A PUBLICATION OF THE PATRICK C. WALSH RESEARCH FUND | THE BRADY UROLOGICAL INSTITUTE | JOHNS HOPKINS MEDICINE

DISCOVERY VOLUME 16 | WINTER 2020

Innovations in Prostate Imaging and , Smarter

INSIDE THIS ISSUE

The Father of Active Surveillance.....6 Fix the Gleason Grades!...... 9 Oligometastasis: Good News ..... 10 Sarcomatoid Bladder Cancer...... 18 Cancer and the ...... 22 THE PATRICK C. WALSH WINTER 2020 | DISCOVERY RESEARCH FUND COVER STORY: Advanced Imaging, Better Biopsy, Smarter Treatment,

founders’ circle Fewer Side Effects Partnerships with donors make Prostate cancer is a curable And to make these safer, to perform But there are other new innovations. the procedure by avoiding the rectum and In an ongoing funded discoveries possible. Thank you to disease for many patients. those who have committed $500,000 the risk of – instead reaching the through The Patrick C. Walsh Prostate or more to The Patrick C. Walsh Prostate In fact, for some men, it prostate through the perineum, an area of Fund, we are investigating Cancer Research Fund. skin located between the scrotum and rectum. whether PSMA-targeted PET imaging requires no treatment at all – plus mpMRI can improve the diagnosis Individualized Why change the way urologists perform Anonymous (3) of clinically significant prostate cancer. but we at the Brady want prostate biopsies? With the traditional Mr. and Mrs. Robert B. Aikens PSMA (short for prostate-specific mem- Treatment to make sure we correctly , potentially dangerous The Ambrose Monell Foundation brane antigen) is a molecule that sits on bacteria can be transmitted from the Mr. and Mrs. Robert Baker Family Through and safely identify those the surface of prostate cancer cells. Foundation rectum to the blood stream. This is very concerning for men on active surveillance, Hopkins radiologist Martin Pomper, M.D., Mary Ann and Bill Becker men. For men who do need Discovery who typically require multiple biopsies. Ph.D., has engineered a number of radio- George and Mary Nell Berry treatment, we want to address Partin: Unprecedented precision in treatment. With the transperineal approach, instead active compounds that target PSMA and Dr. and Mrs. Peter S. Bing their cancer with few to no of passing through the rectum, the needles can be used for PET imaging. One of these Mr. Keith L. Bremer go through an area of skin, which can be agents, called 18F-DCFPyL, has been Elva E. and William W. Carty We have always provided precision treatment for every man with prostate cancer side effects. thoroughly cleansed before the procedure. studied extensively by colleagues at the Jennifer A. Chalsty who comes through our doors. Now, surgical innovation, dramatic improvements We used to routinely swab a man’s rectum Brady and is poised for approval in the U.S. in imaging, better understanding of molecular biomarkers, more accurate biopsy ACTIVE SURVEILLANCE: John S. Chalsty to see what bacteria he had, and we techniques and more precise diagnosis have come together to allow us to provide BETTER IMAGING, SAFER BIOPSY Can prostate cancer treatment be Deeks Family Foundation would give him antibiotics based on those truly individualized treatment. This means that we can tell a man with confidence minimized even further? Yes. The R. Christian B. Evensen H. Ballentine Carter, M.D., as Director bacteria. Despite our best intentions, that he can safely enter active surveillance; it also makes us far less likely to miss innovations in imaging are allowing some- Mr. Donald E. Graham of the Brady’s Prostate Cancer Program, sometimes those antibiotics would fail significant cancer that needs to be treated, and for men at higher risk, it gives us thing that has never been considered safe or Phyllis and Brian L. Harvey showed that most men with low-grade to prevent an . Additionally the opportunity to offer additional treatments aimed at curing their disease and feasible before: focal ablation of the prostate. Heather C. and Patrick Henry maximizing their quality of life. prostate cancer do not require immediate antibiotics can cause complications on their Charlton C. and F. Patrick Hughes treatment, and instead can be monitored own. With the transperineal approach, For men with a very small amount of Milestones: I am proud to report that H. Ballentine Carter and Trinity Bivalacqua Nancy and William Kimsey safely with active surveillance. Based on we don’t have to give any antibiotics. intermediate risk prostate cancer, instead have received two of the highest awards in our field (see pages 6 and 20). Bal Carter Edward B. Lipkin that strong foundation, our next step is to of treating the entire prostate, we can treat has retired after a remarkable 32 years at the Brady, but his legacy will continue for In the Brady’s Active Surveillance Beverly A. and Gary L. McDonald minimize the number of blood tests and just the portion of the gland that has the many more years, thanks to a research fund (see page 8) established in his name. Program for Prostate Cancer, at least 90 prostate biopsies that are required for men cancer – greatly minimizing the potential Jean and Ian MacKechnie percent of men are getting a transperineal We continue to lead the field in treatment and research in bladder, kidney, on surveillance. Most men on active side effects of incontinence and erectile Beth W. and A. Ross Myers biopsy. It is safer and is quickly becoming and testicular cancer (see pages 18, 22 and 23), and to treat an ever-broader range surveillance who go on to require treatment dysfunction that are sometimes seen with Nancy and Jim O’Neal the new standard of care throughout of patients who, not so many years ago, would have had incurable disease. likely had higher-grade cancer all along; radical and radiation. To Jack W. Shay and Thomas C. Quirt the world. Mohamad Allaf, M.D., Vice it simply evaded detection on previous make this possible requires sophisticated The Frank E. Rath Spang & Company Chairman at the Brady, and colleagues biopsies. We are now focusing on ways to equipment that allows the user to record Charitable Trust Best wishes, have developed a technique to perform decrease the intensity of active surveillance the exact location of cancerous areas found Mr. and Mrs. Paul W. Sandman MRI-guided through by doing a better job detecting significant on an MRI- or PET- targeted biopsy, a The Peter Jay Sharp Foundation the transperineal approach. It’s not only at the time of initial diagnosis. concept known as prostate cartography. Irene and Bernard L. Schwartz cleaner, but there is reason to believe the Because this makes it possible to know Virginia and Warren Schwerin The key to this goal begins with advanced transperineal approach is more accurate, exactly where the biopsy needles went, we Donald and Susan Sturm imaging; particularly, multi-parametric better able to sample the prostate’s anterior can now return to areas that were positive Carolyn and Bill Stutt Alan W. Partin, M.D., Ph.D. MRI, or mpMRI (a form of MRI that looks region – the area where cancer commonly for cancer and deliver focal treatments. develops in African American men. Mr. and Mrs. Charles B. Thornton, Jr. The Jakurski Family Director and Professor at the prostate in several ways, including Luciana and Joe Vittoria with a contrast dye injected in the blood). The James Buchanan Brady Urological Institute With our novel biopsy techniques and This sophisticated form of