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A PUBLICATION OF THE PATRICK C. WALSH PROSTATE CANCER RESEARCH FUND | THE BRADY UROLOGICAL INSTITUTE | JOHNS HOPKINS MEDICINE DISCOVERY VOLUME 12 | WINTER 2016 What Kind of Prostate Cancer Do I Have? Epstein Develops a Less-Confusing System Carter and Epstein: Making active surveillance safer and the Gleason scores easier to understand. INSIDE THIS ISSUE: From the Director Changing Prostate Cancer ................... 2 Charred Food Bad, Veggies Good .... 6 Prostate Cancer in African American Men ..................... 7 Immunotherapy for Prostate Cancer .............................. 8 Genetic Risk for Prostate Cancer............................. 10 Attacking Early Metastatic Prostate Cancer............................. 18 Walsh Prostate Cancer Research Fund Awards The Research You Have Helped Make Possible.................................. 19 Bladder, Kidney, and Testicular Cancer News.................. 24 Active Surveillance: Good News for Men with Low-Risk Prostate Cancer After all the worry — the elevated PSA, then the biopsy — the diagnosis is finally here. You just found out that you have prostate cancer and the Gleason score is a 3+3=6. What does that even mean? You look it up; the literature your doctor provided says that “the score is the sum of the most common and second-most common Gleason patterns.” Apparently, the lowest score is 2 (1+1) and the highest is 10 (5+5) — and you are a 6. That looks like you’re on the more significant end of the spectrum. It’s not easy for most men to understand their prostate cancer stage right away, because the way Gleason scores are determined is just plain confusing. Epstein’s new system cuts through the numbers. The Brady’s Active Surveillance program has reached a milestone: 20 years of carefully following men with low-risk prostate cancer. “What we have learned since 1995 can help many men with low-grade, low-risk prostate cancer, and their doctors, determine their best course of treatment,” says urologist H. Ballentine Carter, M.D., the Bernard L. Schwartz Distinguished Professor of Urologic Oncology, a pioneer in the active surveillance of prostate cancer. “There is increasing evidence that monitoring favorable-risk prostate cancer does not lead to worse outcomes when compared to immediate treatment. This is good news for the majority of men diagnosed today.” Wrong. Nobody gets a Gleason 2; they aren’t ever diagnosed on needle biopsies. “In fact, Gleason 6 is as good as it gets,” says urologist Patrick C. Walsh, M.D., University Distinguished Service Professor of Urology. It’s not easy for most men to figure this out right away, because the way Gleason scores are are determined is just plain confusing – unless you’re a pathologist, seeing how a bunch of cells look under the microscope, and noticing which two combined patterns of cells are most prevalent. When the Active Surveillance program first started, “many urologists believed this approach was ill-advised for any man with a diagnosis of prostate cancer,” Carter notes, “for fear of losing the Brady pathologist Jonathan Epstein, M.D., the Rose-Lee and Keith Reinhard Professor of Urologic Pathology, wants to make it easier for men to understand their prostate cancer Continued on page 4» Continued on page 3» WINTER 2016 | DISCOVERY THE PATRICK C. WALSH PROSTATE CANCER RESEARCH FUND Continued from page 1 » founders’ circle Anonymous (3) Partin Honored: Alan W. Partin, M.D., Ph.D., the Jakurski Family Director and the Chairman of the Brady Urological Institute, received a Distinguished Contribution Award at the American Urological Association’s 2015 annual meeting. Presented by the AUA’s president, William W. Bohnert, M.D., the award cites Partin’s “contributions to science, most importantly, the creation of the ‘Partin Tables,’ which are used by urologists throughout the world.” Mr. and Mrs. Robert B. Aikens Ambrose Monell Foundation Mr. and Mrs. Robert C. Baker Family Foundation Mary Ann and Bill Becker George and Mary Nell Berry Dr. and Mrs. Peter S. Bing Mr. Keith Bremer Elva E. and William W. Carty Jennifer A. Chalsty John S. Chalsty The Deeks Family Foundation R. Christian B. Evensen Phyllis and Brian L. Harvey Heather C. and Patrick Henry Charlton C. and F. Patrick Hughes Beverly A. and Gary L. McDonald Jean and Ian MacKechnie Beth W. and A. Ross Myers Nancy and Jim O’Neal Jack W. Shay and Thomas C. Quirt The Frank E. Rath Spang & Company Charitable Trust Mr. and Mrs. Paul W. Sandman The Peter Jay Sharp Foundation Irene and Bernard L. Schwartz Virginia and Warren Schwerin Donald and Susan Sturm Carolyn and Bill Stutt Mr. and Mrs. Charles B. Thornton, Jr. Luciana and Joe Vittoria changing prostate cancer “What does my diagnosis of prostate cancer mean?” For a century, our doctors and scientists here at the Brady have worked to answer that question on every level. Our discoveries have transformed the way organ-confined disease is treated and continue to bring new hope to men with metastatic disease. Our Active Surveillance program, pioneered by Bal Carter, has helped many men with slow-growing, small-volume disease avoid surgery safely; and now work by uropathologist Jonathan Epstein is actually changing the way the disease is diagnosed. For example, Gleason score 3 +3 is its own category, Grade Group 1; Gleason 3 + 4 is Grade Group 2, and Gleason 4 + 3 is Grade group 3. There are only five groups, and Gleason score 8 is a distinct group, because those men have different disease than men with Gleason scores 9 and 10. The World Health Organization has accepted this system, and it will soon be used at hospitals everywhere. In this exciting issue of Discovery, we’re proud to tell you about our latest work in immunotherapy, in dietary prevention, our work with robots, our advances in understanding genetic risk, our successes in molecular biology, and other breakthroughs including the successful imaging of individual cells of prostate cancer throughout the body — which opens up new targets for treating metastatic disease. We also bring to you our continuing advances in diagnosis, treatment and active surveillance of kidney cancer, in refining treatment for bladder cancer, and a new advance in the laparoscopic treatment of testicular cancer. Your generosity makes us able to do more, so that we can continue to improve the lives of people with urological diseases. Thank you for being our partners in discovery. For additional news and updates from the Brady Institute, please follow us on our web site at urology.jhu.edu or any of our social media sites: Facebook: Brady Urology; Twitter: @brady_urology; bradyurology.blogspot.com 2 Best wishes, Alan W. Partin, M.D., Ph.D. Jakurski Family Director and Chairman of The Brady Urological Institute diagnosis. “Jonathan Epstein is unique in many ways, and one of them is that he does something that almost no other pathologist does – he actually talks to patients frequently,” says Walsh. “He understands how confusing this system is for most people to understand, and he wanted to fix this problem.” Epstein’s new system, compared to the current Gleason system, is far simpler, with just five groups of cancer. One innovation is that it puts the confusing Gleason 7 score — which is very different, depending on whether it’s 3+4 or 4+3 — into two different groups. As Epstein explains: “The current prostate cancer grading system was developed between 1966 and 1974 by Donald Gleason. The system assigns histological patterns 1 through 5, adding the most and second-most common patterns with Gleason scores ranging from 2 to 10. There are more than 25 different possible combinations with this system.” Doctors and scientists have tried to fix this; the Gleason system was revised in 2005 and again in 2014. “The current application of Gleason grading differs dramatically from the original system,” Epstein continues. “Scores 2 through 5 are no longer assigned and certain patterns that Gleason defined as a score of 6 are now graded as 7.” But the Gleason 7 score itself is still pretty confusing: “A Gleason score 7 can represent mostly well-differentiated cancer, with a smaller component of more poorly differentiated cancer” — that would be Gleason 3+4=7 – “or mostly poorly differentiated cancer with a smaller component of well-differentiated cancer,” the score of Gleason 4+3=7. “Another weakness of the Gleason system is that the lowest score is now assigned a 6, although it is on a scale of 2-10.” In a study of more than 25,000 men treated for prostate cancer at Hopkins and four other institutions, Epstein and colleagues verified a simplified system that cuts through the numbers. Epstein presented the new system at the 2015 meeting of the American Urological Association in New Orleans. “It’s more accurate than the current Gleason system, with only five grades,” Epstein says, “and the lowest grade is 1, as opposed to 6.” This also has the potential to reduce overtreatment of indolent prostate cancer, he notes. “We hope that this will permit more rational and less emotional decision-making; that men who are assigned a Grade Group 1 out of 5 will know that their cancer has an indolent nature. Tumors that are a pure Grade Group 1 at radical prostatectomy have no metastatic potential.” This might also reassure men in this group who choose active surveillance. “Some men with Grade Group 2 tumors may also be candidates for active surveillance, or for radiation therapy instead of surgery depending on their age, extent of cancer, and general health.” In addition to making a clear distinction between the two Gleason 7 scores, the system separates Gleason 8 cancer from Gleason 9 and 10 tumors. “Gleason scores 8-10 are usually combined,” Epstein says. However, “although they are high-grade tumors, they still have significantly different prognoses.” Now, these are separated into Grade Groups 4 and 5. HERE IS THE BREAKDOWN FOR THE NEW GRADE GROUP SYSTEM: Grade Group 1 (Gleason score 3+3=6) Grade Group 2 (Gleason score 3+4=7) Grade Group 3 (Gleason score 4+3=7) Grade Group 4 (Gleason score 8) Grade Group 5 (Gleason scores 9-10) Will this new system be coming soon to a hospital near you? Yes. It has been accepted by the World Health Organization, and will be used in conjunction with the current system “until it becomes widely accepted and practiced,” says Epstein. n Radical Prostatectomy with Two Robots What could make robot-assisted laparoscopic radical prostatectomy even better? How about another robot? Dan Stoianovici, Ph.D., Director of the Urology Robotics Program, and his world-renowned Robotics Laboratory have designed, built and tested a robot that maneuvers an ultrasound probe. This novel robot, called the transrectal ultrasound probe manipulator (TRUS robot, for short), allows surgeons to do something very important: See — and preserve, if no cancer is there — the tiny neurovascular bundles, which contain the nerves that are needed for erection, and are critical for recovery of sexual potency. In a recent study, working with surgeon Misop Han, M.D., the David Hall McConnell Professor in Urology, and other Brady colleagues, Stoianovici tested the TRUS robot in a brand-new procedure called tandem-robot assisted laparoscopic radical prostatectomy, or T-RALP, done in 49 men whose average age was 59. The TRUS robot was used together with the daVinci surgical robot, to take ultrasound images “at critical points of the operation,” says Stoianovici. The results showed that the T-RALP is safe and feasible, and that it “can potentially improve the visualization of the neurovascular bundles, and subsequently improve postoperative recovery of potency in men.” 3 WINTER 2016 | DISCOVERY Continued from page 1 » opportunity to be cured. Virtually every man diagnosed — more than 90 percent — was treated with either some form of radiation or surgery. All this has changed, in large part to a better understanding of what happens to men with favorable risk prostate cancer who remain untreated.” Brady resident Jeff Tosoian, M.D., M.P.H., and Mufaddal Mamawala, the biostatistician in charge of keeping track of men in the Brady’s Active Surveillance program, recently reported on what happened to men who, over the last 15 years, entered this program rather than undergoing immediate treatment. They delivered their findings at the American Urological Association’s 2015 meeting in New Orleans; their results were published online September 1 and fast-tracked for publication in the Journal of Clinical Oncology. About 1,300 men have entered the program so far. Their average age is 66, Carter says, and two-thirds of these men entered with “very low-risk prostate cancer.” They had Gleason score 6 cancer in no more than two biopsy cores; cancer was present in 50 percent or less of each core; their PSA density (PSA divided by prostate volume) was 0.15 or less; and they had no cancer that could be felt on a rectal examination. The remaining one-third of these men had “low-risk” prostate cancer. This means that they had no cancer that could be felt on a rectal exam, a PSA below 10 ng/ml, and Gleason 6 cancer on their biopsy. “A number of interesting findings from this update should help inform men regarding the safety of active surveillance,” says Carter. “First, we can now tell men that if they qualify for the active surveillance program and are monitored carefully, their risk of dying from another cause instead of prostate cancer over the next 15 years after diagnosis is 4 percent (24 to 1). Fewer than 1 percent — only 0.4 percent, (a risk of 250 to 1) — of men in our active surveillance program either died of prostate cancer or developed advanced disease. Second, over 15 years, fewer than 5 percent of these men developed 4 a more serious grade of cancer (Gleason 4+3 or above).” The key here is who is eligible for the program: The criteria are very specific (see above), making sure that only men with the least risk of having aggressive cancer even get enrolled. Also, these men are monitored faithfully, with regular follow-up visits and biopsies. The key here is who is eligible for the program — only men with the least risk of having aggressive cancer. Also, these men are monitored faithfully, with regular follow-up visits and biopsies. “Our results show that men who are diagnosed with very low-risk or low-risk (favorable risk) prostate cancer should think carefully before pulling the trigger to treat their cancer,” states Carter. “They may well be a candidate for no immediate treatment and just careful monitoring.” Better understanding of the kind of cancer a man has — whether his risk of having aggressive disease is lower or higher — means that more men are opting to wait on treatment. “Today, about 30 to 40 percent of men diagnosed with favorablerisk prostate cancer are being managed with surveillance, compared to fewer than 10 percent in 2010.” n Chan Receives Award A big award for Daniel W. Chan, Ph.D., Director of the Clinical Chemistry Division and Center for Biomarker Discovery and Translation, and Co-Director of the Pathology Core Laboratories: Chan was selected to receive the Human Proteome Organization’s very first HUPO Translational Proteomics Award. This honor, presented at the 2015 HUPO Congress in Madrid, “is the most important proteomics award in my career,” says Chan. n Active Surveillance: A Tailor-Made Approach? Previously, doctors have only been able to see prostate cancer, either as a tumor or at metastatic sites, when there have been enough cancer cells gathered together to make a critical mass that would show up on MRI or another form of imaging. There was no way to target prostate cancer cells specifically. “In our program, we have generally recommended relatively intense monitoring, with prostate biopsies done annually for most men,” says Carter. However, it may be that some men could be monitored safely with a longer interval between biopsies. In a recent study using data collected over the last 15 years in the Active Surveillance program, Hopkins medical student Ridwan Alam and biostatistician Mufaddal Mamawala examined the likelihood that a man in active surveillance will eventually