Contrary to its namesake, the research team says PSMA is not Undeterred, Isaacs, one of the world’s leading experts in only found in the prostate but also in blood vessels in brain, kidney, apoptosis (cell death through the natural cell life cycle) began bladder, breast, colon, and lung cancers, so it has the potential to putting his extensive understanding of how cells die to formulate a work against many different types of cancer. Laboratory findings in version of the toxin that would be lethal only to cancer cells. He breast, kidney, and bladder cancers reported by the team in Science recruited the help of fellow prostate cancer researcher and clinician Translational Medicine support this theory. Samuel Denmeade, and for more than a decade the two worked to To date, the Johns Hopkins team, and collaborators from the chemically modify the toxic weed to specifically and safely target University of Wisconsin and the University of Texas-San Antonio, has prostate cancer cells. treated 29 patients with advanced cancer in a clinical trial assessing Thapsigargin kills by making cells think they need calcium the safety of the drug. New trials will evaluate the safety and the when they do not, Denmeade explains. As a result, cells are flooded effectiveness of G202 in patients with prostate and liver cancers. with unending amounts of calcium and die. The trick was to “What we like best about this drug,” says Isaacs, “is that it re-engineer the lethal toxin to deliver its killing power only to causes the cancer cell itself to bring about its own demise.” • prostate cancer cells. For this, Denmeade and Isaacs created a compound that remains inactive until it comes in contact with cells Editor’s Note: This research was funded by the Department of Defense that secrete a protein known as the prostate-specific membrane Prostate Cancer Research Program, the Prostate Cancer Foundation, antigen (PSMA). This modification meant that the toxin would David Koch, the Danish Cancer Society, the Danish Research Council, now selectively target the prostate and, unlike its predecessor, the Aarhus University Research Foundation, and the National would leave heart cells, brain cells, and other normal cells alone. Institute of Health’s National Cancer Institute SPORE(CA058236 In laboratory studies that used human prostate tumors transplanted and CA006973).

2012/2013 PROMISE &PROGRESS 31 Carducci, Sam Denmeade, Emmanuel tification of new biomarkers for monitor - ular genetic clues that predict which cancers Antonarakis, and others to determine ing disease progression and treatment are predestined to be sensitive to treatm ent, how to best integrate them into clinical effectiveness. Eisenberger and team are we may be able to personalize treatments,” practice. “We have to figure out who exploring various novel approaches, he says. “Conversely, we can use genetic should get which drug or combination of including natural compounds that could biomarkers to identify men who will not drugs,” says Carducci. prevent or keep prostate cancer in check, respond to hormone therapy and design Carducci says the drug discovery targeted hormone therapies, and immune better treatments for this group.” pipel ine at the Kimmel Cancer Center has approaches that sensitize prostate cancer “The generous contribution from Jones played a key role in advancing the treatm ent cells to drug treatment. Day allows us to take on these projects,” of prostate cancer. Drugs like Tasquinimod , The gift will also help support the work says Eisenberger. “As a result, we expect an interesting new agent that appears to of laboratory scientists, including to improve and prolong the lives of men work both through the immune system and Srinivasan Yegnasubramanian who is with prostate cancer.” by cutting off the blood and nourishment working to identify biologic markers of that tumors need to grow and spread, are response to treatment. “We want to THERANOSTICS AND MORE finding much success. understand why two men with metastatic In a new approach dubbed “theranostics” Eisenberger believes a $1.5 million gift prostate cancer and similar clinical fea - because it combines the diagnostic prop - from Jones Day, a Washington, D.C.-base d tures and tumor pathology can have drasti - erties of molecular imaging with cancer law firm, will strengthen these advances cally different responses to the same thera - therapy, a multidisciplinary team of by supporting work to identify molecular py,” says Eisenberger. They are studying experts, including Radiation Oncology signatures that allow for personalized tumor samples from 60 patients whose Director Ted DeWeese, and cancer imag - therapies and improve quality of life for cancer spread to the bones and other sites ing experts Martin Pomper and Zaver men with prostate cancer. It will fund and were then treated with androgen Bhujwalla, developed an idea that takes several projects, including a tissue bank, deprivation therapy, a type of therapy that advantage of important molecular compo - laboratory and clinical collaborations suppresses androgen, a hormone that is nents of cancer and allows researchers aimed at rapidly identifying new targeted known to fuel the growth and spread of and clinicians to see inside the cancer cell immune and drug therapies, and the iden - prostate cancer. “If we can uncover molec - and view them as they are being treated. The team is developing ultra- tiny structures called nanopar - DeWeese ticles filled with an anticancer drug that also sensitizes cancer cells to radiation and a radiopharmaceutical or cell-imaging agent. The nanoparticle is targeted to PMSA, a biomarker for prostate cancer, so that it zeroes in on and delivers its anticancer payload specifically to prostate tumors. The particle is labeled with a radioactive isotope, which can be imaged or used to treat cancer. It is given intravenously so that it can attack cells growing anywhere in the body. In other work, DeWeese and prostate cancer researcher Shawn Lupold became the first to show that targeted small inhibitory RNA (siRNA) could be used for prostate cancer therapy. This breakthrough research focuses on siRNA, small molecules that have the ability to interfere with the expression of genes. DeWeese and Lupold used aptamers, a guidance system of sorts, to get