MRI shows Our cover story continues on imaging strategies, we can ensure the For additional news and updates from Urologist-in-Chief, Johns Hopkins Medicine suspicious areas of the prostate that can the next page > lowest possible risk of side effects to the Brady, please follow us on our be targeted for biopsy. With the use of men on active surveillance. Prostate web site at www.hopkinsmedicine. MRI-targeted biopsy, the likelihood of MRI and transperineal biopsy are not org/brady-urology-institute identifying clinically significant prostate ON THE COVER just for men on active surveillance: or any of our social media sites: cancer increases substantially. We are The Marburg Building was built in 1889 and is one the vast majority of new patients of the three original hospital buildings remaining Facebook: Brady Urology; making it a priority to ensure that all men presenting with an elevated PSA level and still in use. In 1982, it was renovated to serve Twitter & Instagram: @brady_urology in the active surveillance program are nowundergo an MRI-guided trans- as the new home for the James Buchanan Brady routinely imaged with MRI and then, perineal prostate biopsy. Urologic Institute. when appropriate, given a targeted biopsy. 2 3 WINTER 2020 | DISCOVERY

Cover story, continued > The Urinary Microbiome Begins in Childhood Preventing Blood Brady urologists have begun performing focal (controlled freezing of Previously in Discovery, we reported on a populations in the urinary tract begin to Clots After Radical the prostate) in highly selected men using startling finding made by Brady molecular show up, “and if the development of the Prostatectomy a technique called “preoperative thermal biologist Karen Sfanos, Ph.D.: Contrary to urinary microbiome could be influenced by They don’t happen often, but Brady dosimetry”. Utilizing special software, popular belief, urine is not sterile! Sfanos antibiotics in childhood.” The team, which urologists would like to prevent them cryoablation procedures can be planned found not only that bacteria do exist in included Johns Hopkins medical student altogether: blood clots in the legs or lungs with precision – similar to the way radiation the urinary tract, but that this bacterial Borna Kassiri, who worked in the Sfanos after radical prostatectomy. oncologists determine where to deliver community, or microbiome, may contribute laboratory as part of a Persky summer radiation, and how much the dose should be. to the development of urologic diseases. fellowship, examined both urine and fecal A new study, led by Brady Chief Resident Sfanos and colleagues also reported last samples collected from young boys, ranging Hiten Patel, M.D., M.P.H., and directed Because this is still a very new concept, year in the Journal of Urology that the in age from three months to eight years. by Mohamad Allaf, M.D., Vice Chairman the efficacy and safety of the procedure bacteria in the urine of men with prostate and Professor of Urology, has shown that a is being rigorously evaluated. One avenue “Surprisingly, we found that all of the cancer are different from the “urinary blood-thinning drug, heparin, given subcuta- for study is through a collaboration samples contained microbial populations,” microbial communities” in men who don’t neously (under the skin), can help – and, im- started at the FDA, known as the SPARED says Sfanos. “Furthermore, we discovered have prostate cancer. portantly, that it doesn’t cause extra problems. registry. SPARED is a multi-center effort significant differences in both the urinary to evaluate the outcomes of various Sfanos and her team found and fecal microbiomes in children with Patel and Han: Reassuring news: The vast majority of our prostatectomy patients don’t need all the pain For half a century, Patel notes, subcutaneous forms of focal that are being prior antibiotic exposure.” The study, they are prescribed after they leave the hospital. bacteria in urine and fecal samples heparin has gotten a bad rap: “Many performed throughout the country. recently accepted for publication in the urologists in the U.S. have been wary of true for both the open procedure and The FDA remains aware of the many of boys as young as three months. journal, Urology, provides one of the first subcutaneous heparin, because of early Reducing after robotic prostatectomy; the investigators unknowns of ablative therapy for prostate characterizations of the urinary microbiome reports that it might increase the rate of found no difference in prescribing or use cancer, and has provided resources to Building on this work, Sfanos’ team, in in prepubertal males. n Radical Prostatectomy lymphoceles (buildup of lymphatic fluid between these groups of patients. allow urologists to study the safety and collaboration with pediatric urologist in the pelvis) after radical prostatectomy. efficacy of this emerging form of prostate Ming-Hsien Wang, M.D., aimed to “We saw a reduction in The team’s intervention had notable But Patel and Allaf thought heparin cancer treatment. determine exactly when the microbial prescribing by nearly 47 percent, success: “We saw a reduction in opioid deserved another look, and Patel has just prescribing by nearly 47 percent, a reduction completed the largest-ever prospective But what about the multi-focal nature in opioid use by nearly 27 percent, and randomized trial, assessing the impact of of prostate cancer? Hopkins scientists a reduction in opioid use by increased disposal of leftover opioids by subcutaneous heparin in 500 men who previously have shown that the majority nearly 27 percent, and increased nearly 14 percent,” says Patel, who presented underwent radical prostatectomy at Johns of men with prostate cancer will develop disposal of leftover opioids by the study’s results at the 2019 meeting Hopkins. The trial is called PREVENTER tumors in multiple, distinct areas of the of the American Urological Association. (PREvention of VENous ThromboEmbolism gland. However, just because the cancer nearly 14 percent.” “Only five patients required additional Following Radical Prostatectomy). is multifocal doesn’t necessarily mean A first-of-its-kind Brady intervention study opioid medication.” you have to treat all the areas. Perhaps “We found that the rate of symptomatic points the way to smarter prescription and just treating certain areas, like those blood clots (those felt by the patient, use of opioids after radical prostatectomy. Patel and colleagues also identified risk you can see on MRI or those that have a usually due to pain or swelling in the legs) Among other findings, the Brady’s Opioid factors for higher use of opioids after certain molecular signature, is sufficient, after radical prostatectomy is already very Reduction Intervention for Open, Laparo- . One of these, for some men, was especially for older men who need a less low, at about 2 percent, without using scopic, and Endoscopic Surgery (ORIOLES) simply having a higher prescription; fewer durable solution for their prostate cancer. subcutaneous heparin,” says Patel. “While initiative determined that the vast majority pills prescribed led to fewer pills taken. Also, there are some men who truly have not statistically significant, subcutaneous of our patients don’t need all the pain Also more likely to take more opioids were only one or two small areas of cancer— heparin further reduced the rate of blood medication they