be diagnosed on biopsy with a higher-grade cancer that would likely need treatment. Their results were published in the Journal of Urology. They found that the risk of “grade reclassification” — finding a higher grade of cancer on biopsy — is highest during the first two years on surveillance. “About half of all grade reclassification occurs then, in men with both very low-risk and low-risk disease.” This is thought to be because the first biopsy or two might simply have missed higher-grade cancer that was there all the time. Grade reclassification also occurred, outside those first two years, in men with “low-risk,” instead of “very low-risk” disease. Another striking finding: With each prostate biopsy that showed the cancer was holding steady, still indolent, and with no change in grade, the risk of finding more aggressive disease fell by 30 percent. Carter and colleagues have used these findings to construct a risk calculator for men on active surveillance. It will be available soon, and will be easy to use, Carter says. “Men and their physicians will put in the year of diagnosis, age, PSA density, whether or not the cancer was found on one or both sides of the prostate, and total number of biopsies without reclassification. The calculator will then estimate the risk of finding a higher grade of cancer at the next biopsy.” Using this risk-assessment tool, Carter has found that 30 percent of men in the Brady’s active surveillance program have “less than a one-in-10 chance that a repeat biopsy in the next year would show higher-grade cancer.” And 25 percent have a one-in-four risk of grade reclassification at the next biopsy. “Thus, for men at lowest risk, a prostate biopsy may be deferred for several years.” Breakthrough in Prostate Cancer Imaging Have any cancer cells escaped the prostate? This is the question that every man who has prostate cancer, and every doctor treating him, wants to answer. Now there’s a way to find out without making an incision or taking another biopsy sample. It’s a brand new technique, called PSMA imaging, and it uses a PET (for positron emission tomography) scanner. The technique was developed by Martin G. Pomper, M.D., Ph.D., the William R. Brody Professor of Radiology and Director of the Division of Nuclear Medicine and Molecular Imaging, and the original support to develop it came from a grant made by Patrick C. Walsh Prostate Cancer Research Fund. “This truly is individualized medicine, and we can really help patients with it,” says Pomper; in fact, men with prostate cancer from around the world have flown to Johns Hopkins just to have this test done. “The results from this new radiotracer have changed how the disease is being managed in some patients. It, and others like it being used in Europe, have caught on like wildfire.” At medical meetings devoted to prostate cancer, sessions are now being taught on PSMA imaging. Here’s why this is such a breakthrough: Previously, doctors have only been able to see prostate cancer, either as a tumor or at metastatic sites, when there have been enough cancer cells gathered together to make a critical mass that would show up on MRI or another form of imaging. There was no way to target prostate cancer cells specifically. But what if there could be a way to make those cells light up somehow? With this in mind, Pomper figured out a way to engineer a harmless radioactive tracer that would attach itself specifically to prostate cancer cells. The tracer targets something on the surface of these cells: a molecule called PSMA, for (prostate-specific membrane antigen). “PSMA is a protein that is present in high concentrations on the surface of prostate cancer cells,” Pomper says. “PET is a sensitive imaging technique that can allow us to see tumors deep within the body. PET works by detecting the radioactive molecules we made to ‘tag’ the prostate cancer cells specifically.” this — alphabet soup alert here — into a second-generation, PSMA-targeting PET agent called DCFPyL. Pomper is excited about the potential for DCFPyL to help men throughout the prostate cancer spectrum. “This agent has vastly higher sensitivity and specificity, and it provides sharper images,” he says. “That will enable us to expand the use of imaging, not only to primary disease, but to see if the disease has returned after initial treatment, to help make treatment more accurate, and even as a monitoring tool for men on active surveillance. We believe that the images we are getting are the clearest ever obtained for prostate cancer in a human being.” As a bonus, because PSMA is also expressed in the blood vessels of other types of cancers, this technique may also help spot other tumors, including certain forms of kidney cancer, he adds. Pomper and colleagues recently published their results in Molecular Imaging and Biology. n Previously in Discovery, we reported that Pomper had discovered and tested the first PSMA-targeting PET agent in a clinical trial. Now he has refined 5 WINTER 2016 | DISCOVERY Charred Food Bad, Veggies Good for the Prostate “This provides even more evidence that eating vegetables may protect against cancercausing agents like those in overcooked meats.” Those of us who love steaks and hot dogs on the grill were chastened a few years ago, when scientist Bill Nelson, M.D., Ph.D., the Marion I. Knott Director and Professor of Oncology and Director of the Sidney Kimmel Comprehensive Cancer Center, began investigating something called “PhIP.” PhIP (a short name for a long chemical compound) is found in meats cooked at high temperatures — think of charred burgers, or fried chicken. It is a “pro-carcinogen,” a chemical that turns into something that can attack and mutate DNA, and is known to cause prostate, breast, and colorectal cancer in rats. But there’s good news: It pays to eat your veggies. “When we fed rats tomatoes and broccoli along with PhIP, the animals lived longer, and showed reduced incidence and severity of prostate neoplasms (new, abnormal cell growth; particularly of PIN, prostatic intraepithelial neoplasia — funny-looking cells that are linked to prostate cancer), intestinal cancers, and skin cancers as compared to rats fed PhIP alone,” says Nelson. “This provides even more evidence that eating vegetables may protect against cancer-causing agents like those in overcooked meats.” 6 There is also a twist to the story: Food safety pays off, as well. Nelson, along with pathologist Angelo De Marzo, M.D., Ph.D., and scientist Karen Sfanos, Ph.D. has also explored the idea that prostate cancer may involve a combination of “environmental insults” — bad things in the diet, plus something else that weakens the body, like an infection. They wondered whether chronic inflammation — caused by bacterial infection — would make a difference in rats that had consumed PhIP. Using a specific strain of E.coli, isolated from a patient with chronic prostatitis/chronic pelvic pain syndrome by urologist Anthony Schaeffer, M.D., and further studied by urologist Edward Schaeffer, M.D., Ph.D., the R. Christian B. Evensen Professor, they found, to their surprise, that the charred food plus the nasty bug (many people have E.coli in their gut and it is harmless, but some strains can get into meat when it’s processed, and can survive if the meat is undercooked) seemed to have a systemic effect, causing an increase in the development and progression of cancer in the skin and digestive tract. The rats that received the double punch of E.coli plus PhIP fared worse than rats that ate the PhIP alone. In one study, the bacteriaand PhIP-consuming rats developed more precancerous lesions within the prostate and might have developed even more problems – except they also died sooner. In further experiments, Nelson, De Marzo and Sfanos found that “when we inoculated PhIP-fed rats with E.coli in the prostate, the animals developed acute and chronic prostate inflammation out of proportion to that seen with PhIP ingestion or E.coli inoculation alone, and had more prostate neoplasms, intestinal cancers, and skin cancers. “This hints that prostate infections and dietary carcinogens might interact to promote chronic prostate inflammation and prostate cancers, and that prostate infections might augment carcinogen effects on other tissues, as well,” says Nelson. Nelson, De Marzo, Sfanos, and colleagues recently published two papers on these striking new findings in the journals PLoS ONE and Cancer Prevention Research. n Shorter Telomeres in Normal Cells Can Point to Prostate Cancer Every time a cell divides, we lose a minuscule portion of the telomere’s DNA, and become more vulnerable to illness. Brady scientist Alan Meeker, Ph.D., is one of the foremost experts on a tiny but very complicated subject: telomeres. These are bits of specialized DNA found at the ends of every chromosome. They are like little shields, tips that protect the chromosome from wear and tear — think of an aglet on a shoelace, keeping the strings from fraying. Every time a cell divides, we lose a minuscule portion of the telomere’s DNA; as we age, our telomeres get progressively shorter. They’re a buffer between our chromosomes and the outside world, and as they shrink, we become more vulnerable to illness. Back in 2009, Discovery reported on Meeker’s discovery with Brady scientist Donald Coffey, Ph.D., The Catherine Iola and J. Smith Michael Distinguished Professor of Urology, that the shortening of telomeres is an important contributing factor to the development of prostate cancer, and that men who inherit short telomeres have a higher risk of developing cancer. Since then, Meeker has continued to work with Hopkins scientists to learn more about telomeres, and with Christopher Heaphy, Ph.D., he found that, in men who underwent radical prostatectomy, those with telomere abnormalities in both their prostate cancer cells and in nearby cells that otherwise appeared normal “had a 14-fold increased risk of dying from their disease.” Next, “given these interesting results, particularly the presence of short telomeres in the nearby normal-appearing cells, we hypothesized that the presence of shorter telomeres in diagnostic biopsies would also be associated with risk of prostate cancer.” In collaboration with colleagues at the Johns Hopkins Bloomberg School of Public Health, Meeker and Heaphy studied telomeres in normal cells in biopsies from men who received a placebo in a national prostate cancer prevention study, the Prostate Cancer Prevention Trial. “We found that men with short telomere lengths in their biopsies had a higher likelihood of having prostate cancer compared to men who had normal telomere lengths,” says Meeker. These findings suggest that telomere shortening in normal-appearing cells may help predict the presence of prostate cancer. “In order to test this idea, we are validating these findings, and also performing studies to better understand the biology of this subset of cells with short telomeres within the prostate tumor microenvironment.” This work was recently published in the journal, The Prostate. n A “Double Whammy” for Detecting Prostate Cancer in African American Men Because of the groundbreaking research of urologist Ted Schaeffer, M.D., Ph.D., scientists know that prostate cancer is more aggressive in men of African descent than it is in Caucasian men. They also know, thanks to Schaeffer, that not only is cancer more aggressive in these men; it’s harder to find. Schaeffer discovered that African American men are twice as likely as Caucasian men to have aggressive cancers develop in the anterior area of the prostate. They discovered that not only are the cancers different, but the difference is potentially dangerous. “If you think of the prostate as a house, and the rectum as the basement, we come up through the basement with the biopsy needle,” says Schaeffer. In most Caucasian men, prostate cancer is located in the posterior part of the prostate, “immediately adjacent to the rectum — so it’s basically on the first floor. But in African American (AA) men, aggressive cancers are hiding up in the attic, which is much more difficult to sample on an ordinary prostate biopsy. For this reason, many AA men are misclassified as having indolent disease — they are falsely reassured that their cancer is not the kind to worry about — and their diagnosis of aggressive cancer is delayed.” Building on this work, Schaeffer has explored whether these cancers themselves are different — not just in location, but in their molecular makeup. In other words, “are the fundamental building blocks different in tumors that begin in the posterior location?” To find out, Schaeffer and colleagues examined the genetic codes of more than 100 prostate cancers from both anterior and posterior locations, in both AA and Caucasian men. (Caucasian men can develop anterior tumors that are aggressive, but they are more common in AA men.) They discovered that not only are the cancers different, but the difference is potentially dangerous. “We found that these anterior cancers make less PSA than the posterior tumors do, and that anterior cancers are less dependent on male hormones for their growth than posterior tumors are. This was true in men of both races, but had the strongest association in AA men.” The problem, Schaeffer says, is that “we use PSA levels as a screening tool to look for cancers. So that this may be a ‘double whammy’ for men with anterior cancers: First, anterior cancers are already harder to detect with traditional prostate biopsies. Second, if they make less PSA, men with these tumors may not be offered a biopsy at the earliest possible stage,” because a doctor might look at the PSA number and think all is well. “We don’t yet have a biomarker that is capable of specifically picking up an anterior tumor, but this is certainly a dream of mine,” Schaeffer adds. “However, the advent of MRI-ultrasound fusion biopsies shows significant promise in picking up these hard-to-find cancers.” Schaeffer believes that all men who have had a negative prostate biopsy should undergo an MRI scan, to make sure there isn’t an anterior tumor lurking in the prostate’s attic. But “men of African descent with an elevated PSA may want to consider getting an MRI as a first step.” n Congratulations to Schaeffer One of the things the Brady is most known for is training the next generation of leaders in Urology. In exciting news, urologist Edward Schaeffer, M.D., Ph.D., has been appointed the new Chair of Urology at the Northwestern Feinberg School of Medicine in Chicago. He will be the Edmund Andrews Professor of Urology. “This is a great and well-deserved opportunity for Ted,” says Alan W. Partin, M.D., Ph.D., Jakurski Family Director of the Brady Urological Institute. “His leadership, scholarship, mentorship and fellowship will be greatly missed. We congratulate him on his contributions to the Brady and on this outstanding recognition of his achievements.” Schaeffer: Schaeffer, left, is the R. Christian B. Evensen Professor. Here he is with Evensen, one of the charter founders of the Patrick C. Walsh Prostate Cancer Research Fund. In his years at the Brady, Schaeffer has “seamlessly combined surgical acumen and scientific discovery,” says urologist Patrick Walsh, M.D. 7 WINTER 2016 | DISCOVERY found on T cells, white blood cells that fend off infections and help fight cancer. In melanoma, bladder, lung and kidney cancer, these drugs have shown dramatic results, causing long-term remission of disease in some cases. In prostate cancer, however, giving PD-1 blockade alone has not had promising results. “Results of immunotherapy in prostate cancer have been less impressive than in other diseases, with immune checkpoint (see side story) blockade showing little evidence of response in several clinical trials,” Drake says. “But based on our published data, we hypothesized that combining immunotherapy with hormonal therapy — earlier in the course of disease — before the cancer stops responding to hormonal therapy — could lead to better outcomes.” Drake: “We hope these promising results will drive a translational clinical trial.” Immunotherapy Plus Short-Term Hormonal Therapy: Promising Results But when we gave immunotherapy just before hormonal therapy, the results were striking. A significant proportion of animals never developed castration-resistant disease.” The body’s own immune system can pack an amazing punch. When the body decides to recognize something as an enemy and the full power of its militia kicks in, the effect can be powerful — too powerful in the case of an autoimmune disease, and not powerful enough in cancer. Although the idea of cancer-targeted immunotherapy has been around for decades, only recently has it begun to show some stunning successes in melanoma, lung cancer, kidney cancer, and bladder cancer. In prostate cancer, however, success has come more slowly. Brady scientist Charles Drake, M.D., Ph.D., an immuno-oncologist and one of the thought leaders in the field, is taking a new tack. 8 Using an animal model that “reliably responds to castration,” or androgen ablation, the medical shutoff of testosterone, “but later develops castrationresistant disease, we tested the relative timing of hormonal therapy and immunotherapy,” Drake explains. “Immunotherapy alone, either early or late in the disease’s course, was ineffective. But when we gave immunotherapy just before hormonal therapy, the results were striking. A significant proportion of animals never developed castration-resistant disease.” There are different types of immune checkpoint inhibitors. Drake and colleagues tried PD-1 blockade, and found that it was “unimpressive.” Then they tried CTLA-4 blockade, which was more promising, and a new compound was better still. A CTLA-4 antibody that targets and depletes regulatory T cells (which suppress the immune system) “was the most efficacious immunotherapy we found,” Drake says. “Taken together, we hope that these promising results will drive a translational clinical trial, in which anti-CTLA-4 is administered in combination with a short course of hormonal therapy in men with high-risk disease whose PSA has returned and is on the rise.” Drake and colleagues presented these results at the American Association for Cancer Research’s annual meeting in 2015. n Ross: Freezing the prostate may make the tumor more vulnerable to immunotherapy. Cryotherapy Plus Immunotherapy May Equal New Hope for Men with Metastatic Prostate Cancer Think about aggressive treatment for metastatic prostate cancer, and what comes to mind? Most likely, it’s not cryotherapy or immunotherapy — or putting these two therapies together. But that may soon change, if a small trial at Johns Hopkins is as promising as Brady scientists Ashley Ross, M.D., Ph.D., and Charles Drake, M.D., Ph.D., hope it will be. “One thing that advanced prostate cancer does well is adapt to and overcome therapy,” says Ross. “You give antiandrogens, and the cancer develops castrate resistance. Give stronger anti-androgens, and chemotherapy, it figures out a way around them, too.” But recent success in treating other forms of cancer — particularly melanoma — with checkpoint-blocking drugs such as PD-1 inhibitors (see side story), has given rise to the hope that this new approach to immunotherapy will work in prostate cancer, too, allowing “the immune system to kill cancer cells and adapt just as quickly as the cancer does to continue to eradicate disease.” PD-1-blocking drugs target the Programmed Death 1 (PD-1) molecule — a checkpoint for the immune system The combination of a PD-1 blocker and cryotherapy may provide the long-awaited kick in the pants the body needs to attack advanced prostate cancer. The combination of a PD-1 blocker and cryotherapy may provide the long-awaited kick in the pants the body needs to attack advanced prostate cancer. In the past, immunotherapy “has produced a much more muted effect in prostate cancer: slight decreases in PSA, a mild trend to better survival, nothing huge,” says Ross. One reason is that “with prostate cancer, the body doesn’t seem to mount a great immune response; it needs some help.” What it needs is a jump-start, and this is where cryotherapy comes in. system how to recognize prostate cancer at distant metastatic sites, and not just delay its progression but kill it.” Working with medical oncologist Drake and post-doctoral fellow Benjamin Benzon, Ross and scientists in his laboratory have been testing ways that local therapies — applied right to the prostate — can augment the systemic immune response against cancer. “We needed a way to help the prostate cancer expose more of its tumor antigens so the immune system will recognize it better. To explore this, we generated mouse models of metastatic disease and tested surgery, radiation, cautery and cryotherapy. Cryotherapy appeared to cause the greatest anti-cancer response, allowing T cells to attack tumors at distant sites, as well,” says Ross. The act of freezing the prostate, while not enough to eliminate cancer in distant metastatic sites on its own, may just cause enough chaos within the tumor — denaturing some of its proteins, disrupting its cells — that “we could teach the immune The trial, done in collaboration with Drake at Hopkins and with Merck, is open to men with fewer than five metastases and an intact prostate. “It’s a single-arm trial,” says Ross. “Everyone will get cryoablation of the prostate, an FDA-approved, minimally invasive treatment. They will get hormone deprivation for eight months, and a course of immunotherapy with an anti-PD-1 molecule called Pembrolizumab. At one year, we will look to see what their PSA is and if their metastatic lesions have disappeared. We are hoping that we will see regression of their metastases and very low PSAs in at least 50 percent of the men.” For more information on this and other trials, please call Ross at 443-287-7225. You can also read more about the trial at Clinical Trials.Gov (trial number NCT02489357, https://clinicaltrials.gov/ ct2/show/NCT02489357). n What are Immune Checkpoints, and How Can We Block Them? Immune Checkpoint Blockade to Treat Cancer: The immune system is all about communication. For an immune cell – a foot soldier in the body’s effort to protect itself against enemy invaders – to be activated, two signals need to be made. Signal 1 is controlled by the T cell, a white blood cell, that recognizes a tumor-specific protein, called an antigen, through its receptor. Think of Radar O’Reilly in MASH, listening to his headset and hearing something suspicious. Signal 2 comes from B7 molecules. Here’s where the communication gets scrambled: In tumors, T cells often pick up a “checkpoint” molecule called CTLA-4, which sticks to B7 molecules like glue. This is bad, because it effectively hijacks Signal 2 – blocking the communication back to the foot soldier – and the T cell never gets the signal to “go fight the bad guy.” A second and maybe even more important checkpoint is controlled by the interaction between PD-L1 on the tumor cell and PD-1 on the T cell. “Recent advances in our understanding of the immune system have resulted in a sea change in the treatment of aggressive malignancies,” says Brady scientist Charles Drake, M.D., Ph.D. He should know; he is doing groundbreaking work on immunotherapy in prostate cancer. “In particular, we now know that in many patients, their immune cells have already seen the tumor and are poised to destroy tumor cells. However, those tumordestroying immune cells are often held back by a series of molecules known as immune checkpoints.” Normally, Drake explains, these checkpoints function to protect the body from auto-immune attack; “but in cancer, tumors hijack those pathways to protect themselves, instead.” The world of immunotherapy involves a lot of alphabet soup-sounding names. For example, the most important checkpoint pathway is controlled by two molecules that act on two different kinds of cells. The initials “PD” stand for “Programmed Death.” PD-L1 is made by tumor cells, and PD-1 is on the corresponding immune cells called T cells. “When tumors are under attack, they crank up the production of PD-L1,” says Drake, and this is a bad thing. “PD-L1 protects the tumor cells by binding to PD-1 on those invading white blood cells called T cells — effectively turning them off.” Imagine a smoke alarm going off, and the home security system calls the fire department and says, “Don’t worry, it’s just a false alarm,” so the house keeps on burning. But scientists have figured out how to break this cycle — in other words, to call the fire department back and say, “Hurry up! We need you!” Drake is excited about blocking another immune checkpoint that targets the molecule CTLA-4. Interestingly, blocking both of these checkpoints, CTLA-4 and PD-1, “leads to a higher response rate than blocking either one alone,” notes Drake, and a Johns Hopkins team led by Emmanuel Antonarakis and Drake is planning a trial of dual-checkpoint blockade in men with advanced prostate cancer that expresses a mutated androgen receptor called ARV7 which makes them particularly resistant to androgen-targeting therapies. Note: Not all men express AR-V7; there is a brand-new blood test, only available at Johns Hopkins, that can tell whether you are in this group (see story on PAGE 13). 9 WINTER 2016 | DISCOVERY The results of this study indicate that not all men with a family history of prostate cancer have equivalent risk. Kathy Wiley and William Isaacs: This work will help identify men “who could benefit from earlier and more frequent screening.” Will I Get Prostate Cancer? New Study Calculates Genetic Risk For more than a decade, investigators led by William Isaacs, Ph.D., the William Thomas Gerrard, Mario Anthony Duhon and Jennifer and John Chalsty Professor of Urology, have made tremendous progress in discovering major genetic factors linked to an inherited risk of prostate cancer. In fact, a decade before that, Brady investigators led by Isaacs and urologist Patrick C. Walsh, M.D., showed that prostate cancer runs in some families, and that men with a family history of prostate cancer tend to develop it at a younger age; before this, prostate cancer was thought simply to be a really common disease in men. Some of the risk factors Isaacs and colleagues at Hopkins and elsewhere have discovered include common and rare genetic variants, such as mutations in the genetic sequence called single nucleotide polymorphisms, or SNPs, and in the genes, HOXB13 and BRCA2. In a new study, Isaacs, along with Jianfeng Xu and Brian Helfand at NorthShore Research Institute in Chicago, have looked to see which is more accurate at predicting a man’s risk of developing prostate cancer: a family history of the disease, or specific genetic risks, determined by looking at his DNA (specifically, by measuring “SNP profiles” found in blood cells or saliva). 10 “It is well established that men who have a first-degree relative with prostate cancer are at increased risk for prostate cancer,” says Isaacs. “What is not known is the degree to which these men are at a higher risk. In the past, each man with a first-degree relative was assumed to have the same increase in risk, depending on how many affected first-degree relatives he had.” For example, a man whose father had prostate cancer would be at an elevated risk of developing prostate cancer, but a man whose father, brother, and grandfather had prostate cancer would be at an even higher risk. In the study, Isaacs, Xu and Helfand examined DNA samples from men with a family history of prostate cancer to determine the number of risky SNPs — altered stretches of DNA — these men inherited. “Interestingly, although most of these men carried more genetic risk factors than men without a family history, some men carried less,” says Isaacs. “These men were more likely not to develop prostate cancer than men without a positive family history. Indeed, the results of this study indicate that not all men with a family history of prostate cancer have equivalent risk.” In fact, Isaacs continues, there is a wide range of risk, “and this can be estimated through measuring prostate cancer risk SNPs to calculate a genetic risk score.” This study has been submitted for publication. Additional studies are needed to validate these findings, he adds, but this study provides a strong basis for developing a simple and inexpensive test to assess differences in prostate cancer risk among sons and brothers of men with prostate cancer. “Such an assessment could be useful in identifying men who would most likely benefit from earlier and more frequent disease screening.” n Surviving Prostate Cancer: Good News for Radical Prostatectomy Patients So you had radical prostatectomy and things have been going pretty well. You feel good, and your PSA remains undetectable. It’s been several years now; are you out of the woods? “Overall, men are highly unlikely to die from prostate cancer after surgery — even men with high-risk prostate cancer. If you do not experience recurrence for several years, your likelihood of survival for 10 more years is outstanding.” “After radical prostatectomy, about a third of men experience a return of PSA,” says urologist Misop Han, M.D. the David Hall McConnell Professor in Urology. “However, only a very small number of men who have had surgery ultimately die from prostate cancer. So, men contemplating surgery or those who have already had surgery may wonder, What is my chance of surviving from prostate cancer if I have not had PSA recurrence for several years after surgery?” Han and Brady epidemiologist Bruce Trock, Ph.D., recently set out to answer that question, using the Brady’s massive database to track results from more than 14,000 men who had surgery at Johns Hopkins between 1984 and 2013. They divided men into three risk groups: low, intermediate, and high. Then they calculated what they call the Conditional Survival probability — the likelihood of survival for 10 additional years. They found that men in the low- and intermediate-risk groups had a very high probability — at least 96 percent — of not dying from a return of prostate cancer at 10 years, “regardless of the time duration without recurrence,” says Han. “In other words, these men are highly unlikely to die from prostate cancer, regardless of whether they experience recurrence or not.” In the high-risk men, the probability of survival from prostate cancer at 10 years was 91 percent for those who experienced recurrence within one year. “However, if these high-risk men do not have recurrence for more than three years, their probability of survival from prostate cancer for 10 additional years is even higher — greater than than 99 percent. “These results give much hope for men with prostate cancer,” said Han. “Overall, men are highly unlikely to die from prostate cancer after surgery — even men with high-risk prostate cancer. If you do not experience recurrence for several years, your likelihood of survival for 10 more years is outstanding.” n MicroRNAs: Genes that May Make Radiation and Chemotherapy More Effective Your dishwasher is broken again. You’ve kept it going, but maybe you’ve fixed it too often; maybe it needs to go. On the molecular level, your body faces similar dilemmas all the time when it comes to fixing damaged DNA. DNA is a precious thing, and the body works hard to keep it in good shape, but there’s a delicate balance, explains Brady scientist Shawn Lupold, Ph.D., the Frank Hinman Scholar: “Too little DNA repair can lead to an accumulation of changes — to uncontrolled cell growth, cancer development, or even cancer progression. On the other hand, too much DNA repair can be detrimental, too, if it helps cancer cells resist treatment like chemotherapy or radiation.” Although cancer biologists know a lot about how to work with and around some of the body’s DNA-fixing mechanisms, there’s a new repairman in town, genetically speaking: A newly discovered class of genes called microRNAs. Lupold has been studying these genes and their role in the development and progression of prostate cancer with other Brady scientists, including Theodore L. DeWeese, M.D., Ph.D., the Sidney Kimmel Professor and Director of Radiation Oncology and Molecular Radiation Sciences. Although what microRNAs do is