32 PROMISE &PROGRESS 2012/2013 the RNA molecule to its target inside of medical oncologist Emmanuel cancer cells where it shuts down cancer Antonarakis and urologists Alan Partin Walsh cells’ ability to repair the injury that radia - and Edward Schaeffer, is excited to have a tion inflicts and, as a result, they die. The potentially curative treatment to offer aptamers, which allow the repair-blocking these men. They hope to find out what inhibitory molecules to be targeted specifi - immune cells are already present at the cally to cancer cells, are unique to Johns time of prostatectomy and figure what Hopkins and considered the gold stan - army of immune cells they need to cause dard. Moreover, it is a platform technolo - an attack against prostate cancer cells. gy that can be used not only for prostate They believe the vaccine/drug treatment cancer but any cancer type, simply by could work to mop up the microscopic changing the aptamer. cancer cells missed at surgery. Yet another nanotech approach DeWeese is exploring for prostate cancer REHAB AFTER PROSTATE treatment uses alpha particles, a type of CANCER TREATMENT radium isotope, that are naturally target - The two big quality-of-life issues that men ed to the bone where prostate cancer most experience following prostate cancer sur - often spreads. It captures the killing gery are urinary incontinence and erectile power of decaying radium, but in this dysfunction. Urologic oncologist and form it has a short life of about ten days prostate cancer surgeon Trinity and only causes damage in the limited Bivalacqua and nurse practitioner Kristen path it travels in the body. Radium has a Burns are helping men through a new chemical relationship to calcium, and so PROSTATE CANCER rehabilitation/survivorship clinic. acts in the human body like calcium, LEGEND Bivalacqua is skilled at both open and naturally traveling to the bone. robotic prostatectomy, giving him both Urologist Patrick Walsh is perhaps Investigators are studying a combined the most famous and revered figure the unique perspective and the experience nanoparticle/alpha particle/radiation in the world of prostate cancer. to help men recover from prostate cancer treatment. The nanoparticle, loaded with For 30 years he served as director of surgery. “If we’re going to work to cure its radiation-sensitizing anticancer drug, the internationally renowned Brady everyone, we want be sure we also try to is given simultaneously with the bone- Urological Institute at Johns Hopkins. eliminate the adverse quality of life metastasis-targeting alpha particle to He transformed prostate surgery by issues,” says Brady Urological Institute exquisitely and precisely attack prostate developing an anatomical approach to Director Alan Partin. Any prostate cancer cancer and its spread. remove the cancerous prostate with - patient who receives surgery or radiation out causing life-changing side effects, therapy is a candidate for rehabilitation. FIRST-OF-ITS-KIND taught the procedure to hundreds of Some men who experience problems may TREATMENT urologists-in-training; and gathered only need counseling while others could A first-of-its-kind prostate cancer com - information from patients that propelled require a more invasive intervention to bined therapy will make surgery an prostate cancer research forward. alleviate symptoms, but the team says they option for more men. Clinical studies, led In June 2011, he performed the want patients to know that this service is by Charles Drake, a cancer immunology procedure he pioneered for the last part of the care we offer them. Initially, expert and co-director of the Prostate time. It was his 4,569th prostatectomy. they will focus on Johns Hopkins prostate Cancer Multidisciplinary Clinic, will He remains a familiar figure at “The cancer patients only, but eventually they include a prostate cancer vaccine. GVAX, Brady,” and through the Patrick C. hope to expand the program to help the immune system-boosting vaccine Walsh Prostate Cancer Research Fund patients across the country. • developed more than a decade ago by continues to advance the u nderstand - Kimmel Cancer Center investigators will ing and care of prostate cancer. • FOR MORE ON PROSTATE CANCER be given after surgery in combination WWW.HOPKINSKIMMELCANCERCENTER.ORG with the anticancer drug cyclophos - phamide and a new prostate hormone therapy drug called MDV 3100. The treat - TITANS OF PROSTATE CANCER ment is for men who are diagnosed with high-grade prostate cancers that are likely Following the Johns Hopkins model, leaders in to recur. In the past, these men were not the Prostate Cancer Program never disconnected candidates for surgery because of the like - lihood that microscopic tumor cells, invis - discovery from the patient. Keeping the two ible to surgeons, had already broken away aligned, its investigators and clinicians have made from the tumor and destined the cancer to return. Drake, who is collaborating with more advances than any other place in the world.

2012/2013 PROMISE &PROGRESS 33 IN THE NEWS THE LATEST CANCER NEWS from the JOHNS HOPKINS KIMMEL CANCER CENTER

NEW APPOINTMENTS AND ARRIVALS

Amy DeZern, M.D. , assistant professor of Erick Lutz, Ph.D. , has joined the oncology is a new member of the Gastrointestinal (GI) Cancer Program as Hematologic Malignancies and Bone an assistant professor of oncology. Lutz is Marrow Transplant Program. She is a the fourth Viragh Research Scholar from distinguished clinician and clinical investi - the Skip Viragh Clinical Research Center gator who trained with Kimmel Cancer in Pancreas Cancer. He will develop a Center hematology and oncology experts human immunology laboratory program Robert Brodsky, M.D., and Mark Levis, for GI cancers focused on deciphering the M.D. In addition, she earned her master’s immune response within the tumor in health science from the Bloomberg microenvironment. Dr. Lutz completed his School of Public Health. Her work will fellowship under the mentorship of include development of a translational Elizabeth Jaffee, M.D., uncovering the clinical investigation program focused basic immunologic principles that define on malignant and non-malignant bone immunotherapy-induced immune responses marrow failure states. and developing new technologies to study immune responses within developing Ivana Gojo, M.D. , associate professor of human tumors. oncology, has joined the Hematologic Malignancies and Bone Marrow Transplan t Channing J. Paller, M.D. , assistant pro - Program. She will work with Dr. Judy fessor of oncology, will extend genitouri - Karp to direct leukemia drug development. nary cancer services to the Washington, Her clinical research in leukemia, includ - D.C. campus of the Kimmel Cancer Center. ing the development of several leukemia Paller is a clinician-scientist focused on trials, is nationally recognized. developing and evaluating new therapies for urologic malignancies, including prostate Edward Harhaj, Ph.D. , has been appoint - cancer. She is particularly interested in the ed an associate professor of oncology in role of natural products for prevention or the Viral Oncology Program. He is a basic treatment of prostate cancer. As a fellow, scientist who has conducted seminal work she worked with Michael Carduc ci, M.D., in the area of inflammation and viral inter - to study the benefits of pomegranate ference with natural immune responses. extract and muscadine grape skin extract He is a recognized leader in the biology of for men with prostate cancer and earned the Human T-Cell Lymphotropic Virus-1 Young Investigator Awards from the (HTLV-1) and NF- kBm, which plays a key American Society of Clinical Oncology and role in regulating immune response. Eastern Cooperative Oncology Group. HTLV-1 is linked to HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis, Deborah Schwartz, R.N., M.P.H., a neuroinflammatory disorder similar to C.R.N.P. , has joined the Kimmel Cancer multiple sclerosis and an aggressive T cell Center Hematology Service as a nurse leukemia known as adult T cell practitioner. She will support the develop - leukemia/lymphoma (ATLL). ment of critical pathways and educational programs to standardize hematology care. She is currently completing the credential - ing process to perform lumbar punctures, bone marrow aspirates, and conscious sedation. Her previous experience includ es caring for critically ill pediatric and adult burn patients in a level one-trauma center.