are prescribed after they men with a higher body mass index (BMI); something that can now be more readily clots by about 1 percent.” The scientists leave the hospital. and men who had used opioids for other determined using advanced imaging and conditions before surgery. “Notably, just also screened for asymptomatic blood biopsy techniques—and ablation may The study involved two groups of patients: having had a history of pain – without clots – clots too small for the patient to serve as the preferred treatment option 214 men in the pre-intervention group, and opioid use – before surgery was not a feel – using Duplex ultrasound in about for these men, regardless of age. 229 men in the post-intervention group. significant predictor of greater use.” After one-third of patients. “Before intervention, on average, patients the intervention, only 2.2 percent of Because this is all so new in concept, we “Most importantly, we did not observe any were prescribed 30 pills of 5 mg , patients reported needing additional are proceeding very cautiously. All men increase in adverse events or bleeding,” but used only three pills,” says Brady Chief opioid medication, fewer than 1 percent who are undergoing focal treatment will Patel continues. “The occurrence of Resident Hiten Patel, M.D., M.P.H., who needed to obtain a prescription, and only be enrolled in the SPARED registry and symptomatic lymphoceles was the same, launched and led the study, along with 1.3 percent had long-term opioid use. “This required required to adhere to strict regardless of whether patients received urologist Amin Herati, M.D., and urologist is the first pre-post opioid intervention follow-up surveillance. We cannot be too subcutaneous heparin or not. Our findings Misop Han, M.D. “Overall, 77 percent of study in urology to report an improvement cautious, but we also must push boundaries suggest it is safe to give subcutaneous the opioid medication that was prescribed in prescribing practices after radical if we are to continue to improve the care heparin around the time of radical prosta- was never used,” and just over 9 percent of prostatectomy and to demonstrate factors of men with prostate cancer. n Sfanos and Kassiri: “We discovered significant differences in both the urinary and fecal microbiomes tectomy,” and this may be most beneficial patients properly disposed of their leftover associated with greater use,” says Patel. n (communities of bacteria) in children with prior antibiotic exposure.” for men at higher risk, including those with pain pills – which can be dangerous to blood disorders or a history of blood clots. n leave lying around. These findings were 4 5 WINTER 2020 | DISCOVERY

Bal Carter is the 2019 winner of the prestigious Eugene Fuller Triennial Prostate Award, given once every men who had no prostate disease, benign Active Surveillance in Prostate Cancer Because of Carter’s work, urologists now three years by the American Urological Association to an individual who has made an outstanding contribution enlargement, or localized or metastatic He also changed the way prostate cancer recommend that men start getting their to the study of the prostate and its associated diseases. This award is named after the famous 19th-century prostate cancer –and then work backward, is treated for many men with localized PSA tested in their forties. But when New York City urologist, Eugene Fuller, who pioneered the open suprapubic surgical approach for treatment of benign prostatic enlargement, and supported by a trust fund established by his family. Since 1977, the Award describing the changes in PSA over the disease. “In 1994, (Brady pathologist) should they stop? Carter recalls asking has been awarded to 13 urologists, nine of them former Brady residents or faculty: Clarence Hodges, William previous 20 to 30 years. Jonathan Epstein published his landmark that question at a meeting with other W, Scott, Patrick C. Walsh, John T. Grayhack, Donald S. Coffey, William J. Catalona, Thomas A. Stamey, and work on the use of prostate biopsy BLSA scientists. “No one really knew “I had never heard of it,” Carter continues. Peter C. Albertsen. The award was presented by AUA President Robert Flanigan. criteria and PSA density to predict the what would happen if you measured “He said, ‘Why don’t you go and shake presence of small-volume, low-grade PSA very early in life, in midlife, and the trees and see what falls out? I know The Father of Active Surveillance prostate cancer at radical prostatectomy,” then looked at outcomes later on. I had they have a large frozen serum bank, and says Carter. “Recognizing that PSA testing gotten really interested in screening for we might be able to use some of that Carter, retiring as the Bernard L. Schwartz Distinguished Professor was uncovering a substantial number of cancer, so I combed the literature. It just to look at the question: do PSA levels of Urologic , reflects on his 32 years at the Brady. prostate cancers consistent with what dawned on me, mainly from cervical rise faster in men who have aggressive was found at autopsy in most men who cancer screening literature: What if Entering the PSA Era threshold, and instead had focused on disease vs. men who don’t have prostate died of other causes, and that these men very young men have PSA levels that So here we have Carter at the right place to changes in PSA to alert us that someone cancer?’ Sure enough, that’s the way it were undergoing radical prostatectomy are extremely low, and have cumulative begin a fruitful career. But what about the has an aggressive cancer, in the long run turned out. I did the work, but believe for , we began to use the Epstein numbers of negative tests – would that right time? In the late 1980s, discoveries by we may have identified more individuals me, virtually everything that came out of criteria to enroll men in a longitudinal suggest later in life that they are very Walsh and others had dramatically shaken with the cancers that need to be treated, the Brady in that era, Pat was the insti- study of expectant management, or low-risk? As it turns out, if you’re in up the field of prostate cancer treatment. and eliminated more who don’t need to gator, the mind behind the hypothesis. The history of Johns Hopkins active surveillance.” In 1995, Carter your 50s or early 60s and you have very Walsh’s transformation of the radical be treated. But that will require a care- He’s just an amazingly brilliant man. I’ve medicine is rich in fortuitous began the Brady’s active surveillance low PSA, it’s unlikely that you’re going prostatectomy into a safer operation, and fully done, prospective trial.” never worked with anyone who could coincidence: the right people who program for men with low-risk prostate to be diagnosed with prostate cancer his discovery of the neurovascular bundles think more clearly. He has an amazing happen to be at the right place at Once PSA screening started, as Carter, cancer (about 40 percent of all men later in life. Is there an age and a PSA (allowing preservation of potency) suddenly way of getting to the bottom of things.” the right time. We are fortunate that Walsh and others had predicted, there who are diagnosed with the disease). level where you could tell an older man, made surgery into the gold standard for one of these is urologist H. Ballentine was a bubble – tens of thousands of men Patrick Walsh, in turn, places the credit Since then, and with the help of Patricia ‘Congratulations, you made it, and you curing localized disease. At the same time, Carter, M.D., who came to the Brady in were diagnosed with prostate cancer – squarely on Carter. “Simply stated and Landis, who has coordinated the program don’t ever need to have a PSA test again?’ the discovery of PSA made it possible, for 1987, after graduating second in his class at and then, over time, this leveled out. But without exaggeration,” Walsh says, “Bal for more than 20 years, the program has Sure enough, you reach an age around the first time, to learn about prostate cancer the Medical University of South Carolina in the early 1990s, Carter notes, “nobody has changed the way prostate cancer enrolled more than 2,000 men. 70, 75, and your PSA is less than 3, it is from a blood test. The problem was that and completing an internship and knew that PSA levels would change. is treated today around the world.” extremely unlikely that you will be diag- nobody knew what to do with PSA, or how residency at New York Hospital-Cornell Until they started looking at it.” Although Carter is “a great surgeon,” he “Because of Bal Carter, active nosed with lethal prostate cancer.” to use it along with the digital rectal exam Medical Center. has done his best not to operate on men and the new use of transrectal ultra- surveillance has become What about intervals for screening? “Have You Ever Heard of the BLSA?” who don’t need it. “He was a voice of sound-guided biopsy in diagnosing prostate In another study, published in JAMA, “I was awarded an American Urological Carter started looking at it, in studies reason at a time when the diagnosis and accepted as a standard-of-care cancer early. Widespread screening for Carter and colleagues found that “PSA Association (AUA) Scholarship to work that would lay the foundation for PSA treatment of the disease underwent prostate cancer did not exist. approach to the management of levels really don’t change rapidly in most with Don Coffey (the Brady’s longtime screening and also for safe, vigilant revolutionary changes. With the intro- Director of Research) for two years,” people, even those who are going to “Until several papers were published, by active surveillance as a mainstream treat- duction of widespread PSA testing in favorable-risk disease around Carter recalls. “His lab was an amazing develop prostate cancer. We found that William Catalona, William Cooner, and ment for low-risk prostate cancer. How 1990, the diagnosis of prostate cancer place to be, not just for the opportunity to the world,” says Brady Director intervals of two to four years were per- others, demonstrating that PSA was the that came about, he says, “was really reached epidemic acceleration and led work with Don, but with so many people fectly reasonable for detecting the type most effective way to go about identi- the brilliance of Pat Walsh. When I first to abuses fed by the greed of many fellow Alan Partin, M.D., Ph.D., The who shaped my career, including: Evelyn of cancers we wanted to detect.” fying prostate cancer early as a primary joined the faculty, he came to me and urologists. Those are tough words, but Barrack, Tom Chang, Bill Nelson, John Jakurski Family Director and screening tool, there was controversy said, ‘What do you think would happen there is no other way to explain it. Bal Looking back over his 32 years at the Isaacs, William Isaacs, Ken Pienta, Alan about even using PSA,” Carter recalls. if we looked at changes in PSA?’ I said, ‘I emphasized the harm of overdiagnosis Professor, “and because of his Brady, Carter says, “I would not change Partin, and Jonathan Simons,” to name a “There were voices saying, ‘Beware, think they’ll probably rise faster in people and overtreatment, proposed solutions work, many men have been anything. I landed in the perfect spot, few. The galvanizing research environ- we’re going to uncover a lot of cancers who have prostate cancer. How can we based on improved screening practices, with unbelievable mentors and col- ment inspired Carter to stay in academic that never should have come to light.’” study that?’ And he said, ‘Have you ever and developed guidelines for identifying able to avoid the side effects of leagues. It could not have been for me a medicine as a surgeon-scientist, and in heard of the Baltimore Longitudinal men who should not be treated. He began better place, or better situation. I got to Next came controversy over the PSA unnecessary treatment.” 1989, then-Director Patrick Walsh hired Study of Aging (BLSA)?’” The BLSA was by learning about PSA.” do everything I wanted to do.” With his Carter as a member of the Brady faculty. threshold: what was the magic number conceived in 1958, when gerontologists In recognition of his preeminence wife, Lillian Carter, Ph.D., a professor of that would indicate the need for a prostate Using blood samples that had been “To say that Patrick Walsh had an impact at the Baltimore City Hospitals were as an educator, Carter was elected health education at Towson University, biopsy? “In retrospect, that was probably collected for decades by the BLSA, Carter on my professional life would be an trying to find a better way to study aging. President of the American Board of Carter has moved to “a house we built the wrong thing to be asking,” Carter described how age and prostate disease understatement. His generosity in At that time, and even today, scientists Urology. And in recognition of his in 1993 on Bald Head Island,” in North says. “There was just not a good under- influenced PSA. “Based on his unique mentorship truly launched my career in would compare men and women who outstanding contributions in the field Carolina. He is learning Spanish, which standing then of PSA as a continuum.” observations, he proposed new ways to were in their twenties to people who he intends to use while hiking in Latin urology.” Carter also credits his “amazing interpret PSA levels, and specified intervals of prostate cancer, he was awarded the Carter pioneered the concept of PSA were decades older. But these scientists America, and very soon will be hiking colleagues” at the Brady, who “generously for testing that were the most informative,” highest honor bestowed by the Society velocity – the rate at which PSA rises had a better idea: to revisit the same across England with a Brady alumnus, gave advice to a junior faculty member,” says Walsh. As Chairman of the AUA’s of Urologic Oncology, the Charles over time. “But that’s never been tested person every two years, with a history urologist Joel Nelson. “I’m also going to including Fray Marshall, Chaz Brendler, Guidelines Panel, Carter developed Huggins Medal, and the American as a screening tool. I honestly believe if and physical and blood samples that were be looking for volunteer work,” he says, Jacek Mostwin, Ray Stutzman, Bob Jeffs, recommendations for how all urologists Urological Association’s Eugene Fuller we had not focused on a single, absolute stored. This made it possible to look at “to help people who are not as fortunate and John Gearhart. should screen for prostate cancer. Triennial Medal and its Distinguished Contribution Award. as I have been throughout my life.” n 6 7 Ballentine Carter by Peter Egeli: Oil on canvas, 2019, Courtesy of The Alan Mason Chesney WINTER 2020 | DISCOVERY Medical Archives of The Johns Hopkins Medical Institutions.