very complicated and is still not fully understood, basically they send messages that produce action. “Each microRNA gene encodes a short RNA transcript” that results in “selectively turning off the synthesis of specific proteins and enzymes,” says Lupold. In a recent study with DeWeese and Koji Hatano, a visiting urologist and fellow from Osaka University in Japan, Lupold learned more about how microRNAs regulate DNA repair pathways in cancer cells. “Using a novel and high-throughput screening strategy, our team evaluated more than 800 different human microRNAs,” says Lupold. They were looking for microRNAs that seemed especially adept at inhibiting DNA repair and sensitizing prostate cancer cells to radiation therapy — for a new weapon that would not only make radiation therapy more powerful against prostate cancer, but would also hinder the cancer cells’ ability to recover from the attack. This work was published in April in the journal, Nucleic Acids Research. Hatano, who was first author on the paper, identified miR-890 as “one of the most potent radiation-sensitizing microRNAs in the study,” says Lupold. This particular microRNA “inhibited the ability of cancer cells to repair the most lethal type of DNA damage, double-stranded breaks. This led to an over 50-percent increase in prostate cancer cell sensitivity to ionizing radiation. Most importantly, we demonstrated that miR-890 specifically targets and inhibits the expression of multiple DNA repair genes and pathways.” They were looking for a new weapon that would not only make radiation therapy more powerful against prostate cancer, but would also hinder the cancer cells’ ability to recover from the attack. In laboratory studies, the team injected the microRNA into established prostate tumors in mice, and two days later treated the animals with radiation therapy. “The tumors treated with miR-890 were significantly reduced in size and growth when compared to controls,” says Lupold. The next step, currently being worked on by Lupold and DeWeese, is to find the best way to deliver these microRNAs to prostate cancers, “with the ultimate goals of selectively sensitizing prostate cancer tumors to radiation and chemotherapy, while sparing the healthy tissues right next to the cancer.” In other studies of microRNAs, Lupold’s lab is exploring the role of these genes in other aspects of prostate cancer, such as androgen signaling. n 11 WINTER 2016 | DISCOVERY PIN: Some high-grade PIN cells may be more dangerous than they look. High-Grade PIN: Wolf in Sheep’s Clothing? If it is high-grade PIN that is found in multiple cores or is present in tissue from both sides of the prostate, then a repeat biopsy is recommended. PIN, short for “prostatic intraepithelial neoplasm” is a condition in prostate biopsy tissue that pathologists see under the microscope. The cells are funny-looking; pathologists consider them not to be cancerous, but not normal-looking, either, and for years, PIN has been considered a sort of precursor for prostate cancer. “Although PIN shares many hallmarks of prostate cancer, it does not appear to invade the surrounding normal tissue,” says molecular pathologist Michael Haffner, M.D. “When PIN cells are found in isolation, and no actual cancer cells are found, it’s not always clear what to make of the finding. “As a matter of precaution, urologists usually recommend repeat biopsies if there are many cores of tissue with this finding to make sure that everything’s okay – that the PIN itself is not progressing to become cancer, or that cancer cells were not missed the first time around. 12 But new findings by Haffner, molecular pathologist Angelo De Marzo, genomics expert Srinivasan Yegnasubramanian and oncologist Bill Nelson may call for extra precaution in some men. By way of a series of genetic analyses, they were able to trace the evolutionary ancestry — to look back in time, in effect — of PIN lesions in prostate tissue specimens. “Surprisingly, we found that many lesions that look like a precursor lesion have identical genetic fingerprints of invasive cancer cells,” says Haffner. “Therefore, at least a subset of PIN lesion likely represents cancer cells that have invaded into normal prostate glands — a potentially dangerous ‘wolf in sheep’s clothing.’ This study provides important new insights into how prostate cancer cells can grow and spread, but also establishes new molecular markers that can be used as helpful tools in the future to discriminate less harmful precursor lesions from invasive cancers.” Urologist Patrick C. Walsh, M.D., reassures men who have PIN that it is most likely just that — precursor cells that are not cancer. “But if it is high-grade PIN that is found in multiple cores or is bilateral (in tissue from both sides of the prostate), then a repeat biopsy is recommended.” n For Castrate-Resistant Prostate Cancer: High-Dose Testosterone Hormonal therapy takes away a driving force of prostate cancer – testosterone. It can work well for many years, but eventually the prostate cancer cells figure out how to adapt to the low-testosterone environment, and they begin to grow. But studies in the lab of Brady scientists John Isaacs, Ph.D., and Samuel Denmeade, M.D., have shown that these “testosterone-deprived prostate cancer cells can be paradoxically killed” by treatment with something they didn’t expect — high amounts of testosterone, says Denmeade. Based on this observation, Denmeade and colleagues recently carried out a pilot clinical trial that showed that a monthly injection of high-dose testosterone could be safely given to men with castrate-resistant prostate cancer, and that it produced a therapeutic benefit in some men. These exciting findings were published in the journal, Science Translational Medicine. In addition, Denmeade says, “we observed that after treatment with high-dose testosterone, in most cases the prostate cancer cells became re-sensitized and were no longer resistant to treatments that lower or block testosterone.” In other words, the treatment had a double impact: After being bombarded with testosterone, prostate cancer cells were once again susceptible to hormonal therapy. The treatment had a double impact: After being bombarded with testosterone, prostate cancer cells were once again susceptible to hormonal therapy. These results were promising enough for Denmeade to received funding from both the National Institutes of Health and the Department of Defense’s Prostate Cancer Research Program to perform more clinical studies at Johns Hopkins. He and colleagues will be testing this concept in larger groups of men with prostate cancer that has become resistant to standard hormone deprivation treatments. “Our goal with these clinical studies is to establish a role for high-dose testosterone as an inexpensive treatment that could improve quality of life, reduce disease burden and potentially reverse therapeutic resistance in men with advanced prostate cancer,” he says. “We hope to establish this as an effective therapy that can improve survival, overcome resistance to hormonal therapy, and meaningfully improve quality of life, functional activity, and sexual function in men with castrate-resistant prostate cancer.” Denmeade was the principal investigator on the pilot study. Co-authors on the paper include Michael Schweizer, Emmanuel Antonarakis, Hao Wang, Seun Ajiboye, Avery Spitz, Haiyi Cao, Jun Luo, Michael Haffner, Srinivasan Yegnasubramanian, Michael Carducci, Mario Eisenberger, and John Isaacs. n Boosting Testosterone Not Shown to Raise Prostate Cancer Risk “Testosterone therapy was not found to increase PSA levels, or to promote the occurrence of prostate cancer.” Does testosterone therapy raise your risk of getting prostate cancer or having a heart attack? For definitive answers, large-scale, long-term controlled studies are needed, says Arthur L. Burnett, M.D., the Patrick C. Walsh Distinguished Professor of Urology. However, in the meantime, results of a meta-analysis study led by Burnett suggest that, for prostate cancer at least, the risk is not changed by taking extra testosterone. Testosterone therapy — boosting low testosterone with supplemental medication — is often prescribed for men with low blood levels of testosterone, for symptoms including reduced libido and sexual activity, fewer spontaneous erections, decreased energy and depressed mood. “But controversies surround the role of testosterone therapy, particularly with respect to prostate cancer and cardiovascular health risks, and these concerns have heightened recently,” says Burnett. In an effort to address the prostate cancer side of these worries, Burnett collaborated with Peter Boyle and colleagues of the International Prevention Research Institute in Lyon, France. They pored over data from about 20,000 men who participated in 24 population-based studies that evaluated the association between blood testosterone levels and the risk of prostate cancer. “We found that the risk of prostate cancer was neither increased or decreased among men with high levels of testosterone compared to lower levels,” says Burnett. “Also, testosterone therapy was not found to increase prostate specific antigen (PSA) levels, or to promote the occurrence of prostate cancer.” The meta-analysis was presented as a prize abstract selection at the Press Program of the American Urological Association 2015 Annual Meeting. Burnett hopes that these findings will be helpful to clinicians and patients who are worried that boosting low testosterone will cause prostate cancer to develop. n test available are: Alison Mass Bommarito and Salvatore J. Bommarito, R. Christian B. Evensen, A.R. Deane Nesbitt, Jr., Joseph F. Rascoff, Harvey G. Sherzer, Carolyn and William C. Stutt, F. Patrick Hughes, and John C. Corckran , Jr. For Men with Advanced Prostate Cancer: New Hopkins Test Can Tell if Some Drugs Won’t Work The study that led to this new AR-V7 test began about one year ago and was conducted in the Molecular Diagnostic Laboratory, led by James Eshleman, M.D., Ph.D., Professor of Pathology, in conjunction with Luo’s laboratory. “We walked through every bit of detail of this test,” Eshleman says, a complex process, “and carried out a complete analysis to justify using the test on men with advanced prostate cancer.” The Molecular Diagnostic Laboratory at Hopkins is a CLIA-certified lab. (Any facility that performs laboratory tests on human specimens for the purpose of diagnosis or treatment is required by Federal law to have a CLIA certificate, and Medicare requires the CLIA certificate number before any claims can be processed.) For the first time, a blood test is available to help men with advanced prostate cancer determine if certain medicines will work – or if they can avoid the trouble and cost of taking expensive drugs that won’t fight their cancer. This test, developed and tested at Johns Hopkins, promises to predict treatment response and resistance in men with prostate cancer that no longer responds to standard hormonal therapy. “This is a major milestone.” The test targets a faulty androgen receptor (AR) molecule called AR-V7, discovered in 2008 by Brady scientist Jun Luo, Ph.D. “This is a major milestone,” says Luo, who also pioneered the first AR-V7 blood test in his research laboratory. “Transforming a discovery and moving a test from bench to bedside has been a major challenge historically.” That the test is available now to patients at the Brady represents several victories — of collaboration among scientists and physicians in several disciplines, and of Brady philanthropists who saw a need and responded with what urologist Patrick Walsh, M.D., calls “an emergency influx of generosity.” Walsh, University Distinguished Professor of Urology, notes that “the Brady Institute itself wouldn’t have been possible without private philanthropy — starting with a large endowment from James ‘Diamond Jim’ Brady a century ago. Time after time, friends of the Brady have stepped in and their support has made it possible for us to continue to do great things. In this case, this gift helped get the test to the men who need it most as soon as possible.” The philanthropists who helped make this For men with advanced cancer that has become resistant to hormonal therapy, there are now six FDA-approved drugs that have been shown to improve survival. “We ultimately hope that biomarker tests such as AR-V7 will help clinicians decide among these six drugs in a more rational manner,” says Emmanuel Antonarakis, M.D., Ph.D., Associate Professor of Oncology, who was the clinical lead investigator on this project. “Having a robust clinical test for measuring AR-V7 in blood is only the first step, however.” Antonarakis cautions that further prospective clinical trials will be required before the AR-V7 test is clinically validated and before information from the test can be used to guide treatment decisions for all men with advanced prostate cancer. The AR-V7 blood test offered by the Molecular Diagnostic Laboratory has not yet been approved by the FDA and is available only at Johns Hopkins. For more information on how to request this test, please contact: Katie Beierl, [email protected]. n 13 WINTER 2016 | DISCOVERY “He is a remarkable man, who first had a dream — he believed he was meant to do cancer research — and then came to Hopkins and made it happen.” Don Coffey: Awarded the American Association for Cancer Research’s highest honor. Don Coffey: the Man, the Movie You’ve seen him many times on the pages of Discovery. He’s a scientific legend, here at the Brady, throughout Hopkins, and beyond, as the scientists he has trained and inspired begin mentoring their own postdoctoral fellows and students. Now you can see him on the big screen — or someday soon on the little screen, if you want to watch The Donald Coffey Story in the comfort of your own home. (It will be available on our website: urology.jhu.edu) “Don Coffey is an internationally renowned scientist and also a powerful driving force in the careers of dozens of scientists who are trying to understand cancer,” says Alan W. Partin, M.D., Ph.D., the Jakurski Family Professor and Director of Urology. “He ignites the imagination and creativity of people who are asking good scientific questions, and helps them figure out what they need to do to find the answers. In addition, he is a remarkable man, who first had a dream — he believed he was meant to do cancer research — and then came to Hopkins and made it happen. We hope that his life story will be inspiring to new generations of future scientists, and to our patients.” In April 2015, Coffey received the American Association for Cancer Research’s highest honor, the Margaret Foti Award for Leadership and Extraordinary Achievements in Cancer Research. Coffey’s “work on the nuclear matrix established a new paradigm for understanding the biology of normal and cancer cells, while his prostate cancer research helped change the face of that 14 deadly disease,” said Margaret Foti, M.D., Ph.D., the AACR’s chief executive officer. But his impact “extends far beyond his scientific achievements. His outstanding leadership skills, dedication to mentoring young investigators, passionate advocacy for sustained increases in funding for cancer research, and remarkable ability to translate complex scientific concepts into lay language make him an icon in the field and a true champion of cancer research.” In accepting the award, Coffey said that it “fulfills my lifetime dream. Sixty years ago, my wife, Eula, and I accepted our joint calling to serve this mission. Johns Hopkins University, the AACR, and hundreds of colleagues, supported by private and public donors, have all made this possible. We thank all of you.” Coffey is a former president of the AACR, the largest cancer research society, with 35,000 members from 110 countries. In other Coffey news from 2015: At the American Urological Association’s yearly meeting, the Coffey-Crain Award was presented by the British Journal of Urology International, and the Society of Basic Urology presented the Coffey lecture. The Prostate Cancer Foundation held its second meeting of the Coffey– Holden