34 PROMISE &PROGRESS 2012/2013 Richard Zellars, M.D. , associate professor of radia - tion oncology, and Dina George Lansey, M.S.N, R.N, O.C.N. , Research Associate and Clinical Recruitment Specialist, are heading the Kimmel Cancer Center’s initiative to increase minority accrual to clinical trials. Zellars has been appointed Assistant Director for Clinical Trial Accrual and will develop and oversee initiatives to increase accrual to thera - peutic clinical trials with a special emphasis on minority accrual. He will continue his academic and clinical positions as a breast and gynecologic cancer radiation oncologist. Lansey, who has extensive experience as both an outpatient clinic nurse and clinical trials research nurse has helped direct efforts to improve clinical trials communication, continuity of care, and data management. Overcoming cultural and institutional barriers and increasing minority participation in clinical trials is a priority of the Kimmel Cancer Center, and Zellars and Lansey have a longstanding interest in addressing racial disparities in cancer. Zellars created and co- leads CUPID (Cancer in Under-Privileged Indigent or Disadvantaged), a summer training fellowship aimed at attracting to the specialty oncology medical stu - dents who have a demonstrated interest in caring for poor and underserved minority populations. •

Edward Allan Sison, M.D. , has joined the Katherine Thornton, M.D. , has returned Pediatric Oncology Program as an instruc - to the Kimmel Cancer Center as the clinical tor in oncology and pediatrics. He is a director of the Sibley Medical Oncology physician-scientist focused on translational Program. Thornton will be responsible for research of childhood leukemia, including the start-up and continuing medical over - the developme nt of therapies targeting sig ht of the medical oncology consulta - high-risk childhood leukemia. tion/outpatient clinical service at Sibley, which is part of the Washington, D.C. campus of the Kimmel Cancer Center. She will also develop and promote clinical research at Sibley, including educational and training programs for fellows from Johns Hopkins, the National Cancer Institute, and Howard University.

2012/2013 PROMISE &PROGRESS 35 IN THE NEWS HONORS AND AWARDS

Fifteen-year-old Jack Andraka received Jef Boeke, Ph.D. , was elected fellow to top honors (the Gordon E. Moore Award) the 2012 class of the American Academy and a $75,000 prize of Arts and Sciences, one of the nation’s at the 2012 Intel most prestigious honorary societies and a International Science leading center for independent policy and Engineering Fair. research. Andraka won for his development of a new The Kimmel Cancer Center recognized The Giant 8th annual Triple Winner method to detect pan - Bobbie Burnett and her Caring Campaign raised more than $1.5 million creatic cancer. Using an approach similar Collection , which reached a landmark for the Kimmel Cancer Center Pediatric to that of diabetic test strips, the high goal of more than $1.1 million in donations Oncology Program. This adds to the $10 school student created a simple dip-stick to cancer care and research through the million Giant has already donated to our sensor to test blood or urine for the level production and sale of stained glass angels. pediatric cancer program. of mesothelin, a pancreatic cancer Burnett was honored with a cere monial biomarker. Andraka received guidance lab coat and Governor’s citation. This Alexandra Gubin, M.S.W., L.G.S.W. , and laboratory space from Kimmel year’s Caring Collection donation is sup - has been named patient navigator for the Cancer Center pancreas cancer researcher porting the research of Chris Gocke, M.D . Kimmel Cancer Anirban Maitra, M.D. Center’s new Pediatric Barbara Biedrzycki, Ph.D., R.N., Oncology Adolescent The 10th annual Avon Walk for Breast C.R.N.P., A.O.C.N.P., was elected to a and Young Adult Cancer was held in Washington, D.C., three-year term as the Oncology Nursing Patient Navigation and Johns Hopkins Society’s (ONS) Directo r Program. The program received a grant of at Large. ONS is a pro - was created in conjunc - $1.3 million grant to fessional organization tion with the Ulman Cancer Fund and help the support of more than 35,000 will assist teenagers and young adults the care of women at the Johns Hopkins registered nurses and with cancer in understanding treatment Avon Breast Center of Excellence . healthcare profession - options through individual and group als dedicated to quality support and by facilitating connections to The St. Baldrick’s Foundation , a volun - oncology nursing and cancer care. financial, psychosocial and educational teer-driven charity dedicated to raising resources. money for childhood cancer research, has Michael Carducci, M.D. , and Antonio awarded grants to Colleen Annesley , Wolff, M.D. , were named 2012 Elizabeth Jaffee, M.D. , was honored at M.D ., for her research on acute myeloid Washington, DC-Baltimore-Northern the 4th annual Office of Women in leukemia, and Kathy Ruble, Ph.D. , for Virginia Super Doctors. Super Doctors Science and Medicine event with the Vice research on the long-term effects of is a listing of physicians from more than Dean’s Award for the Advancement of cancer treatment and specifically ways 40 medical specialties who have attained Women. Jaffee was recognized for her to use physical activity to lower the risk a high degree of peer recognition or groundbreaking work in science and of late health effects. professional achievement. The listing is medicine. published as a special supplement in The inaugural Laura Ziskin Prize in leading newspapers and city and regional Richard Jones, M.D. received the translational cancer research was awarded magazines. Leukemia & Lymphoma Society to Stephen Baylin, M.D., Ph.D., to study Translational Research Program Award. the epigenetic mechanisms that cancer Allen Chen, M.D. , was appointed the cells use to modify normal gene function. new physician advisor The prize will be shared with Baylin’s for the Department of wife Feyruz V. Rassool, Ph.D., a breast Oncology and will lead cancer researcher at the University of its Quality and Safety Maryland School of Medicine. Ziskin, Program. who died of breast cancer, was co-founder of Stand Up to Cancer.

36 PROMISE &PROGRESS 2012/2013 The students at the 2012 American Association of Cancer Paul Reed Smith Guitars hosted the Research/American acclaimed “One Night, One Show, One Society of Clinical Cause,” featuring Journey at the Modell Oncology Methods in Center for the Performing Arts at the Lyric Clinical Cancer Opera House. The event raised $250,000 for Research workshop the Living with Cancer Resource Program selected Judy Karp, at the Hopkins Kimmel Cancer Center. M.D. , for the Merrill J. Egorin Outstanding Mentor Award.

The National Comprehensive Cancer Network (NCCN) Foundation recognized Ronan Kelly, M.D., M.B.A. , with its Young Investigator Award for research focused on assessing or improving outcomes of cancer care.