The H. Ballentine Carter, M.D., and respond differently to treatment. Since then, Isaacs’ research group has GLEASON GRADE GROUPS They deserve their own spots in the worked to understand more about Prostate Research and Innovation Fund scoring system. Thus, “the old system was mutations in these genes, including BRCA2 GRADE GROUP GLEASON SCORE “We know a lot, but certainly there is more to learn, about less accurate,” Epstein says. and ATM. “We wanted to find out whether there was a correlation between mutations 1 3 + 3 Guess what? At many hospitals world- the markers, the disease itself, and how to deal with it when in genes associated with lethal disease and wide, Gleason scoring is still less accurate. something should be done.” 2 3 +4 the grade of prostate tumors,” says Isaacs. In a new study, published in European 3 4 + 3 In a collaborative study with Ambry Urology, Epstein and colleagues looked at Urologist H. Ballentine Carter, M.D., has donors have committed nearly $1.5 million. Genetics, the scientists studied 1,694 men 4 4 + 4 how Gleason scores were grouped world- dedicated his career to filling the “gaps in Many of those who have contributed are who underwent radical prostatectomy wide. “We found that the most common knowledge” in the use of prostate-specific new donors to Johns Hopkins, who were 5 9 or 10 at Johns Hopkins, including 708 patients method in current use was still the D’Amico antigen (PSA) to detect prostate cancer. moved to give by Carter’s standards for with the two highest tumor grades (grade risk stratification groups (categorized Some of his major contributions (see Page care. Others are surgical patients whose groups 4 and 5) and 988 patients with low- as Gleason < 6, 7, 8–10),” Epstein says, 6) include: cancer was successfully treated by Carter grade (grade group 1) disease. They looked “which is incorrect as it combines Gleason as long as 25 years ago, and still others are for mutations in 14 DNA repair genes – the PSA velocity (PSA’s rate of change over scores, despite very different prognoses.” men who have been in active surveillance Fix the Gleason Grades! genes Isaacs and his group previously had time) is associated with the presence of Things are getting slightly better; in 2016, for years, or even decades. shown to be most commonly mutated in prostate cancer, and directly associated the authors found, only 10 percent of At many hospitals worldwide, metastatic prostate cancer. with lethal prostate cancer. published articles used Grade Groups or One of these generous donors is Bill informed decisions about treatment, Clarke, who met Carter nearly 20 years Gleason scoring is still less Gleason Score equivalents, and in 2017, “Overall,” Isaacs says, “we found that Frequency of testing: Testing every other and also to avoid needless treatment. ago, at age 49, when Carter performed his this nearly doubled to 19.4 percent. the number of men carrying inherited year is sufficient to find the cancers that “We can back up that decision with an accurate. radical prostatectomy. Clarke was not the (germline) mutations in the 14 genes most need to be diagnosed. incredible database that has been the Unfortunately, says Epstein, “today only first in his family to have prostate cancer; was significantly higher in patients with core of Bal’s research over the years.” Several years ago, world-renowned a minority of published articles on Median PSA levels based on age: PSA his father had also had a radical prostatec- high-grade disease,” compared to men Brady pathologist Jonathan Epstein, M.D., prostate cancer group Gleason scores levels above the median for age can predict tomy done in Boston, by a surgeon using With this Fund, “we will continue with the lowest-grade cancer. “We also the Rose-Lee and Keith Reinhard Professor accurately. This could lead to inaccurate the development of prostate cancer 20 or the then-new -sparing procedure de- research in refining the data, and continue found that three genes, ATM, BRCA2, and of Urologic Pathology, came up with a results and affect patient care with 30 years from now. veloped by Patrick Walsh. After his cancer the path that Bal has been on,” continues MSH2, were mutated at a much higher much-needed solution to confusion in different prostate cancer grades. Our was cured, Clarke says, “I stayed in touch Clarke. “We know a lot, but certainly rate in high-grade cancers.” When it’s safe to stop PSA testing: A man grading prostate cancer: he developed a study calls for more widespread adoption with him, and I also was in a position to there is more to learn, about the markers, over 75 who has a PSA below 3 ng/ml (this new grading system called Grade Groups. of the five Grade Groups.”n Isaacs and colleagues were surprised to the disease itself, and how to deal with it “represents two out of three men in the help him with his research.” Epstein and colleagues validated this over- find that men in grade group 5 had about when something should be done. It is my population,” Carter says) is highly unlikely hauled system in a large, multi-institutional 20 times the number of mutations as men Clarke, a philanthropist who has been intention to honor Bal’s career with my to develop lethal prostate cancer. study. Worldwide, pathologists found in grade group 1, and three to six times very involved with the Bloomberg School contribution. Bal became a friend, it to be such an improvement that it was more mutations than men in grade group 4. Active surveillance can be done safely in of Public Health, says, “Giving back to and shared his research with me. I could High-Grade Prostate endorsed by the 2014 International “While much more work is necessary, the men with favorable-risk prostate cancer. Bal Carter’s work made a lot of sense to see how much he appreciated, not only Society of Urological Pathology strong enrichment of mutations in these In 1995, when Carter began the active me, and I have been a partner in that sense being able to do the operations and cure Cancer and Inherited Consensus Conference. three critical DNA repair genes and tumors surveillance program for prostate cancer since 2003. Indeed, I really gravitated patients, but also to do the research so Gene Mutations among men in grade group 5 is greater at the Brady, “there was substantial toward the research, because it was using that he and the people who came after In the Grade Group system, Grade Group 1 than expected,” says Isaacs. “This suggests resistance to monitoring men with a some of the same techniques that I had him could treat patients in a better fashion. (GG1) is a Gleason score of 6 or lower, GG2 “We found that three genes, a fundamental association between loss of diagnosis of prostate cancer, regardless been using in my career as a commodity That’s really what it’s all about to me.” n is Gleason score 3+4=7, GG3 is Gleason ATM, BRCA2, and MSH2, were normal tissue architecture, acquisition of of grade,” he recalls. “Our goal was to futures trader.” Clarke developed computer score 4+3=7, GG4 is Gleason score 8, and aggressive tumor behavior, and inherited demonstrate the safety of this