Academy in La Jolla, California. Coffey delivered the 16th Biennial “Science Creativity and Human Destiny” lecture at The Johns Hopkins University, and he was invited to provide the very first paper to launch the Asian Journal of Urology. n Potential New Pathway to Kill Prostate Cancer “This pathway has been considered untouchable, and efforts have not been invested to exploit it as an avenue to deactivate cancer cells. But our research has proven otherwise.” There is a brand new way to target cancers, and cancer biologist Marikki Laiho, M.D., Ph.D., the Willard and Lillian Hackerman Professor in Radiation Oncology, is one of only two scientists in the country funded by the National Institutes of Health to work on it. It’s called RNA polymerase I transcription. This adventure in new science began when Laiho’s group discovered a small synthetic chemical molecule, called BMH-21, and showed that it has a unique way of killing cancer cells. “We learned that the molecule is a novel inhibitor of RNA polymerase I,” she says. “RNA polymerase I transcription is an intricately coordinated transcriptional program. It is highly activated and insufficiently controlled in cancers, but despite its ability to support cancer growth, it has received little attention as a possible new target for therapy.” Transcription in this case means “reading the DNA into RNA, that is, converting the universal genetic code into a new biomolecule, RNA,” says Laiho. “RNA polymerase I drives a fundamental process that synthesizes the RNA component for the ribosomes (tiny factories inside cells where proteins are made), and hence, is essential for making cellular proteins. These building blocks are necessary for the life and health of cells. For this reason, this pathway has been considered untouchable, and efforts have not been invested to exploit it as an avenue to deactivate cancer cells. But our research has proven otherwise.” Laiho’s findings suggest the promise of inhibiting RNA polymerase I transcription in a potential new class of cancer-fighting drugs. “We have shown that it has therapeutic benefit, and it is well-tolerated in preclinical models. We hope that our findings will invigorate basic science efforts on RNA polymerase I transcription. We still lack basic knowledge of the factors associated with this fundamental process and their regulation.” Laiho believes BMH-21 has “particular relevance for the treatment of prostate cancers,” and is turning her work toward developing this molecule into a clinical drug. Her team has received the Harrington Discovery Institute’s Harrington-Scholar Innovator Award and the Prostate Cancer Foundation Global Challenge Award for this work. Laiho and colleagues are now exploring the role of BMH-21 in advanced prostate cancer. n Two Non-Cancerous Causes for Higher PSA “The greater the amount of inflammation in the prostate, the higher the PSA level.” How can prostate cancer screening be improved? Brady epidemiologist Elizabeth Platz Sc.D., M.P.H., the Martin D. Abeloff, M.D., Scholar in Cancer Prevention and colleagues are studying a group of men you might not expect to be helpful here — men who don’t have prostate cancer. “We are looking at factors that can affect blood levels of PSA other than prostate cancer,” she says. the Prostate Cancer Prevention Trial,” a large investigation in which men who were not diagnosed with prostate cancer during the trial itself were asked to have a biopsy when the study ended, even if they did not appear to need one. “We only included men who had a PSA lower than 4 ng/ml and a normal digital rectal exam, and who did not have prostate cancer found in their biopsies.” Platz and colleagues found that the men with more inflammation in their biopsied tissue had higher PSA levels, “and the greater the amount of inflammation, the higher the PSA level.” Although the scientists do not know exactly how inflammation raises PSA, they think that the inflammation disrupts the PSA-producing cells in the prostate and also makes the blood vessels within the prostate more permeable, causing PSA to leak into the bloodstream. Platz and colleagues hope that information from this study will one day help reduce unnecessary biopsies, “both for men who have never been screened, and men who have been screened and biopsied, but cancer was not found.” In another study, led by biostatistician Sarah Peskoe, Platz and colleagues looked to see whether testosterone affects PSA levels in the blood. “While we know that testosterone helps signal to prostate cells to make PSA, no one had quantified the association between testosterone and PSA in the blood in a general population of men who haven’t been diagnosed with prostate cancer,” says Platz. In this study, the investigators looked at data from 378 men, between the ages of 40 and 85, who participated in the National Health and Nutrition Examination Survey, which ran from 2001 to 2004. “We only included men who did not have a prostate cancer diagnosis and had not had a recent biopsy, rectal examination, cystoscopy, or known prostate infection or inflammation,” says Platz. The scientists found that men who had higher testosterone levels also had higher PSA levels. “We also found that the odds of having a clinically elevated PSA were greater among men with higher testosterone levels. Our findings may indicate that in prostate cancer screening, American men who have higher testosterone levels may be more likely to undergo unnecessary prostate biopsy,” flagged by their higher PSA. “While we are not advocating that men should have their testosterone measured at this time, we expect that knowledge of the testosterone-PSA association may help refine tools for clinical decision-making in men who have an elevated PSA.” Platz and colleagues published the results of these two studies in Prostate Cancer and Prostatic Diseases, and Prostate, respectively. n This is happening in two different studies. In one, led by urologist Martin Umbehr, M.D., a postdoctoral fellow studying with Platz, “we evaluated the extent to which inflammation in the prostate, which is very common, affects PSA levels,” explains Platz. With Angelo De Marzo, she was one of the first to conduct studies linking inflammation and prostate cancer. “Although urologists have long known that prostate inflammation may cause PSA to be elevated, previous studies looked at men who underwent prostate biopsies because they had an elevated PSA. Our analysis included data from 224 men from the placebo arm of Platz and De Marzo: Learning about prostate cancer by studying men who don’t have it. 15 DISCOVERY | WINTER 2016 New Tests Show Genetic Changes Linked to Aggressive Prostate Cancer ERG is a troublemaker, a gene that may promote the growth of cancer. With PTEN out of the picture, it stars in its own episode of “genes gone wild.” When the cat’s away, the mice will play. That’s what’s happening, on a very tiny scale, in aggressive prostate cancer, and it’s being demonstrated in important work by urologic pathologists Tamara Lotan, M.D., Angelo M. De Marzo, M.D., Ph.D., and colleagues. “Two of the most common genetic changes that we see in aggressive prostate cancer are the loss of the PTEN gene and rearrangements that lead to over-expression of an oncogene called ERG,” says Lotan. In this case, the cat — the keeper of the peace — is a gene called PTEN. PTEN is a tumor suppressor. Its job is to put the brakes on the out-of-control growth that leads to cancer. Without the restraint of PTEN — the gene is knocked out in about half of lethal prostate tumors — cancer cells start behaving badly. Previously in Discovery, we reported that PTEN is one of the few genes whose loss has been consistently associated with aggressive prostate cancer. Two years ago, Lotan, De Marzo, and others at Hopkins found a strong correlation between the loss of PTEN and the signs of aggressive prostate cancer, including the Gleason grade of the tumor as well as the stage of the tumor and the time it took for metastases to develop; this work was published in Clinical Cancer Research. In a larger follow-up study just published in European Urology Focus by Lotan’s team, the scientists found that PTEN loss correlated with faster recurrences after radical prostatectomy. ERG, on the other hand, is a troublemaker, a gene that may promote the growth of cancer. With PTEN out of the picture, it 16 stars in its own episode of “genes gone wild.” Lotan’s team has worked with De Marzo and other Johns Hopkins investigators to develop and test simple, inexpensive assays that show the status of PTEN and ERG in prostate tumors. In work recently published in Modern Pathology, Lotan and colleagues showed that men who have Gleason 6 tumors with PTEN loss are about three times more likely to be upgraded to Gleason 7 or higher at radical prostatectomy. Further, Lotan’s team showed that prostate tumors with PTEN loss are two to three times more likely to be lethal compared to tumors without PTEN loss, “even after adjusting for the usual clinical and pathologic signs we currently use to predict prognosis,” Lotan says. “Interestingly, PTEN loss is more tightly associated with lethal disease when the tumor does not have ERG gene rearrangement – suggesting a significant interaction between these important genes in the progression of prostate cancer.” Lotan recently presented these findings at meetings of the United States and Canadian Academy of Pathology, and of the American Association for Cancer Research. Validated tests developed by Lotan, De Marzo and colleagues are now being offered in the clinical lab at Johns Hopkins, and Lotan’s team is working with investigators from several other academic centers to develop these tests into FDA-cleared prognostic and predictive biomarkers. n Could “Nerve-Sparing Brachytherapy” Help Preserve Sexual Function? The “neurovascular bundles of Walsh,” discovered by Patrick C. Walsh, M.D., are tiny, delicate, and important: they contain the nerves that control erection. “An unfortunate risk of any treatment for prostate cancer is that many men who undergo curative surgery or radiation will subsequently develop erectile problems,” explains radiation oncologist Danny Song, M.D. For men who undergo At Last, a Desperately Needed Mouse Model of Aggressive Prostate Cancer surgery, the nerve-sparing techniques discovered by Walsh have been shown to help preserve sexual function. But until now, “there has been no clear understanding of what exactly leads to this side effect in patients undergoing radiation,” says Song, who recently set out to change this. “Prior studies have attempted to answer this question by evaluating the dose of radiation received by the neurovascular bundles, which are tiny cables of blood vessels and nerves that run along the sides of the prostate. However, these studies have not shown a difference in erectile function when comparing patients who received high vs. low doses to these structures.” So Song took a different approach. In a recent study of 366 men who underwent brachytherapy (the implantation of radioactive seeds at precise points to kill prostate cancer), Song and colleagues measured radiation doses to various anatomic structures around the prostate. “Patients who received lower doses to the cavernosal nerves had less risk of erectile problems.” “We also looked at the area where the nerves converge at the apex of the prostate, the place where the urethra joins the prostate,” Song says. “These nerves are essentially the combined neurovascular bundles from both sides of the prostate, which join on their way down to the penis. One could consider this to be the main ‘hub’ where the nerves meet on their way down to the penis.” Song and colleagues discovered that the risk of erectile dysfunction was high in men who received higher doses to the cavernosal nerves, “but patients who received lower doses to the cavernosal nerves had less risk of erectile problems. We are excited by these results and hope that, armed with a better understanding of the area that needs to be avoided when placing seeds, radiation oncologists will be able to use this knowledge to improve sexual function and quality of life for their patients.” n From left, An, Yegnasubramanian, and Haffner: Figuring out how cancer cells move through tissue and bone. Pro st ate Can ce r Me t astasis: Ne w D isco ve rie s Taking “AIM”at Invasive Cancer “To invade other tissue and migrate far distances, cancer cells need to alter their cytoskeletal properties.” In other words, they need to become tiny shape-shifters. One of prostate cancer’s worst features is its ability to spread to distant sites, particularly bone, and to start new, malignant outposts. How do they do it? Research by scientists Srinivasan Yegnasubramanian, M.D., Ph.D., Michael Haffner, M.D., Ph.D., Steven An, Ph.D., and colleagues has turned up an important clue — and a potential new avenue for treatment. “In order to invade other tissue and migrate far distances, cancer cells need to alter their cytoskeletal properties,” says Yegnasubramanian. In other words, they need to become tiny shape-shifters. But exactly how they become malleable enough to move through tissue and bone has been poorly understood. With support from the Patrick C. Walsh Prostate Cancer Research Fund and the David H. Koch Foundation, Yegnasubramanian, Haffner, An, and colleagues have identified a protein that appears to suppress the ability of normal cells to invade. This protein, called AIM1, “binds and modulates the major component of the cytoskeleton in normal prostate epithelial cells,” Yegnasubramanian adds. They found that AIM1 seemed to have an out-ofbody experience in invasive primary prostate cancer, separating itself from the cancer cell’s cytoskeleton. “Additionally, AIM1 was often deleted and/or reduced in expression in metastatic prostate cancer.” In laboratory models of prostate cells, when the scientists cut the expression of AIM1, the cancer cells began to remodel themselves, and “this increased their invasive and migratory potential. Taken together, these findings implicate the loss of AIM1 function in conferring prostate cancer cells with the ability to invade and produce invasive cancer and metastases.” This work continues, and now the investigators are working to identify the molecular mechanisms through which AIM1 can do its sleight-of-hand, allowing cancer cells to become invasive. “When we understand this, we may be able to prevent or treat prostate cancer metastases — the major cause of prostate cancer morbidity and mortality,” says Yegnasubramanian. “We are also evaluating whether AIM1-mediated changes can be used as a biomarker to identify aggressive prostate cancers with metastatic potential.” n How do scientists develop a new treatment for prostate cancer? First, they need a safe way to test it before they even think about trying it in humans. “Unfortunately, the tools available to researchers make it difficult to develop and test targeted immunotherapy and treatments for bone metastases, two areas of great need in prostate cancer therapy,” explains Brian Simons, D.V.M., Ph.D. “New drugs are currently tested primarily on xenografts -- human cells growing in mice without a functioning immune system.” But if mice don’t have an immune system, they can’t very well serve as models for any treatment that requires the body’s own ability to fight disease. Another problem: “Very few of these models develop metastatic tumors,” which limits the development of treatments for bone metastasis. If mice don’t have an immune system, they can’t very well serve as models for any treatment that requires the body’s own ability to fight disease. Simons has developed a new laboratory model that has the potential to do a lot of good for men desperately in need of treatment for advanced prostate cancer. Working with Edward M. Schaeffer, M.D., Ph.D., the R. Christian B. Evensen Professor of Urology, and a team of investigators, he has come up with a mouse model of bone metastatic prostate cancer that has many features of very aggressive human prostate cancer. “When injected into mice, these cells frequently form bone metastases that initially respond to anti-androgen therapy, but then become castration-resistant tumors,” he says. Already, this model is being used to test new immunotherapy treatment strategies and imaging systems to detect bone metastasis. 