David Loeb, M.D., Ph.D. , was awarded a grant from the Liddy Shriver Sarcoma Initiative to support his research of the molecular mechanisms and pharmacolog - As part of its Hyundai Hope on Wheels pro - ic inhibition of bone sarcoma metastasis. gram, Hyundai dealers named pediatric oncolo - gist Eric Raabe, M.D., Ph.D. , a 2012 Hyundai The Lustgarten Foundation awarded Scholar and presented him with a donation to nearly $4 million in new research grants support his brain cancer research. to advance the development of early detection and effective treatment options for pancreatic cancer. Johns Hopkins recipients were Ana De Jesus-Acosta , M.D. , Ralph Hruban, M.D. , Daniel Laheru, M.D. , and Anirban Maitra, M.D.

Maura Kadan, R.N. , M.S.N., O.C.N., Peggy Lang, C.R.N.P., M.S.N., Marian Raben, M.S., PA-C. , provided informa - tion on cancer screening, education, clini - cal trials, treatment and cancer care at the 2012 B’More Healthy Expo. An estimated 20,000 people attended the convention designed to get people moving, taking corporate decision makers, lawmakers Martin Pomper, M.D., Ph.D. , and John action and making choices to be healthier. and policy architects, venture capitalists Issacs, Ph.D. , each received a Prostate and other investment professionals, and Cancer Foundation Challenge Award. Kimmel Cancer Center Director William the patient and consumer groups who They were among nine recipients selected Nelson, M.D., Ph.D. , was selected to be a stand to benefit most from biotechnology. from a pool of 96 applications received guest on BioCentury as part of a panel from 10 countries. The awards, a $9 mil - discussion to explore why collaborative Timothy M. Pawlik, M.D., M.P.H. , head lion investment over a two-year period, boundaries need to be reinvented to of the Johns Hopkins Liver Tumor are made to accelerate scientific discovery translate curiosity-driven science into Center, has been appointed the new direc - and new treatments for prostate cancer. patient value. The program spotlights the tor of surgical oncology at the Johns views of key scientific opinion leaders, Hopkins University School of Medicine.

2012/2013 PROMISE &PROGRESS 37 lives, spent less time in the hospital, and important, than focusing on the number lived three months longer. The same of cancer cells in the body. results were seen in other studies. These An American Cancer Society study findings led the American Society of found that just one in four cancer patients Clinical Oncology to recommend that felt they had adequate treatment of their every seriously ill cancer patient get pal - symptoms, such as pain and shortness of liative care. breath. One in three felt they were getting Secondly, it reduced costs. Effective adequate emotional support, and half said symptom management keeps patients out they would have benefitted from more of the hospital, and as a result, there is a education on how to manage pain and significant cost savings. control symptoms when they were dis - Managing burgeoning health care charged from the hospital. As providers costs, whether we like it or not, is part of of care, we may think we explain these our reality. Insurance premiums for a things, but that is not always the patient family of four have risen from $7,000 to perception. We have to ask patients: over $15,000 in the last ten years. Patients Are you bothered by pain, anxiety, or are faced with it when they consider shortness of breath? What can I help you with? What did you understand from what we talked about?We have to make MEET TOM SMITH sure that we’re not only giving the mes - THE BENEFITS OF PALLIATIVE CARE sage but that our message was received and understood by patients and families. THOMAS J. SMITH, M.D. , is one of the world’s leading experts in palliative Too many patients are dying in the care and an accomplished cancer clinician and researcher. He recently joined hospital. It’s not good for them or their the faculty of the Kimmel Cancer Center as the Harry J. Duffey Family Professor families. They don’t want to be there. I of Palliative Medicin e and Director of Palliative Medicine at Johns Hopkins. would like to see hospice care integrated Smith shared his thoughts on the evolution of palliative care and his goals for sooner for patients because patients who the Kimmel Cancer Center. have good palliative care and hospice care What is palliative care? expensive treatments with large copays, tend to live longer. It should be part of the I usually tell people that it is hard to and providers of care need to think about normal process of care for any patient define, but you know it when you see it. it too. We simply cannot sustain these who has an advanced cancer that we In literal terms, it means the management rising costs. When we looked at our own cannot cure. Then, when a third-line of symptoms—controlling pain, shortness patients, we found that one-third had treatment doesn’t work, patients can of breath, depression, anxiety and those chemotherapy within two weeks of their make a smooth transition to this team. things that affect patients’ quality of life. deaths. There is more and more evidence The greatest misperception is that pallia - that this is not helpful, and in fact, it could What do you have planned for the pain tive care is only end-of-life care. In fact, it be harmful and actually shorten peoples’ and palliative care program? is survivorship care. We now know that lives. More money does not always I would like to see Johns Hopkins where palliative care is beneficial for all patients translate into better care, and by the it rightfully should be, a national leader with advanced cancer from the time of same token, spending less money does in palliative care. The Duffey family diagnosis, not just at the end of life. not equate to lesser care. We need to shares our vision, and we are fortunate Palliative care was introduced as a recognize when continuing chemotherapy because they have provided us ongoing medical specialty in 1990, but just a or radiation therapy is no longer the best funding to make this happen. We plan handful of hospitals offered it. Today, thing for the patient. to add doctors and advanced practice 90 percent have some type of palliative nurses to our team. Currently, we have care program or service. What is the Kimmel Cancer Center doing outpatient and inpatient palliative care to develop its palliative care program? consultations. By 2013, we hope also to What caused the big shift? The first thing we did was to evaluate our have an inpatient unit. There were a couple of things that hap - own performance to see where there was We have already established a pallia - pened. First and foremost, we proved room for improvement. We have an excel - tive care research fellowship and have that palliative care had a favorable impact lent team of palliative care providers that received two research grants. We would on survival. Two separate studies found includes physicians, social workers, and like to add a clinical fellowship. We are that patients with advanced cancer who nurses, but we also recognize there are establishing and expanding interdiscipli - received palliative care lived longer than things we can do better. For example, I nary relationships with the School of patients who did not. A study of lung think we can do a better job of talking to Public Health and the School of Nursing cancer patients showed that those who patients and asking them about their to ensure we are truly providing the best had palliative care from the onset, used goals. Focusing on quality of life is just and most advanced care possible in less chemotherapy at the end of their as important, and sometimes more keeping with the Johns Hopkins tradition.