approach models to make sense of vast amounts of GG5 is Gleason score 9-10. “In part, we mutated at a significantly higher inactivation of specific, key components for carefully selected men. We now know data, and “to understand where the trends proposed the new grading system because If you are interested in contributing to rate in high-grade cancers.” of critical DNA repair pathways.” Better that for these men, the risk of death were.” For example, “by analyzing price data of anecdotal evidence that Gleason scores the H. Ballentine Carter, M.D., Prostate understanding of this association “could from prostate cancer, or development of and comparing it to what has happened in were incorrectly combined in the literature,” Previously in Discovery, we reported on Research and Innovation Fund as a provide a basis for novel, gene-targeted metastatic disease, is 26-fold lower than the past, you can know with some form of says Epstein. A big problem: cancer that the work of William Isaacs, Ph.D., the means of supporting the Prostate Cancer treatment.” n the risk of death from other causes over certainty what will happen in the future. is Gleason 3 + 4 = 7 is different from William Thomas Gerrard, Mario Anthony Program at the Brady and honoring 15 years.” That basically is the same technique that cancer that is Gleason 4 + 3 = 7, yet both Duhon and Jennifer and John Chalsty Dr. Carter’s legacy at Johns Hopkins, Bal was using – assembling data so he used to be lumped together as Gleason 7 Professor of Urology, and colleagues To honor Carter’s research legacy and please contact MaryAnn Jones at could know more about where men were disease. Gleason 8 cancer is different from showing that inherited mutations in a few ensure the continuation and further- [email protected] on the spectrum of prostate cancer. Gleason 9 and 10, yet Gleason 8-10 were genes involved in repairing damaged DNA ance of his work at the Brady Urological or 443-287-6048. crammed into the same category in the are significantly more common in men Institute, patients, their families, and “I’m really proud of what Bal has done,” old system. who die from metastatic prostate cancer, distilling findings from decades’ worth Carter’s colleagues established the H. compared to men who have less aggressive, of data, to help patients with localized There are important differences in these Ballentine Carter, M.D., Prostate Research more slow-growing cancer. and Innovation Fund. Already, the fund’s prostate cancer and their doctors make cancers; they have different prognoses

8 9 WINTER 2020 | DISCOVERY

Johns Hopkins, this PSMA-targeting tracer “eventually they did survive.” So it is with few months, have multiple new areas of balance tips, and ADT is no longer enough PDCD4 (Programmed Cell Death 4), a Oligometastasis: can highlight areas of cancer as small as the seeds of cancer; either the cancer cancer. “For these men, the SABR doesn’t to keep the cancer in check; this is called tumor suppressor gene. Postdoctoral fellow Good News from the a BB – much smaller than can be seen on cells themselves, or their messages (in the control the disease at all.” -resistant prostate cancer (CRPC). Kenji Zennami began studying this gene regular PET or CT imaging. “PSMA-PET form of genetic and chemical telegrams) in prostate and tumor models, Imagine a green lawn, with one or two Lupold, looking at different targets for ORIOLE Study allows us to treat lesions we otherwise are dispatched to the primary tumor, the in work he and Lupold’s lab recently dandelions, Tran tells his patients: “You treatment, has been studying genes activated couldn’t see,” Tran explains “A CT or mother country. If the mother country published in Molecular Cancer Research. “The men in the SABR group can pluck those two or three weeds, and by the androgen receptor (AR). An androgen bone scan would miss those lesions, and is no more – if it has been eradicated by wait and see. Sometimes you get lucky; such as binds to an AR like a “We found that androgens significantly did considerably better. patients would presumably not do as well.” surgery or radiation – then small cancer sometimes another weed or two pops up, key in a lock. This, in turn, “activates” the reduced PDCD4 production in prostate outposts might get similar support from This is a definite signal that At six months, 61 percent of the men in the and you pluck them. It’s like Whack AR, “allowing it to enter the nucleus of cancer cells, and that ADT or AR inhibition visiting each other. But if those outposts observation group progressed – compared a Mole. You can do that for a while,” the cell, bind DNA, and activate a large (androgen receptor-blocking drugs such we can perhaps modify are destroyed by SABR, even if there are a to only 19 percent of the men who with repeated SABR treatments. “But number of genes,” Lupold explains. “This as enzalutamide) triggered PDCD4 few cancer cells remaining in the tissue or metastatic disease.” received SABR. “We also saw a significantly unfortunately, sometimes there will be a pathway is exceedingly critical for prostate expression. This activity was reduced bloodstream, it doesn’t matter: the decreased risk of new metastatic lesions whole bunch of seeds all at once, and at cancer cells.” In CRPC, androgen-resistant when we blocked miR-21, providing a environment is too hostile, and the numbers The boundary used to be very clear: using PSMA PET-CT,” says Tran. “The that point, you need weed killer all over cancer cells can make use of the AR direct link between the AR, miR-21, and are too few for new colonies to survive – prostate cancer was either confined to men in the SABR group did considerably the lawn,” or systemic therapy. pathways – which are supposed to be shut PDCD4.” When they shut down PDCD4, “or, if they did, it would take much longer.” the prostate or prostate bed, or it wasn’t. better. This is a definite signal that we can down – through tricky genetic maneuvers: prostate cancer cells multiplied – and Looking ahead: In a follow-up trial, Like a light switch with no dimmer, there perhaps modify metastatic disease.” Insights: In the ORIOLE trial, Tran and imagine a crook jimmying a lock or making cancer cell death slowed. “Like miR-21 called RAVENS, men with oligomestatic was no in-between: a man with only one colleagues looked for circulating tumor a skeleton key. These genetic alterations over-expression, PDCD4 inhibition caused This was a Phase 2 study, and “we need prostate cancer are randomly given either was believed to face the same DNA (ctDNA), and identified certain gene “allow cancer cells to use androgen-like prostate cancer cell growth and hormone larger Phase 3 trials,” he says. “But this is SABR alone, or SABR plus radium-223 fate, eventually, as a man with widespread signatures that can tell if a man is more molecules, or low levels of androgens, to resistance.” These results were so striking very positive, and we hope that in the (Xofigo). “What we have seen in the men metastases. It was just a matter of time. likely to respond to SABR. “Patients who re-activate the pathway. In fact, some that