17 A New Way to Attack Early Metastatic Disease There are bits of cancer that have spread, or metastasized, beyond the prostate, but not that many, and not at very many locations in the body. Cancer in this state is still vulnerable, and still responds to treatment. In the blockbuster movie, Independence Day, terrifying space aliens invade earth. From one mother ship, dozens of equally deadly, smaller ships spread out around the planet. But these evil aliens are beaten by a tiny home force. The secret? They attack the mother ship, and without its protection, the smaller ships are vulnerable. This is a pretty good model for what radiation oncologist Phuoc T. Tran, M.D., Ph.D., wants to do with metastatic prostate cancer in its earliest stages. He believes that by eliminating the bigger sites of cancer, tiny new ones won’t be able to flourish. It’s an idea that has shown success in the treatment of breast cancer, “where improved local control decreases metastatic as well as local relapse,” Tran says. “This local treatment model is true for prostate cancer, too. Better control of localized cancer by adjuvant radiation to the area around the prostate (called the prostatic bed) lowers the risk of other metastases and improves overall survival. We believe that sites of macroscopic disease — visible on MRI or other images — support the maturation of microscopic spots of cancer into future metastases.” Going after the cancer that can be seen “has substantial clinical implications” for the cancer too small to be seen, he adds. “This is hardly ever performed in prostate cancer.” In the spectrum of cancer, from localized to advanced metastatic disease, is a kind of midpoint called an oligometastatic state. There are bits of cancer that have spread, or metastasized, beyond the prostate, but not that many, and not at very many locations in the body. Cancer in this 18 state is still vulnerable, and still responds to treatment. For example, “in patients with oligometastatic sarcomas or colorectal cancer, local radiation to the primary tumor combinedwith chemotherapy, can result in long term diseasefree survival in between 25 and 40 percent of patients,” says Tran. “Our own clinical experience suggests an oligometastatic state exists in a subset of prostate cancer patients who may benefit from local radiation treatment to all sites of macroscopic metastatic disease.” Picture, if you will, the bloodstream. It goes throughout the body, flowing in one direction. Cancer cells that make their way into the blood, like seeds floating on a river, leave the original tumor — the mother ship — and drift for a while, eventually coming to rest at a distant site, where they may start to grow. This is the generally accepted model of how cancer spreads. But Tran suspects that these circulating tumor cells (CTCs) get homesick — that they pay an occasional visit back to the original tumor, or maybe visit one of their siblings that has struck out on its own and built a home. These visits are invigorating: “The CTCs become more robust,” he says, “and this cyclical process of CTCs interacting with more established cancer results in the release of signals that foster tumor growth.” Like a domino effect, then, tumor growth leads to angiogenesis — the paving of new roads, made of blood vessels, to supply the tumor; angiogenesis is followed by immune evasion – the cancer mutates to dodge the body’s militia of immune cells — and ultimately, “the formation of new, macroscopic metastases.” This theory of macroscopic metastases being self-seeding communal sanctuaries is supported by recent genomic data from studies of human prostate cancer cells, Tran says. What’s the best way to target these little blots of cancer? Tran believes the key is stereotactic ablative radiation (SABR), “a highly focused, localized, high-dose radiation delivered in a hypofractionated course,” meaning in several large doses, spread out over several days. “It’s ideally suited for treatment of oligometastatic patients, and has shown high local control rates with minimal toxicity,” he says. “SABR effectively targets the microenvironment of tumors, and in melanoma patients, has been shown to have antitumor effects on the irradiated tumor and an abscopal effect” — think of a shock wave, affecting areas not part of the original blast — “on distant metastases when combined with other immune systemstimulating agents.” Tran is starting a multi-institutional study aimed at killing oligometastatic cancer through SABR and immune systemtargeting agents. This program is partly funded by an award from the National Cancer Institute to radiation oncologist Ted DeWeese and Director of Nuclear Medicine Martin Pomper, and by a Movember-Prostate Cancer Foundation Challenge award to Tran, who is the principal investigator, and to urologist Ashley Ross, DeWeese, Pomper, Adam Dicker (from Thomas Jefferson University), Max Diehn (from Stanford University), Charles Drake, Hao Wang, Kenneth Pienta and Mario Eisenberger. In 2015, among other honors and awards, Tran was appointed Clinical Director of Radiation Oncology and was named Associate Editor for the journal, Cancer Research. n Capturing Cancer Cells in the Bone, Years Before They Cause Trouble Brady surgeons and scientists are working together, using a surgical technique pioneered by three of our urologists, to target potentially lethal prostate cancer before it has a chance to spread. “The key here involves what we call disseminated tumor cells, or DTCs,” explains Ken Pienta, M.D., the Don Coffey Professor of Urology. “We can detect them at the time of radical prostatectomy — these tiny prostate cancer cells that have escaped the prostate and taken up residence in the bone marrow.” Important note: DTCs are not the same thing as bone metastases. Just because a man has these cancer cells in his bone marrow doesn’t mean that he has cancer growing in his bone, Pienta hastens to point out. The purpose of this story is not to scare anybody, but to tell you about exciting work that has the potential to allow doctors to see into the future, through a microscope, and identify troublemaking cells years before they are able to cause a problem. At the moment, Pienta and colleagues don’t know exactly what to make of these DTCs. “They remain poorly defined,” he says, “but we think they are a mixture of passively sloughed, nonlethal cells that are going to die anyway — which means they’re nothing to worry about — but in some cases they could also be actively migrating, cancer cells that could eventually develop into clinical metastases. It is very important to study these DTCs so we can determine how to stop the lethal ones. Previously, it was reported that nearly all men have these cancer cells in their bone marrow at the time of surgery. Now we have the know-how to prove how many men have these cancer cells in their bones, so we can go after that cancer.” In laboratory research, Brady resident Michael Gorin has developed sensitive new methods to detect and capture these cells for analysis, Pienta says. And three Brady surgeons — Ashley Ross, Ted Schaeffer, and Alan Partin — have pioneered a painless technique to sample the marrow from the pubic bone just before radical prostatectomy, when the patient is asleep. “This has never been done before and represents an exciting new advance for the field,” says Pienta. “The team has already obtained samples from more than 50 men and we are busy characterizing these cells. We expect to study 500 men in the coming year; this will be the largest study ever performed to characterize DTCs in men at the time of surgery.” Pienta and colleagues believe this research will identify the early steps by which lethal prostate cancer “develops and metastasizes to the bone marrow microenvironment, opening the door for early therapeutic intervention to decrease deaths from prostate cancer.” n Long days, short weekends, unparalleled research experience: Mentor Sarah Amend, a postdoctoral fellow in Kenneth Pienta’s lab, with student Sounak Roy. Summer Urological Research Experience (SURE) It may not be a particularly restful summer vacation, but it “SURE” is a one-ofa-kind chance for students who are interested in urological and cancer research to learn from some of top scientists in the field, in the laboratory and at lectures and seminars. “It’s a wonderful opportunity for young investigators to see how research done at the bench can be translated into patient care,” says Ken Pienta, M.D., the Donald S. Coffey Professor of Urology and Director of Research. The 10-week program offers a stipend of $3,000. Housing is provided near the Johns Hopkins University, and shuttle transportation to the medical campus is free. “This summer internship requires a full-time commitment,” says Pienta. “Interns should be prepared for long days and short weekends. But the experience is unparalleled.” If you would like to support this wonderful program or even sponsor a student, please see the envelope in this issue of Discovery. Want to learn more? To find earlier issues of Discovery – and much more – check out our website: urology.jhu.edu If you do not wish to receive this newsletter, please write to us at The James Buchanan Brady Urological Institute, The Johns Hopkins Medical Institutions, Baltimore MD 21287-2101. 19 THE PATRICK C. WALSH PROSTATE CANCER RESEARCH FUND — AWARDEES 2016 THE PATRICK C. WALSH PROSTATE CANCER RESEARCH FUND Read About the Research You have Helped Make Possible. the patrick c. walsh prostate cancer research fund It’s been going strong for a decade 2 0 1 5 A WA R D EES now. Since its inception in 2005, H. Ballentine Carter, M.D., The Carolyn and Bill Stutt Scholar, Departments of Urology and Oncology the Patrick C. Walsh Prostate Cancer Research Fund has awarded millions of dollars to Johns Hopkins scientists in every discipline with good ideas worth pursuing that can help us understand more about prostate cancer — and help us save lives with better ways to treat and prevent it. Applications are reviewed by a Scientific Advisory Board composed of noted Hopkins scientists and lay members. These awards wouldn’t have been possible without the tremendous and amazing generosity of our patients and friends. On these pages you’ll find some of the exciting work this year’s award winners are doing, which wouldn’t be possible without your help. Misop Han, M.D., The Nancy and Jim O’Neal Scholar, Departments of Urology and Oncology Sushant Kachhap, Ph.D., Department of Oncology Anthony K.L. Leung, Ph.D., The Irene and Bernard L. Schwartz Scholar, Departments of Biochemistry & Molecular Biology and Oncology Sangeeta Ray, Ph.D., The Dr. and Mrs. Peter S. Bing Scholar, Department of Radiology and Radiological Science Linda Resar, M.D., The Peter Jay Sharp Foundation Scholar, Departments of Medicine, Oncology, and Institute for Cellular Engineering Ashley Ross, M.D., Ph.D., The R. Christian B. Evensen Scholar, Departments of Urology, Oncology and Pathology Daniel Thorek, Ph.D., Department of Radiology Raphael Viscidi, M.D., The Beth W. and A. Ross Myers Scholar, Departments of Pediatrics and Oncology Hui Zhang, Ph.D., The Virginia and Warren Schwerin Scholar, Department of Pathology Understanding Prostate Cancer Progression During Active Surveillance Did the low-grade cancer somehow morph into highgrade disease, or did both low- and high-grade disease just happen to spring up together? Urologist H. Ballentine Carter has done pioneering research in prostate cancer for decades, but he’s never talked about it like this: Think of low-risk prostate cancer as a turtle, intermediate-risk cancer as a rabbit, and high-risk cancer as a bird, he says. “The classification depends in large part on the cancer grade. If turtles, rabbits and birds were put into a fenced area (the prostate), the turtles would never leave, or spread to other parts of the body. The rabbits would sometimes leave, and the birds would often leave.” Carter has been thinking about the different risk levels of prostate cancer particularly as it has to do with low-risk cancer – the men who qualify for the Active Surveillance program, which he began 15 years ago and continues to lead. With funding from the Patrick C. Walsh Prostate Cancer Research Fund, Carter has teamed up with some impressive Hopkins co-investigators — geneticist William Isaacs, pathologists Angelo De Marzo, Srinivasan Yegnasubramanian, Jonathan Epstein and Michael Haffner, and mathematical analyst and scientist Sarah Wheelan. “The purpose of this project is to determine whether turtles can evolve into rabbits and birds,” says Carter. The scientists have identified men in the Active Surveillance program who were initially diagnosed with low-grade disease, but during the close follow-up turned out to have high-grade cancer found on a repeat biopsy, which resulted in radical prostatectomy. Using those pathology specimens, “the low-grade 20 and high-grade components of the cancer within the same prostate will be genetically sequenced to determine how these cancer cells are related,” says Carter. The scientists hope that by making a “genetic fingerprint” of these tumors, they can answer some key questions, including: Did the low-grade cancer somehow morph into high-grade disease, or did both low- and high-grade disease just happen to spring up together? Do these high-grade cancers leave some sort of calling card — a genetic marker that could be used to predict whether men have cancers that are actually birds in turtle clothing? The investigators will also look at a control group — low-grade cancer that has remained low-grade, “to determine if there are high-grade markers within these low-grade cancers,” Carter continues. “Lastly, if we find definitive markers of high-grade cancer within low-grade cancer, we will sequence prostate biopsies to determine if disease that we diagnosed as low-grade actually contained high-grade markers. This information could help men with a diagnosis of low-grade cancer know whether they will eventually need treatment.” n Prostate Biopsy: Can a Robot Make it Better? Misop Han, M.D., the David Hall McConnell Professor of Urology, believes that prostate biopsies don’t provide enough information. “A typical transrectal ultrasound (TRUS)-guided biopsy has significant limitations,” he explains, “because the probe is handled by human hand.” In new research funded by the Patrick C. Walsh Prostate Cancer Research Fund, he and his co-investigators, robotics expert Dan Stoianovici and epidemiologist Bruce Trock, plan to improve TRUS-guided prostate biopsy with a novel robotic TRUS manipulator (called a TRUS Robot), “which was developed in our laboratory.” With robotic guidance, Han believes, the TRUS-guided biopsy will not only be able to provide important information about the precise location of the biopsy cores, but about the stiffness of the prostate. As urologist Patrick Walsh explains, the prostate should feel soft in a digital rectal exam, “like the pad of your thumb. But if there is cancer, it feels harder,” more like a knuckle. The biopsy needle can’t feel; but Han hopes to fix this: “With the TRUS Robot, we are incorporating a new imaging modality, ultrasound elastography, which can detect the relative stiffness of the prostate. With elastography guidance, regions of elevated relative stiffness will also be included in the biopsy plan,” to make the urologist aware of any “trouble spots” that may need further investigation. n Targeting Prostate Cancer Cells That Hibernate When cancer escapes the prostate, some cells go to the bone marrow, where they are alive but dormant. “These sleeping cells are resistant to conventional therapy,” says scientist Sushant Kachhap, Ph.D., which means that if they wake up and cancer begins to grow outside the prostate, “there are very few therapeutic options.” The dormancy seems to have a protective effect — think of Sleeping Beauty, who managed to sleep for 100 