38 PROMISE &PROGRESS 2012/2013 IN THE NEWS HONORS AND AWARDS

Safeway funded pilot breast cancer C. Michael Armstrong Professor Gregg World renowned urologist Patrick C. research grants to Leisha Emens M.D., Semenza, M.D., Ph.D. , was recognized Walsh, M.D. , who pioneered work in the Ph.D., Edward for outstanding professional achievement understanding and treatment of prostate Gabrielson, and commitment to service with his elec - cancer, was honored with the American M.D., Josh Lauring M.D., Ph.D., tion into the Institute of Medicine, one of Academy of Arts and Sciences’ presti - Saraswati Sukumar, Ph.D., Antonio the highest honors in the fields of health gious Francis Amory Prize on March 14. Wolff, M.D., Luigi Marchionni, M.D., and medicine. Given by the Academy since 1940, the Ph.D. , and Linda Resar, M.D. Also, in prize recognizes major advances in repro - honor of Safeway’s annual campaign to The Tigerlily Foundation presented Lillie ductive biology and medical care. support prostate cancer research, Kimmel Shockney R.N., B.S., M.A.S. , with its Cancer Center Director William Nelson, Inspiration Award. The foundation mis - Bert Vogelstein, M.D. , was awarded the M.D., Ph.D. , and Prostate Cancer sion is to educate, advocate, empower and American Association of Cancer Research Program Co-Director Michael Carducci, provide support to young women with (AACR) Eighth Annual AACR-Irving M.D. , served as guest grocery baggers at breast cancer. Weinstein Foundation Distinguished one of the store’s Baltimore City locations. Lectureship. This Lectureship was Donald Small, M.D., Ph.D. , received the established in 2004 to acknowledge an Cynthia Sears, M.D. , and Peter Searson, Alex’s Lemonade Stand Foundation individual whose outstanding innovation s Ph.D. , are among the first recipients of Innovation Award to support his research in science and whose position as a thoug ht grants geared to answer “Provocative of novel treatment for pediatric cancers. leader have the potential to inspire Questions” in cancer research, a new creative thinking and new directions in project funded by the National Cancer The Tenfold Forty , an organization of 40 cancer research. Institute . Grants are aimed at providing professional women honored Connie answers to one of 24 questions, solicited Trimble, M.D., for her clinical research The Oncology Nursing Society (ONS) has from the research community, that in the treatment of HPV-related cervical awarded Jennifer Wenzel, Ph.D., R.N., address neglected or unsolved areas of cancer with a check to benefit the Cervical C.C.M. , the 2012 Excellence in Writing cancer research. Sears will explore how Dysplasia Center at the Kimmel Cancer Award for Qualitative Nursing Research. and why certain cancers may be caused Center. by infections, and Searson will develop a Christopher L. Wolfgang, M.D., Ph.D. , new method to study how cancer spreads. was selected to lead the hepatobiliary and pancreas surgery unit, one of two newly created sections within the Department of Surgery. Nita Ahuja, M.D. , heads the gastrointestinal oncology, breast, melanoma, sarcoma, and endocrine section.

P&P

ON THE WEB YOU’RE BEAUTIFUL ABINGTON HEIGHTS HIGH Patients and staff in the Division of SCHOOL SCORES WITH Pediatric Oncology created a RED CARD CANCER YouTube sensation with their video Abington Heights High School Boys “You’re Beautiful.” Patients, families Soccer Team in Clarks Summit, and staff lip sync to the popular Pennsylvania continued their support British boy band One Direction’s of Red Card Cancer raising $4,000 song “What Makes You Beautiful.” for the cause. Under the coaching One Direction band member Liam of Steve Klingman, Abington Heights Payne is one of the fans. He High School has separated themselve s tweeted about the video. in supporting Red Card Cancer and carrying the message to the community that, “Together We Can WWW.HOPKINSKIMMELCANCERCENTER.ORG Make a Difference.”

2012/2013 PROMISE &PROGRESS 39 PHILANTHROPY GIFTS AND DONATIONS to the JOHNS HOPKINS KIMMEL CANCER CENTER

COMMONWEALTH CANCER SUMMIT THE COMMONWEALTH FOUNDATION for Cancer Research, under the direction of Board Chairman William Goodwin, has been a leading supporter of translational, bench- to-bedside research at the Kimmel Cancer Center. After a review of research being con - ducted at cancer centers throughout the country, Goodwin and the Commonwealth Foundation identified the Kimmel Cancer Center and the Memorial Sloan Kettering Cancer Center as hotbeds of meaningful research that could be quickly applied to patient care. Investigators from both centers came together last summer for a cancer summit to discuss opportunities for collaboration. Promising personalized cancer detection and treatment approaches inspired by Commonwealth funding include new tests for cancer and vaccines and other cancer- fighting immune strategies.

CLINICAL BIOMARKER individualized treatment approach that TESTS FOR CANCER can be studied and validated in large, The Kimmel Cancer Center has become multi-institutional studies. an incredible engine for biomarker dis - The team has already begun studies of covery and for developing tests and plat - prostate cancer, ovarian cancer, and pan - forms to evaluate and assess their benefit. creas cancer to identify the changes that Central to this is a new clinical sequenc - cause treatment resistance specific to each ing laboratory focused on translating cancer as well as those that translate to genetic and epigenetic research and find - better outcomes. The researchers believe ings into clinical tests that will guide can - that if they can decipher the molecular cer diagnosis, risk stratification, and ther - characteristics that make a seemingly apy. Clinical experts, laboratory medicine aggressive and lethal cancer have a long- experts, and genomics experts are work - lasting response to treatment, they can ing together to figure out how to move potentially use drug interventions to this science and technology forward. convert less responsive tumors and make Investigators believe that extremes in them more amenable to treatment. These patient responses to the same therapy biomarkers could then be used to guide could be rooted in alterations in the can - personalized cancer medicine, getting the cer genome and epigenome. Using right treatments to the right patients. sequencing technology to compare the genetic and epigenetic characteristics of PROVOKING AN IMMUNE cancers that responded well to a treat - RESPONSE TO CANCER ment to those that did not, could reveal Kimmel Cancer Center cancer immunolog y important new predictive biomarkers to experts have had breakthrough discover - differentiate patients who are likely to ies related to an immune inhibitory respond to a particular treatment from checkpoint called PD-1. It is co-opted by those patients who will not. The collabo - tumors to shut down an immune response rative team of clinicians and investigators to cancer cells. Two clinical trials that will apply the technology and method to used antibodies to block PD-1 and PD-L1, two cancer types per year to develop an a related molecule that binds to PD-1,