Lupold believes PDCD4 may be a gate- future, we will be able to change the in that second group – the ones who have don’t have these mutations responded tumors even evolve mechanisms to produce keeper for prostate cancer’s response to Thank goodness, that’s not the case today! course of metastatic disease in some men.” more isolated spots of cancer popping very well,” he says. They also have learned their own androgens.” Pretty sneaky! ADT. He sees PDCD4 as a key “thermostat” up – is, they’re not failing where they Previously in Discovery, we reported What’s happening here? The spread from this and other research that men for prostate cancer, whose presence or received the SABR, but in areas that were In sophisticated, painstaking research on the Baltimore ORIOLE study, led by of cancer is one of colonization, Tran with oligometastasis fall into three basic absence helps determine whether the microscopic, and commonly in the bone.” that took more than a decade, Lupold and radiation oncologist Phuoc Tran, M.D., explains. A few pioneers set forth on a groups. “Some men do really well after cancer cells will die, or go on to become Radium-223 targets cancer in bone. “It colleagues set out to find the particular AR Ph.D. Tran was enrolling patients in this journey to a new land. At first, it’s touch- one course of SABR,” with no recurrence independent of hormonal control. releases a radioactive particle that is very genes that promote prostate cancer cell small study to see if men with oligometas- and-go; their survival is tenuous. Just of cancer. A second group of men have a toxic but is so focused that it only kills in survival and castration resistance. They Lupold sees PDCD4 levels as tasis – up to three small bits of cancer that think of the early colonists in the U.S., small recurrence. “Another site pops up; a radius of two-three cell depths. It’s ideal began by looking at newly discovered have broken away from the main prostate from England, France, or Spain. Until they a microscopic metastasis that we couldn’t a key “thermostat” for prostate for microscopic disease.” genes called microRNAs (MiRNAs). Unlike tumor and started to grow elsewhere – took root in the new land, these nascent see before establishes itself into a most genes, microRNAs do not make cancer, whose presence or would benefit from stereotactic ablative colonies were frail: they needed rein- macroscopic metastasis. It’s a limited In the future, Tran envisions, men proteins; instead, they are troublemakers radiotherapy (SABR, highly focused, forcements from their mother countries return of cancer and it responds to another with oligometastasis will require more absence helps determine that prevent a gene’s protein from being intense doses of radiation), in addition to – medicine, weapons, tools, food – and round of SABR.” Then some men, after a vigilant monitoring, and ideally, regular made. Imagine you go into a diner and whether the cancer cells will die, treatment of their primary tumor. follow-up PSMA-PET scanning. “This order a grilled cheese sandwich; the wait- has the potential to be practice-changing. or go on to become independent Tran believed that the lines of prostate ress writes your ticket and sends it to the We are very excited by our results, and by cancer were not so clear-cut as scientists Tran: “This has the potential to be practice-changing. We are very excited by our results.” short-order cook – but before the ticket of hormonal control. the potential to modulate the course of had assumed; that instead of two circles reaches the kitchen, somebody tears it up! metastatic prostate cancer.” n “We don’t yet understand how PDCD4 – localized and metastatic cancer – that That’s what MiRNAs do on a genetic level: regulates prostate cancer cell proliferation didn’t connect, we might be dealing with a they tear up tickets. Lupold and colleagues or androgen sensitivity,” Lupold adds. Venn diagram, with oligometastasis as the zeroed in on one particular microRNA “Further studies are required to solve this critical area where the two circles overlap. called miR-21. “We discovered that elevated puzzle.” In the meantime, PDCD4 has “It may be that the window of curability is Discovered: A “Gate- levels of miR-21 could stimulate prostate the potential to be a new biomarker for wider than we thought,” he said last year. keeper” Gene for CRPC cancers to develop castration resistance.” higher-risk patients. “Preliminary studies This discovery, led by Judit Ribas and Now, we are pleased to report, the results from human prostate tissues indicate that published in Cancer Research in 2009, of this multicenter trial are even better We’ve known this for decades: some PDCD4 levels are lower in more-aggressive “set us on a new journey: to determine than Tran hoped. In the ORIOLE trial, 54 prostate cancer cells respond to androgens cancer (high Gleason grade).” The next how miR-21 drives castration resistance.” men with oligometastasis were randomly (male hormones), and some don’t. This is steps are to determine whether PDCD4 Specifically: which gene did miR-21 use assigned either to treatment with SABR why androgen deprivation therapy (ADT), also has the potential to become an entirely to accomplish its mischief? or to observation. To find and keep track although “an extremely targeted and highly new mode of treatment for high-risk or of the oligometastases, the study used effective treatment for prostate cancer,” A postdoctoral fellow in Lupold’s lab, advanced prostate cancer. n PSMA-PET scanning, which uses a small is not a cure, says Shawn Lupold, Ph.D.: Fatema Rafiqi, using complex computer molecule linked to PSMA (prostate-specific because it doesn’t stop the cancer cells that algorithms, sifted through thousands membrane antigen, found on the surface aren’t affected by androgens. Even when of genes and analyzed likely candidates of prostate cancer cells) as a radioactive the androgen-dependent cells are under with Ross Liao, now a Johns Hopkins tracer. Developed by Martin Pomper at control, these other cells keep right on medical student. Postdoctoral fellow growing and dividing. Eventually, the Koji Hatano identified a likely suspect: 10 11 WINTER 2020 | DISCOVERY