years and hadn’t aged a day when the prince woke her up. Kachhap is intrigued by these hibernating prostate cancer cells. What makes them sleep? What wakes them wake up? “While we know a great deal about how cancer grows, very little is known about the biology of prostate cancer dormancy,” he says. “This makes targeting these dormant cells a challenge, but also extremely important.” Kachhap believes that the ability to become dormant is acquired “very early in the process of metastasis, when prostate cancer cells leave the prostate and enter the bloodstream.” The dormancy seems to have a protective effect — think of Sleeping Beauty, who managed to sleep for 100 years and hadn’t aged a day when the prince woke her up. “Normally, when cells break off from the parent organ, they die due to a mechanism called anoikis. But detached prostate cancer cells survive by signaling a process called autophagy, where parts of the cell are broken down and the energy is used for survival.” In research supported by the Patrick C. Walsh Prostate Cancer Research Fund, Kachhap will use cell and animal models to investigate what triggers dormancy in prostate cancer cells — whether it’s caused by breaking off from the main tumor, or by autophagy, or something else. “Moving forward, we will test whether inhibiting autophagy can lead to death of dormant prostate cancer cells. We believe this work can lead to new strategies for targeting dormant prostate cancer cells, and inhibiting metastatic cancer.” n Who Can Benefit from Drugs That Stop Cancer Cells from Repairing Themselves? Anthony Leung, Ph.D., an RNA biologist, is interested in drugs that inhibit PARP. PARP — which stands for poly (ADPribose) polymerase — inhibitors have shown promise in treating ovarian, breast, and prostate cancers. “These drugs are designed to target cancers that already have defects in their ability to repair DNA, and rely on remnant repair pathways for survival,” he says. “These remnant pathways are mediated by 21 THE PATRICK C. WALSH PROSTATE CANCER RESEARCH FUND Read About the Research You have Helped Make Possible. the patrick c. walsh prostate cancer research fund Massachusetts Institute of Technology. PARP; so by blocking these pathways, “As its name implies, a PARP inhibitor scientists can kill cancer cells but spare healthy cells with functional DNA repair.” stops the PARP enzyme from working,” explains Leung. “PARP works by putting PARP-inhibiting drugs have been shown a specific mark on proteins. In cancer to extend life and even cause tumors cells, the abnormal activity of PARP to go into remission in patients with even adds marks to proteins that are mutations in the DNA repair genes normally unmarked.” To scientists BRCA 1 and 2. “PARP inhibitors have looking at proteins, such marks are also shown survival benefits for other the equivalent of signposts, and “we patients with difficult-to-treat, castrapredict that people who will respond to tion-resistant prostate cancers,” says these drugs will have a distinctive set Leung. In an ongoing Phase II trial of protein marks. Thus, the ability to of Olaparib, men with advanced, identify these protein marks may likely castration-resistant prostate cancer be the key to predict which patients will have shown impressive responses, he respond well to PARP-inhibiting drugs. adds. “This trial includes patients who Recently, our lab published a highly have not inherited BRCA mutations, but sensitive method to identify such protein do carry mutations to DNA repair genes marks. We are now geared to apply our within their tumors. These encouraging method to a panel of prostate cancer cell data suggest the possibility of expanding lines.” Some of these cancer cells are access to PARP inhibitors to patients with killed by PARP inhibitors, and some are other defects in DNA repair pathways.” not. “Using these data, we will be able to But will they respond? “So far, scientists identify which protein marks can distinhave not been able to predict who will guish responders from non-responders.” benefit from this drug,” says Leung. “At Leung hopes this work will identify a the same time, it is equally important to biomarker that can be used in a blood find out which patients are not responding, test to help determine which men will so as to avoid unneeded treatments — benefit from PARP-blocking drugs. n and, more importantly, false hope in patients. Therefore, we urgently need a sensitive tool that is able to distinguish responders from non-responders.” 22 Ultra-Precise Targeting and Killing of Metastatic Prostate Cancer To scientists, these marks are the equivalent of signposts, and “we predict that people who will respond to these drugs will have a distinctive set of protein marks.” Radiopharmaceutical therapy is an ultraprecise way of targeting and treating cancer cells. Scientist Sangeeta Ray, Ph.D., is integrating molecular PET and CT imaging, “with the ultimate goal of tumor-specific treatment of castrateresistant prostate cancer.” With support from the Patrick C. Walsh Prostate Cancer Research Fund, Leung hopes to develop such a tool, along with Hopkins co-investigators Ken Pienta, H. Ballentine Carter, and Robert Cole; and Phillip Sharp, of the Koch Institute for Integrative Cancer Research at the What will happen next in cancer cells is akin to lighting up a gun’s target with a laser sight — making them much easier to see and kill. With support from the Patrick C. Walsh Prostate Cancer Research Fund, Ray and co-investigator Martin Pomper are developing a very specific, low-molecularweight “theranostic” agent. Theranostic is another new word you may be seeing more of; it’s a combination of therapeutics and diagnostics, and it’s a key term in the growing field of personalized medicine. Ray’s goal is “to treat multiple sites of disease simultaneously, minimizing damage to adjacent normal tissue, and to treat metastases at an earlier point, when the volume of disease is lower,” she says. “Currently, this is challenging to achieve with standard external-beam therapy.” Ray is aiming to develop an imaging agent that targets a molecule on the surface of prostate cancer cells, PSMA (prostate-specific membrane antigen). What will happen next in cancer cells is akin to lighting up a gun’s target with a laser sight – making them much easier to see and kill. “Based on our preliminary studies, the underlying hypothesis is that the lowmolecular-weight agents can be optimized to demonstrate superior tumor penetration and lower toxicity to normal tissues, particularly the kidneys, and to provide greater therapeutic efficacy than currently available treatments.” n Studying the Molecular Switches for Metastasis You may soon be hearing more about a protein called HMGA1. A tiny thing, it is nonetheless critical for rapid growth and development before birth. Normally, it is switched off or silenced in our cells after birth, but becomes abnormally flipped back on in aggressive cancer cells. During fetal development, it helps to maintain the structure and function of the cell’s nucleus, its command post that houses our genetic material and directs the behavior and function of cells throughout our bodies. “Much like a quarterback on a football team, the nucleus tells the cell either to remain in place or move, or to progress into a more specialized position,” explains molecular biologist Linda Resar, M.D. “The nucleus also dictates whether a cell will grow and divide, or remain quiescent.” In work supported by the Patrick C. Walsh Prostate Cancer Research Fund, Resar and co-investigators Robert Veltri and Karen Reddy are studying HMGA1 in prostate cancer. Resar’s laboratory discovered that HMGA1 transforms normal cells into aggressive cancer cells. “Moreover, HMGA1 is a marker of poor outcomes for patients with diverse tumors,” she says. “HMGA1 is present in high levels in aggressive prostate cancers, and it drives tumor cell invasion and aggressive behavior in animal models of cancer.” Resar discovered that HMGA1 functions as a key molecular switch that cancer cells need to grow rapidly and spread. “Our preliminary studies suggest that HMGA1 alters nuclear shape and function to flip on genes that enable prostate cancer cells to leave their primary site, invade and metastasize.” Resar’s laboratory discovered that HMGA1 transforms normal cells into aggressive cancer cells. Resar and colleagues are conducting innovative studies to determine precisely how HMGA1 causes changes to the shape and function of the nucleus, “and whether we can use these alterations to predict which tumors will behave aggressively in men with prostate cancer. We will also uncover the genes and pathways that are turned on by the HMGA1 switch to transform normal prostate cells into invasive cancer cells.” If the investigators can crack the code of how HMGA1 works, they will determine whether these changes can predict tumors that are likely to behave aggressively and move to distant sites. They also hope to develop approaches to target or block these changes in therapy. “Together, our team will define the role of HMGA1 in nuclear structure and function in prostate cancer,” she says. “Results generated here will lay down the groundwork to determine whether HMGA1 and its role in nuclear reprogramming can be used to predict outcomes and optimize therapy for men with prostate cancer.” n Prostate Cancer Screening: Is There a Better Way? Half of the men will, like millions of American men, undergo standard PSA testing and receive a biopsy if the PSA is elevated. The other men will get the same PSA testing, and then will undergo mpMRI, a painless, noninvasive procedure, before biopsy. Prostate cancer screening is not specific enough — even though there are new tools today that might reduce the risk of over-diagnosis, says urologist Ashley Ross, M.D., Ph.D. He believes that one diagnostic test, in particular, shows great promise: “Multi-parametric” MRI (mpMRI), which can show clinically significant cancer. “Though mpMRI is being integrated into clinical practice, it has not been rigorously compared to standard prostate cancer screening,” he says. How good is it? Ross, with co-investigators H. Ballentine Carter and Craig Pollack, aims to find out. “Our hypothesis is that using mpMRI in men with elevated PSA may decrease unnecessary biopsies and the diagnosis of clinically insignificant prostate cancer — which doesn’t need to be treated — with minimal underdiagnosis of clinically significant cancer.” To do this, Ross and colleagues will design and perform a randomized trial. Half of the men will be those who, like millions of American men, undergo standard PSA testing and receive a transrectal ultrasound biopsy if the PSA is elevated. The other group of men will get the same PSA testing, and then will undergo mpMRI, a painless, noninvasive procedure, before biopsy. “For those undergoing MRI and then biopsy, biopsy will be performed with MRIultrasound fusion technology.” In addition, the group will assess the usefulness of biomarkers that recently have come into clinical practice, and determine the cost-effectiveness of the two screening strategies. “The results of this trial will have immediate implications as to how we screen men for prostate cancer.” n Improving Control of Cancer in the Bones One of the worst features of advanced prostate cancer is bone metastasis. A new agent called Radium-223 dichloride has shown success here; it is an alpha particle-emitting radionuclide that is incorporated in the bone material. It emits highly toxic alpha particles that kill cancer in the bone; however, it has a very short range. In fact, it only kills the cells directly next to it in the bone. In research supported by the Patrick C. Walsh Prostate Cancer Research Fund, nuclear medicine scientist Daniel Thorek, Ph.D., with co-investigator Ryan Riddle, hopes to find out exactly how Radium-223 works at sites of bone metastasis. “In initial studies, we have developed small animal models of prostate cancer metastasis in the bone, and we are 23 WINTER 2016 | DISCOVERY more brady urology cancer news Read About the Research You have Helped Make Possible. the patrick c. walsh prostate cancer research fund performing high-resolution imaging to evaluate the magnitude and microdistribution of the agent,” says Thorek. The investigators are evaluating the effect of the Radium-223 on the bone and prostate cancer cells at the sites where the radionuclide is deposited. “This may provide insight into improving dosing, in order to achieve an optimal therapeutic effect on the prostate cancer cells, with minimal surrounding bone cell damage.” They also plan to use high-resolution, noninvasive nuclear imaging to show how Radium-223 is distributed. “This may provide a means to personalize the application of this radionuclide in men with prostate cancer.” n Creating a Vaccine Against Prostate Cancer Trying to work around prostate cancer’s impressive ability to defend itself is like a molecular game of chess. The technology is there; now the key is to figure out the best strategy. Can a man be inoculated against his own prostate cancer? Scientist Raphael Viscidi, M.D., along with co-investigators Brian Simons and Ashley Ross, hopes to find out. “Because the disease can be diagnosed early and the prostate expresses tissue-specific proteins that can be the target of vaccines, we are investigating the value of a novel vaccine for prostate cancer in an animal model,” says Viscidi. To make the vaccine, they are using a virus — actually, part of a virus, a protein that has the ability to form a large particle. “The outer surface of the particle can be decorated with short proteins,” — think of sprinkles on 24 a cupcake — “and these will be derived from tissue-specific proteins made by prostate cancers. We have shown that these novel particles can induce immune cells,” enlisting the body in the fight against prostate cancer. “The physical properties of the particles make them very potent inducers of cellular immune responses,” Viscidi explains. “Unlike most other vaccines, they can be administered on their own to induce immune responses. We are using three tissue-specific proteins made by prostate cancers: prostatic acid phosphatase, prostate stem cell antigen, and stimulator of prostate adenocarcinoma-specific T cells.” In work supported by the Patrick C. Walsh Prostate Cancer Research Fund, the investigators will dot the surface of the vaccine particles with small proteins known to specifically stimulate the immune system of mice. What the team is doing, trying to work around prostate cancer’s impressive ability to defend itself, is like a molecular game of chess. The technology is there; now the key is to figure out the best strategy. For example, Viscidi says, “cancers have recently been shown to block immune responses by expressing inhibitory proteins.” Two of these proteins are CTLA4 and TIM-3. But in a counter move, scientists have developed antibodies that block these proteins. Will it strengthen the immune response if the investigators combine their vaccine with these anti-CTLA4 and anti-TIM-3 antibodies? They plan to find out, using a model known as the TRAMP mouse. “The advantage is that these spontaneously develop cancer in the prostate gland. We will treat mice of various ages, representing stages of prostate cancer from small lesions to metastatic disease, with our vaccine alone or in combination with anti-CTLA4 and anti-TIM-3 antibodies. If the vaccine proves successful in treating cancers in the mouse model, we plan to construct a similar vaccine using human prostate-specific proteins, and test it in men with prostate cancer.” n Looking For a “Smart” Urine Test for Prostate Cancer As helpful as PSA testing has been for millions of men, it does not always tell doctors which man’s cancer is lethal, which man’s cancer is indolent, and which man doesn’t have cancer at all, but another prostate problem that is causing his PSA to rise. In work funded by the Patrick C. Walsh Prostate Cancer Research Fund, scientist Hui Zhang, Ph.D., along with co-investigators Robert Veltri and Bruce Trock, believes these answers may be found in specific