40 PROMISE &PROGRESS 2012/2013 resulted in significant and long lasting genetic blueprints for cancer is using their cells in a specialized laboratory to expand responses against melanoma skin cancer, findings to develop clinical tests per - their numbers and then return them to renal cell (kidney) cancer, and lung can - formed on routinely collected biological the patient where they seek out and cer. The findings in lung cancer were fluids, including plasma, sputum, stool, destroy cancer cells. The Kimmel Cancer particularly significant as it was not and urine, to detect cancers in an early is one of a few cancer centers in the U.S. thought to be an immune responsive can - and curable stage and to monitor the that perform adoptive T-cell therapy, and, cer. Experts say it demonstrates that, effectiveness of targeted treatments in it is the only one using MILs. Currently, with the correct approach, essentially all existing cancers. The tests in development the therapy is being studied in multiple cancers could be made vulnerable to are specific to cancer, have a low rate of myeloma, an incurable cancer of the blood immune attacks. false positives, are cost effective, and high plasma cells, but research indicates that This research adds to the growing throughput so they can rapidly process this personalized cell therapy would be body of evidence that the immune system large quantities of DNA and information beneficial in treating a variety of blood is not passively tolerant to cancer but that and be used routinely. The investigators and bone marrow cancers and likely solid cancer cells actively hijack immune path - envision such tests, which identify the tumors as well. Cell therapy is also being ways to acquire immune resistance. A unique genetic and epigenetic changes explored in other medical disciplines, tumor recognizing it is under attack by that define cancer, becoming part of a including cardiology. immune cells, up regulates PD-L1 to shut person’s regular physical. In multiple myeloma, MILs cell therapy down the immune response. Conversely, These changes are almost always pres - is used in conjunction with bone mar row in their studies tumors that did not ent in early cancers, but the challenge is transplant to prime antitumor immune engage PD-L1 did not respond to treat - advancing the sensitivity of the tests to response and improve the effectiveness of ment. The finding opens the door to detect a minute amount of cancer DNA cir - the transplant. Our experts believe this using PD-L1 as a predictive biomarker for culating within a sea of normal cells. therapy will improve the duration of identifying patients who will respond to Al most all of these changes are present responses and may one day replace the anti-PD-1 therapies, but also as a target before a cancer spreads, and they are not need for any additional treatment. for combined treatments in patients simply associated with cancer, as PSA whose tumors do not express PD-L1. (Prostate Specific Antigen) and other PERSONALIZED PANCREAS Vaccines or other immune-targeted markers currently used for cancer detec - CANCER VACCINES approaches could potentially be used to tion, they are the cause and driver of can - Cancer immunology experts continue to activate PD-L1 and prime them for subse - cer growth and progression. The greatest optimize the effects of the pioneering quent anti-PD-1 treatment. The lung can - success has been achieved in tests for pancreas cancer vaccine they developed cer studies, revealed potential synergy colon cancer and ovarian cancer. Other more than a decade ago. New work with epigenetic-targeted treatments and cancers, such as brain cancers, are prov - includes the use of peptides to individual - anti-PD-1 therapy. ing more difficult. The research team is ize vaccines to the unique molecular The anti-PD-1 success has revealed a working with cancer clinicians to deter - characteristics of each patient’s cancer need for better ways to monitor these mine the best medium—i.e., plasma, stool, and, as a result, improve their response cancers. PD-1 targeted cancers are charac - etc.—best suited to the detection of each against pancreas cancer. terized by progression before regressing. specific cancer. Once the tests are perfect - Peptides are the building blocks of Imaging scans, such as CT, for this type of ed they can be used to monitor people at proteins and are a “table of contents” of therapy do not tell investigators what they increased risk of developing cance r. sorts displayed on the cell surface to need to know. Researchers are exploring reflect the internal molecular structure the possibility of tests that measure tumor PERSONALIZED CELL THERAPY of the cell. Vaccines could use peptides to DNA in the blood to quantitatively analyze Bo ne marrow transplant and blood and prime immune cells to recognize when if the treatment is working . bone marrow cancer experts have devel - something is not right within a cell, as in These findings have inspired new col - oped a personalized treatment approach cancer. Researchers are studying laborations funded by the Commonwealth that uses pati ents’ own immune cells to whether identifying peptides that mark Foundation and Stand Up to Cancer. fight the ir cancer. It focuses on a type each patient’s specific tumor cells and Investigators believe that PD-1 is just the of tumor-specific T-cell. For cancers of incorporating them in the pancreas cancer tip of the iceberg and that there are 10 to 15 the blood, these cells, known as marrow vaccine could boost the immune response additional immune checkpoints that are infiltrating lympho cytes or MILs, are against cancer cells. coordinately and differentially expressed found in the bone marrow where the Other work includes use of multiple in tumors. They are all potentially cancer originates. vaccinations to maintain long-term targetable with antibodies, molecular pro - In their normal capacity, the cells are immune activity against tumor cells. files of the tumors could be used to reveal inactive and somewhat small in number The team’s ultimate goal is to combine these checkpoints and guide treatment. so they have little effect against the cancer , cancer vaccines that target the individual but our experts are using a clinical con - genetic alterations within the patient’s NOVEL METHODS OF cept known as adoptive T-cell therapy, in cancer cell with immune modulating CANCER DETECTION which they retrieve a patient’s own MILs agents that maximize the immune The research team that deciphered the from his or her bone marrow, grow the response against the cancer. •

2012/2013 PROMISE &PROGRESS 41 PHILANTHROPY

PREVENTING BREAST changes that cause breast cancer can be (SAA) Baltimore event has raised more CANCER used to better distinguish those women at than $1 million for the Kimmel Cancer THE JOHN FETTING FUND FOR risk for breast cancer so that clinicians Center creating the Swim Across America BREAST CANCER PREVENTION can intervene early before the cancer can Laboratory at Johns Hopkins directed by “Our goal should be to do more than cure cause her harm. “One in nine women will gastrointestinal cancer physician-scientist breast cancer. We must prevent it,” John be diagnosed with breast cancer, “ says Luis Diaz, M.D. The money is helping Fetting told a group of people who came Fetting. “That means one will get breast Diaz and his team develop gene-based to the Kimmel Cancer cancer but eight will not. We need to tests that can detect cancer, monitor its Center to learn about advance our science so that we can identi - progression, and pinpoint the best treat - the Fetting Fund for fy ‘the one’ and intervene to prevent breas t ments. “We have made a lot of progress Breast Cancer cancer. We also need to use this science to with the Swim Across America donation s. Prevention. Fetting, a identify and reassure the eight who will We are applying it to research against breast cancer clinician not,” he says. “A normal cell does not cancers that are hard to treat and where Fetting for more than three become a breast cancer overnight,” says there are currently no standard therapies decades believes that recent research Fetting. “It happens over many years, so that are curative,” says Diaz. “This sup - breakthroughs about the biology of breast we can look for this genetic and epigenetic port makes it possible for us to take the cancer can now be applied to prevent it signature of breast cancer and figure out best ideas and bring them to patients.” from occurring at all. who has these changes and who does not.” Swim Across America funds also sup - “Over the course of my career, I’ve Kimmel Cancer Center breast cancer port a number of patient-directed initia - seen substantial progress made against experts are examining several ways to tives including new clinical trials for tar - breast cancer, and I’m very gratified by interfere with the biological changes that geting pancreatic cancer and advanced that,” says Fetting. “Screening mammog - set breast cancer in motion. Breast cancer colon cancer; a survivorship clinic for raphy has led to earlier diagnosis, and experts are investigating the protective colon cancer patients who have finished treatments have become more effective, so effects of certain natural chemicals found treatment; and a special three-day couples more patients are surviving and living full in fruits and vegetables and figuring out retreat for colon cancer patients with lives. Still, I think we can do better. With how best to deliver them to individuals. advanced disease and their caregivers. the same kind of concerted effort that has They also are studying ways to halt the Hundreds of swimmers took to the been mounted to cure breast cancer, we molecular and cellular changes that trig - water at Meadowbrook Aquatic Center in can prevent it from ever occurring.” ger breast cancer with drugs that reactivate Baltimore and the Waltjen-Shedlick Farm After battling breast cancer herself, key tumor suppressor genes that had bee n near Gibson Island on September 23 for Leslie Ries became a proponent of preven - turned off through epigenetic alterations. the 2012 event. As in the previous two tion. “Advances in treatment options are Leading cancer experts agree that pre - years, a number of current and former not enough. We have to vention is one of the best ways to manage Olympic swimmers joined the pool and try to protect ourselves, cancer risk, however, it is an area of can - open water events including Brad Snyder our children, and oth - cer research that is currently underfund - and Ian Silverman (both gold medalists at ers from getting this ed. “The Fetting Fund will support this the 2012 London Paralympics), Craig disease,” says Ries who type of work so that we can begin to Beardsley, Brenda Bartlett, Wendy Weil helped to establish the replace fear with hope,” says Ries, and Tara Kirk Sell. During their time in Ries Fetting Fund with her “because we all deserve a future without Baltimore they also stopped by the Kimmel husband Tom to allow laboratory discov - breast cancer.” Cancer Center to visit children with cancer eries to be translated into prevention For more information on the Fetting Fund and their families. strategies. To date, with a lead gift added for Breast Cancer Prevention or to make a This year’s event also included a special by Lorraine and Mark Schapiro, $1 millio n contribution, contact Dina Klicos at 410-516- tribute to Alec Cosgarea. Seventeen-year- has been raised toward the cause. Fetting 4203 or [email protected] old Alec was a world-class swimmer and treated the Schapiros’ daughter. “He was Swim Across America veteran who organ - fabulous, but I wish we never had to go SWIM ACROSS ized “angel swimmers” matching accom - through this,” says Mrs. Schapiro. AMERICA plished swimmers like himself with novice “Prevention is better than a cure, and we MAKING participants as companions for the open need to start moving in that direction.” WAVES TO water swim. Tragically, Alec was killed Fetting says that discoveries made at FIGHT CANCER just months before the event in an automo - the Kimmel Cancer Center that reveal the Over the last three bile accident, but his spirit was an unmis - genetic (mutations to DNA) and epigenetic years, the Swim takable and powerful part of the day’s (nonmutational alterations to DNA) Across America event. Many thousands of dollars were

42 PROMISE &PROGRESS 2012/2013 28 patients with advanced colorectal can - cer who were being treated with a drug that targets an important tumor cell growth pathway known as EGFR. Patients most likely to respond to the targeted agen t have normal copies of the cell-growth- promoting oncogene known as KRAS. Among the study group, only four patients tested positive for mutations of the KRAS gene. Researchers would not expect them to respond to the treatment, but the remaining 24 should have benefit - (Left to right) William ed. So why have so many of these Nelson, Debbie Dawson, Kay Foley, and Luis Diaz patients relapsed? The answer, Diaz, Vogelstein, and Kinzler found, was there all along. The resistance mutations were raised in his memory, and SAA Baltimore a patient’s cancer. Clinicians decide already there. They were simply unde - established the Alec Cosgarea Award for which drugs will work against the cancer tectable until the tumor grew. the top fund raiser under 18 years old. based on the alterations they find inside As cancer cells multiply, they shed “Alec was all about caring for other peo - the cells’ DNA. DNA into the blood and reveal the genetic ple,” said Eric Posegay, high performance Cancer is generally characterized by a mutations contained in the cell. The more coach at Meadowbrook. Alec’s father combination of tumor cell-suppressing cancer cells there are, the more DNA that Andy Cosgarea, a Johns Hopkins orthope - genes being turned off and growth-pro - is shed. Diaz, Vogelstein, and Kinzler dic surgeon, took his son’s place in the moting oncogenes getting turned on. have lead the world in developing blood water, and his younger brother Will organ - Each person’s cancer has a unique combi - and other tests that pluck this obscured ized this year’s “angel swimmers.” nation of these molecular mistakes con - DNA from within a sea of normal cells. Diaz also was among the swimmers. tained within the sequestered DNA of the They used this technology to periodically “I am so proud of Baltimore. The support cancer cell. This genetic fingerprint helps look for cancer DNA in simple blood sam - of our community is not only motivating determine which drugs are likely to work ples obtained from the patients. Five to to the clinicians and researchers but to against the cancer and which ones will not. seven months into treatment, their test patients as well,” says Diaz. “It means a When a treatment does not work, revealed that nine of the patients who lot to them to know their community is resistance mutations are often the cause. began treatment with normal KRAS genes, behind them.” A cancer cell is, after all, a normal cell that now had KRAS mutations. This molecular has errantly acquired genetic traits that evidence foretold that the cancers would allow it to grow immortally and uncontrol - continue to grown even before the advanc - AN EXAMPLE OF WHERE ing disease could be detected in imaging SAA MONEY GOES lably. Resistance mutations occur among these alterations and they add up over time scans, but when did these mutations occur? UNMASKING CANCER’S as cancer cells divide and grow. “Tumors The team called upon the mathemati - HIDDEN DEFENSES cal expertise of Harvard University col - It is perhaps the most challenging and always contain thousands of resistance league Martin Nowak who developed a frustrating aspect of cancer therapy, for cells,” says Luis Diaz, director of the mathematical model to date these alter - doctors and patients alike. A treatment Kimmel Cancer Center Swim Across ations. He found that KRAS mutations works; the cancer shrinks, and then sud - America Laboratory. The more advanced a were present, just undetectable, before the denly the treatment is no longer effective, cancer is, the more resistance alterations it patients even began their targeted treat - and the cancer returns with a vengeance. acquires, giving the cells that contain them ment. Although the studies were in colon New findings from Swim Across America a greater chance to survive treatment. and Ludwig Center researchers have Diaz worked with leading cancer ONLINE OPTIONS begun to unravel what happens within genetics researchers Bert Vogelstein and the cancer cell to cause its resistance to Kenneth Kinzler, co-directors of the WWW.HOPKINSKIMMELCANCERCENTER.ORG treatment. In fact, their research finds, the Ludwig Center for Cancer Genetics and HOW CAN YOU HELP? SEE HO W origins of the cancer treatment resistance Therapeutics, to better decipher and FINANCIAL CONTRIBUTIONS CAN BE were hidden in the cancer cell all along. understand the molecular origins of tar - EASILY AND SECURELY APPLIED. GO Personalized therapies involve drugs geted therapy resistance. ONLINE FOR MORE INFORMA TION. that target specific gene alterations within The team analyzed blood samples from