proteins in the urine. Glycoproteins are proteins that have carbohydrates attached to them. “We hypothesize that glycoproteins specifically altered in aggressive prostate cancer cells can be released to urine and used as biomarkers,” says Zhang, “to distinguish men with lethal cancer from those with indolent prostate cancer.” The scientists hope to identify these using quantitative analysis, looking at urine glycoproteins from lethal and indolent prostate cancer, and then testing these potential biomarkers using glycoproteomic analysis. The end result, they hope, will be a noninvasive urinary test. “Urine biomarkers capable of distinguishing lethal from indolent prostate cancer will help men with lethal prostate cancer to receive appropriate treatment earlier, and help prevent overtreatment in men who have indolent disease.” n Bivalacqua: “Radical cystectomy is not the ideal treatment for everyone.” D IS COV E RY IN BL A D D E R CA NCE R Bladder Cancer Surgery: Who is Likely to Have Complications? “We know that age alone does not tell us how a patient will do after surgery. Some patients are young but frail, while others are older with great physical reserve.” The standard of care for patients with muscle-invasive bladder cancer is radical cystectomy, the surgical removal of the bladder. However, this is a major operation, with a significant risk of complications and potentially, even death. “Radical cystectomy is not the ideal treatment for everyone, especially for higher-risk elderly patients with multiple medical problems,” says Trinity Bivalacqua, M.D. Ph.D., Director of Urologic Oncology. Who would do well with this procedure, and who is a poor candidate? It’s sometimes tough to predict. “Assessing surgical risk is a complicated task, and the surgeon must take several factors into account to determine how well someone will do in the operating room and in the immediate recovery period.” The key is frailty, he says. “We know that age alone does not tell us how a patient will do after surgery. Some patients are young but frail, while others are older with great physical reserve.” Bivalacqua is the senior author of a study that can help identify patients who are more likely to have complications. This work was recently published in Urologic Oncology. In the study, Hopkins investigators led by medical student Meera Chappidi and urologist Max Kates, M.D., validated a modified frailty index or score. “This is an objective measure that is calculated using a set of 11 questions that any patient can easily answer in a couple of minutes during an office visit,” says Bivalacqua. “Patients with high frailty scores may have risk factors that can be optimized before surgery to decrease their chance of having a complication, or they may benefit from bladder-sparing therapies.” Who Could Benefit From Platinum-Based Chemotherapy? Some people with muscle-invasive bladder cancer can benefit from systemic chemotherapy before they undergo radical cystectomy. Chemotherapy administered before the operation is called neoadjuvant chemotherapy, and its proven benefits include improved overall survival and a lower risk of having a recurrence of bladder cancer. However, “it still is not widely administered,” says Trinity Bivalacqua, M.D. Ph.D., Director of Urologic Oncology. There are several reasons why, including concerns about delaying surgery, risk of potential side effects, and the uncertainty that it will be effective. Two new studies by Hopkins investigators in Urology, Pathology, and Oncology, provide insight based on clinical and molecular data; this work was published in Urologic Oncology and PLOS ONE. The researchers identified novel biomarkers “easily detected from routine bladder biopsies,” that can predict patients whose cancer is most likely to respond to this treatment, Bivalacqua says. “This new molecularbased test will help us identify bladder cancer patients who will benefit the most from chemotherapy before radical cystectomy.” n D ISCOVER Y IN KIDNEY CANCER For Small Kidney Tumors: Active Surveillance is a Safe Option How big is the kidney tumor? If it’s small, less than 4 centimeters, “upwards of 30 percent are benign, not even cancer,” says Phillip Pierorazio, M.D. “Of the 70 percent left, half are low-grade, indolent tumors that are not ever going to cause a problem. That only leaves about a third that are potentially aggressive.” This is good news: many of these people can safely avoid surgery. Who can safely avoid surgery? Although several institutions have studied surveillance, these studies have mainly been retrospective, after-the-fact. “Few institutions have followed their patients to make sure that active surveillance is a safe option for them,” says Pierorazio. Six years ago, he and urologist Mohamad Allaf, M.D., the Mohamad E. Allaf Director in Minimally Invasive Urology and Buerger Family Scholar, set out to change this. They started the Delayed Intervention and Surveillance for Small Renal Masses (DISSRM, pronounced “disarm”) Registry for patients with small kidney tumors, and their groundbreaking work is paving the way for people with small kidney cancers to be treated worldwide. Since 2009, they have followed more than 200 patients; Pierorazio and Allaf recently published their results in European Urology. “Our DISSRM Registry follows not only patients on active surveillance, but those who have undergone surgery, as well,” 25 WINTER 2016 | DISCOVERY says Pierorazio. In general, he says, the people who undergo active surveillance are older, sicker and have smaller tumors. “However, these patients have done incredibly well. No patient undergoing active surveillance has had kidney cancer spread from the kidney, and none has died of kidney cancer. These early results demonstrate that active surveillance is a safe option for patients with small kidney tumors and, at least, not inferior to surgery in the short term.” About 10 percent of those who undergo active surveillance end up having surgery, “either because of changes in the tumor or their health status, making surgery a more attractive option.” The next step for the Registry, he says, is to continue to refine selection criteria for active surveillance, to learn more about the significance of growth rates, and to measure quality of life for people in the program. n Is a Kidney Tumor Benign? This Not-SoNew Test Can Tell More cases of kidney cancer are being diagnosed now than ever before, in large part due to an increase in the use of cross-sectional imaging techniques such as CT and MRI. But many of these cancers are slow-growing and benign, and may not ever need to be treated, says urologist Michael Gorin, M.D. The problem, he adds, is that “in standard imaging, it’s hard to tell whether a tumor is aggressive or not. Some tumors, particularly benign oncocytomas and hybrid oncocytic/chromophobe tumors (HOCTs) are unique in that they are composed of cells with numerous densely-packed mitochondria,” the “battery” that makes the cell’s energy. “This test offers the potential of sparing a significant number of patients an unneeded invasive surgical procedure.” In the field of nuclear medicine, radioactive substances that are administered intravenously can be detected on a scan to measure how well or poorly an organ is functioning. One such imaging agent has a difficult name: 99mTc-sestamibi. “It is widely available, often used for heart imaging and to show parathyroid adenomas.” 99mTc-sestamibi targets the mitochondria, and clearly shows mitochondria-packed tumors. Gorin, Mohamad Allaf, M.D., Phillip Pierorazio, M.D. and colleagues recently found 99mTc-sestamibi to be effective in diagnosing oncocytomas and HOCTs. Their preliminary study of six patients was published in Clinical Nuclear Medicine. In a follow-up study, 50 patients who had a newly diagnosed renal tumor were imaged prior to surgery. “This allowed us to compare the results of the imaging test to the gold standard of surgical pathology,” says Gorin. In this study, eight of 50 patients were diagnosed with either oncocytoma or HOCT at the time of surgery. 99mTc-sestamibi and SPECT/CT imaging correctly identified five of six oncocytomas and two out of two HOCTs, resulting in an overall sensitivity of nearly 88 percent. “Using this technology, we can be very certain that patients with a “hot” tumor have a benign mass,” states Allaf. In addition, only two tumors were falsely positive on the imaging test. “Based on these findings, 99mTc-sestamibi SPECT/CT appears to be an excellent test for the preoperative identification of benign renal tumors and offers the potential of sparing a significant number of patients an unneeded invasive surgical procedure,” says Pierorazio. The investigators plan on confirming this with a larger study. Besides Gorin, Allaf, and Pierorazio, authors included Mark Ball, Christian Pavlovich Jonathan Epstein and Alex Baras. In related news: Better Diagnosis of Kidney Tumors all three risk factors had an 89-percent chance of having cancer,” says urologist Mohamad Allaf, M.D., the study’s senior author, “while patients with none of these risk factors have only a 64-percent chance of having cancer.” Ball adds: “This nomogram can help us do a better job of predicting which patients are more likely to have cancer, but it’s not enough yet. Better tests are still needed to predict which patients can forego surgery, and who needs aggressive treatment.” In other recent findings, published in The Journal of Urology, the team studied how areas of a kidney tumor may look different (or heterogeneous) under the microscope. “We found that even the most aggressive tumors have areas that look less aggressive under the microscope,” says Ball, who was the study’s lead author. This may mean that biopsies are not that helpful. “Renal mass biopsy is sometimes used before surgery to confirm the diagnosis, but it’s not a perfect test, and our study shows that it can sometimes give false reassurance,” says urologist Phillip Pierorazio, a coauthor of the study. n Risk-stratification is like “picking out the bad apples and leaving the good behind,” says Brady chief resident Mark Ball, M.D. Because so many tumors — as many as 30 percent of small kidney tumors that are surgically removed — are found to be benign, Ball and colleagues have been working on ways to help predict the risks of kidney tumors. In a study led by Ball and recently published in the journal, Urologic Oncology: Seminars and Original Investigations, the investigators studied more than 1,000 patients from five different hospitals and identified factors associated with a higher risk of being cancer. Men were at higher risk of having cancer than women; other risk factors include a tumor size greater than 3 centimeters, and a high nephrometry score (a measure of tumor complexity on CT scan). “Patients with Gorin: Many kidney tumors are slow-growing and may not ever need to be treated. Ball: We need better tests to predict who needs surgery, and who doesn’t. D IS COV E RY IN T E S T IS CA NCE R Early-Stage Testiscular Cancer: A Laparoscopic Improvement in Treatment When a man is diagnosed with early-stage testicular cancer (specifically, From left, Allaf, Harris, and Pierorazio: New procedure is “technically challenging,” but is a better, minimally invasive cancer operation. Note: Pierorazio sports a mustache grown in “Movember” to support testicular cancer research and treatment. a nonseminomatous germ cell tumor), his treatment choices include active surveillance, chemotherapy, or a procedure called primary retroperitoneal lymph node dissection (RPLND), removal of the lymph nodes to make sure the cancer has not spread. But RPLND is major abdominal surgery. Thus, “more recently, active surveillance has become the most favored management strategy,” says urologist Phillip Pierorazio, M.D., “given the uncertain, long-term side effects of chemotherapy and the short-term side effects of RPLND.” However, men who fail active surveillance are often restricted to chemotherapy as their only option for treatment. “In a disease that is 99 percent curable and with patients who have little surgical risk due to their young age and good general health, the argument could be made for aggressively treating men with low-stage disease with a minimally-invasive procedure.” Testis cancer generally affects young, otherwise healthy men, and — if it weren’t such an arduous procedure — RPLND could eliminate the need for a prolonged course of cancer surveillance or the long-term side effects of chemotherapy. “In a disease that is 99 percent curable and with patients who have little surgical risk due to their young age and good general health, the argument could be made for aggressively treating men with low-stage disease with a minimally-invasive RPLND,” Pierorazio continues. There is a more minimally invasive choice: Robot-assisted laparoscopic RPLND. “This procedure has been shown to offer better perioperative (during and immediately after surgery) outcomes when compared to the open operation, with the same degree of cancer control. However, it is a technically challenging procedure.” Urologists Mohamad Allaf, M.D., and Pierorazio, who perform this operation, recently published the results of the Johns Hopkins experience and a comparison of laparoscopic and robot-assisted laparoscopic RPLND in the British Journal of Urology International. Kelly Harris, a medical student, future urologist, and the lead author of the study summarizes, “Our group has shown that robotic is comparable to laparoscopic, with the added benefits of better three-dimensional visualization and degrees of freedom to afford a better, minimally invasive cancer operation.” n 27 THE BRADY: 100 YEARS A History of the James Buchanan Brady Urological Institute at Johns Hopkins By Patrick C. Walsh and Janet Farrar Worthington Featuring 380 Richly Illustrated Pages © 2015 The James Buchanan Brady Urological Institute and Johns Hopkins Medicine For a century, the Brady has been the world’s leading urological institute. Read about our past, meet our scientists and faculty members, and join us as we look ahead to the next 100 years! In this richly illustrated book, packed with stories that bring some of the greatest names in Urology to life, you’ll learn: • How James “Diamond Jim” Brady was cured of BPH and donated the money to start this institution. “A triumph of storytelling and design.” –Keith Reinhard, Chairman Emeritus, DDB Worldwide Download the e-book FREE at: urology.jhu.edu/about/history/Brady100years Currently available to the public in e-book format only, • How Hugh Hampton Young, a brilliant innovator who designed and built many of his own surgical devices, became the Father of Modern Urology, transforming the field into a major surgical specialty. • How William Scott transformed the urology residency, allowing the Brady to produce some of the world’s best surgeon-scientists. • How Patrick Walsh revolutionized the surgical treatment of prostate cancer, changing the field of prostate cancer treatment and research forever. • How Alan Partin continues the Brady’s tradition of excellence today, as we look forward to our next 100 years! abridged Kindle edition coming soon. The Bestselling Book on Prostate Cancer Comprehensive, reassuring and full of hope. Now available as an eBook and on Kindle! COMPLETELY UPDATED 3RD EDITION With this book you will learn answers to these and other important questions: • Why do I need to have a baseline PSA at age 40? I thought it was age 50! • If there is no magic PSA cutoff point, how can my cancer be diagnosed? Discovery is published by THE JAMES BUCHANAN BRADY UROLOGICAL INSTITUTE Johns Hopkins Medical Institutions Baltimore, Maryland 21287-2101 • What is the most up-to-date information on surgery and radiation therapy? 410.955.8434 | urology.jhu.edu • Have there been any breakthrough tratments in the management of advanced disease? University Distinguished Service Professor of Urology Patrick Walsh, M.D., Janet Farrar Worthington Writer/Editor Hatcher Design Office Art Direction Available from Warner Wellness: www.hgbusa.com or call 800.759.0190 Kieth Weller Principal Photography