2012/2013 PROMISE &PROGRESS 43 PHILANTHROPY cancer, Vogelstein says the findings likely Center is uniquely positioned to make it vative therapeutics. The immune system, apply to all targeted therapies. “This happen.” He points to colonoscopy. It is much like cancer, is quite complex. means that the development of drug a screening test that, when performed Applying immunology to cancer patients resistance with single-agent targeted correctly, detects precancerous polyps in is more difficult still as their immune sys - therapies is a fait accompli,” Vogelstein the colon that can be removed during the tems have already been compromised by concluded. “Long-term remissions of screening to prevent a colon cancer from the drugs used to treat cancer. Dr. Ladle advanced cancers will be nearly impossible ever occurring. “We need similar types of will be working with other senior investi - with single targeted agents.” It’s really strategies for all cancers,” says Nelson. gators to uncover chinks in the immune just a matter of when they will recur. That, Once these techniques are developed, system’s armor that will allow them to he says, simply depends on how long it the challenge then is not to overdetect and turn off the defense mechanism of tumors takes cancer cells with the mutant genes overtreat cancers, and this is where he and ramp up the immune system’s attack to multiply.”This latest research adds to th e again believes Kimmel Cancer Center against them. building body of evidence that metastatic science can inform. The same molecular cancers will be nearly impossible to con - genetic information that is being used to OPTIMIST INTERNATIONAL trol. The ideal opportunity to cure cancer personalize cancer treatments can be used HELPING TO UNLOCK THE lies in detecting it early when tumors are to personalize cancer screening and detec - MYSTERIES OF PEDIATRIC CANCER small and have fewer resistance genes or tion. Rather than a one-size-fits-all, Optimist International has been a vital can be removed with surgery. Nelson says the frequency and intervals partner to Johns Hopkins Pediatric Multi-drug and method combinations of cancer screening can be determined by Oncology in its fight against childhood that simultaneously attack a variety of looking at the cellular cues. It will point cancer. A $1 million legacy endowment genetic cancer drivers or reactivate us toward abnormal cells, like polyps, has helped our clinician-scientists realize silenced tumor suppressor genes are a but also tell us which ones need attention breakthrough better option, and Vogelstein is calling for and which ones can be left alone. The end discoveries. The a change in how the cancer world con - result, says Nelson, is that that we will success of this ducts early clinical trials whose partici - not only improve cancer outcomes, but partnership is pants are almost always patients with also reduce the adverse affects that come best reflected in advanced cancers. “Since we know that with overscreening and overtreating. He the lives of the single agents will not have long-term suc - says, “We will be able to preserve health many children cess, we need to start testing new drugs as by preventing cancer, very accurately pre - who have benefitted from innovative combination therapies much earlier,” he dict who will get cancer, and personalize therapies developed by our Optimist says. “There are a limited number of gene treatments to get the right treatments to Fellows. For the first time in the history signaling pathways that go awry in cance r, patients who need them and spare those of cancer medic ine, the technology exists so it should be possible to develop a small who will not benefit.” to quickly decipher the cellular causes of number of agents that can be used in a every cancer . Kimmel Cancer Center large number of patients.” INNOVATIVE RESEARCH researchers have pioneered the science In addition, Director William Nelson, Brian Ladle, M.D., is the 2012 Optimist that has led us here and were the first to wants to begin using the Kimmel Cancer Fellow at Johns Hopkins. His research crack the genetic code of a pediatric cancer. Center’s clear edge in cancer genetics dis - focuses on immunotherapy and novel What we have learned is now allowing our covery and application to develop screen - new therapies that trigger the body's own scientists to target the very biological ing tests that would detect cancers when immune system to mechanisms that cause a cancer to grow Ladle they are very new and before they cause recognize and attack and spread. With these discoveries, they any symptoms. “We need to move away cancer cells, just as they can begin to alter the course of pediatric from a system in which we see patients do bacteria, viruses, cancers in ways that could only be imag - for the first time when they begin experi - and other foreign ined a decade ago. encing symptoms to one that detect, man - invaders. Since cancer Optimist International has generously ages, and eradicates cancers before people cells arise from normal made an additional commitment to even know they have them,” says Nelson. cells, they most often go undetected by the make sure we get there. The Optimist “Imagine, for example, if we could find immune system, but Johns Hopkins Internation al Innovative Research Fund cancers early enough that we could burn investigators have been on the cutting will allow us to significantly expand our them off much like we do with a wart,” edge deciphering the mechanisms by clinical and research programs in child - says Nelson. “I think this is within the which immune cells are activated, and hood leukemia, pediatric brain tumors, realm of possibility, and I think our plan to apply this new knowledge to inno - sarcomas and other solid tumors, and bone marrow transplantation.

44 PROMISE &PROGRESS 2012/2013

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