Lotan and Faisal: “The poor prognosis of patients accepted for publication in the Journal of these drugs must pass. At some point, trials being conducted to maximize with deletions in the CDKN1B gene has important Clinical Oncology-Precision Oncology. In all men with advanced prostate cancer clinical benefit while avoiding the clinical implications for African American men.” a separate study in the same journal, the will start ADT, and they often never get long-term toxicity of ADT,” Antonarakis group found almost half of patients with a off of it. If the PSA starts to rise and continues. rare prostate cancer variant, called ductal cancer starts to advance, they add One trial, NCT03047135, is testing adenocarcinoma, had similar mutations another drug on top of it – but don’t stop (a PARP inhibitor that has shown success in DNA repair genes. And in collaboration taking the ADT. in treating breast and ovarian cancer in with Brady pathologist Jonathan Epstein, We’ve been stuck with ADT because women who have mutated BRCA1 and Aggressive Cells M.D., Lotan’s group found that half of there hasn’t been a way around it. BRCA2 genes) without ADT in men tumors with giant cells (formed by several in Primary Tumors But now, we have entered the era of with high-risk prostate cancer who distinct cells joined together) carried these “precision oncology,” says medical have experienced a rise in PSA after Under the microscope, pathologists can mutations; this work was published in oncologist Emmanuel Antonarakis, M.D. prostatectomy. “In early results, we have see it: differences in prostate cancer cells, Histopathology. “Our goal is to use genetic information to observed that olaparib is well-tolerated some clearly more ragged-looking and “Our findings all suggest that men with tailor for the right patients at and has very promising activity in some aggressive than other, more well-defined aggressive prostate cancer should be the right time – something we couldn’t men,” says Markowski, “particularly – and orderly cells. “But we don’t know routinely screened for underlying germline do before.” Precision treatment for but not exclusively – in men who have why some prostate tumors behave more mutations in DNA repair genes, and these prostate cancer requires knowing which mutations in BRCA2 and ATM, both of aggressively,” says Brady pathologist patients may also benefit from PARP faulty genes are involved in an individual which are HR genes.” Tamara Lotan, M.D. vice versa. Thus, Faisal, with the direction inhibitors currently in clinical trials,” says man’s cancer, and knowing what to do A second trial, NCT03413995, also Racial Differences of Lotan, performed targeted genome Looking for answers, Lotan worked Lotan. (For more on PARP inhibitors, see with that information. called the TRIUMPH study, is treating sequencing in a group of African American with Hopkins medical oncologists Mario story below). n in Prostate Cancer: Some of the most common defective metastatic prostate cancer patients with patients – the largest cohort to date. Eisenberger, M.D., and Emmanuel genes in prostate cancer are the DNA the PARP inhibitor, rucaparib, “also in New Genetic Targets Antonarakis, M.D., and with two repair genes, whose job is to fix errors the absence of ADT,” Antonarakis says. “We found that mutations in the TP53 gene, physician-scientists at the University of made as cells grow and divide. Genetic “All men in the TRIUMPH study must “Some of these alterations deletions in the CDKN1B gene, and overall Washington, Colin Pritchard and Michael For Some Men with mistakes happen all the time in everyone, have an inherited (or “germline”) HR burden of genome alteration (percent of the Schweizer, to genetically profile aggressive are directly associated with Certain Genes: PARP and it’s the job of these genes – including gene mutation, and must feel comfort- genome with variations) were associated cells found in primary prostate tumors. BRCA1, BRCA2, and ATM – to make sure able postponing ADT.” This study has poor prognosis.” with increased risks of metastasis in “We found that these tumors frequently Inhibitors Instead of ADT African American men,” notes Faisal. “Our that these mistakes are fixed before just begun enrolling patients, but already, Why are African American men 1.5 times have mutations in the genes involved in study was the first ever to correlate tumor “We are using two PARP anything goes wrong. They do their jobs “preliminary observations suggest more likely to get prostate cancer, and DNA repair activity in the cell,” Lotan says. genomic sequencing data with risk of using a repair method called homologous potential benefit of PARP inhibition in more than twice as likely to die of it as men inhibitors, olaparib and metastasis in African American prostate recombination (HR). If one of these HR, or this patient population, especially in men of European descent? Brady investigators Sometimes these mutations cancer.” The team’s findings were presented rucaparib, in two clinical trials quality-control, genes stops working, harm- with germline BRCA2 mutations.” have discovered critical, inherited genetic at the American Urological Association, at seem to have happened ful mistakes can eventually lead to cancer. mutations in men of African descent. to maximize clinical benefit These trials are being supported by the American Society of Clinical Oncology’s Their work gives scientists new genes to spontaneously – just in the “In recent years, we have seen the Hopkins scientist Tamara Lotan, M.D., Genitourinary Symposium, and published while avoiding the long-term look for – and new targets for precision advent of drugs called poly-ADP ribose who is the lead pathologist on both in the Journal of Clinical Oncology and the tumor, but not in other cells. diagnosis and treatment. toxicity of ADT.” polymerase (PARP) inhibitors,” says studies. Lotan’s lab is conducting Journal of Urology. But in many cases, they’re in medical oncologist Mark Markowski, in-depth molecular analyses on tissue “We have identified several molecular and Nobody likes androgen deprivation Faisal and colleagues are most excited M.D., Ph.D. PARP inhibitors zero in on specimens to help determine which genomic alterations of prostate cancer that every cell, which means the therapy (ADT). Not doctors, and about bringing the CDKN1B gene to these faulty HR genes, and in someone men will benefit the most from these are unique to African American men,” says certainly not patients. ADT is a mainstay light: “The poor prognosis of patients with patient was born with a whose cancer has one of these mutated PARP inhibitors. Brady resident Farzana Faisal, M.D., who of treatment for advanced prostate deletions in the CDKN1B gene is a novel genetic defect, called a germline genes, “inhibiting PARP can result in began this research several years ago as a cancer because it prolongs life for years, To find out more about these studies, discovery that has important clinical profound anti-cancer effects.” Johns Hopkins medical student, working mutation, that led to cancer. and sometimes even decades – but at a please call Rana Sullivan (410-614-6337) implications for African American men,” with Brady scientists Tamara Lotan, M.D., cost. Just a few of the many side effects Together, Markowski and Antonarakis or Serina King (410-614-6139). n Faisal says. One foreseeable implication and Edward Schaeffer , M.D., Ph.D. (now “These patients and their family members of ADT (beyond the loss of testosterone are working – as Antonarakis puts it – might be in the type of treatment Director of Urology at Northwestern may be carrying these germline mutations, itself ) are weight gain, depression, and “to exploit these HR mutations to develop recommended: for example, an African University). “Importantly, some of these passing them down from generation to a higher risk of diabetes, heart attack, non-hormonal therapies for men with American man diagnosed with localized alterations are directly associated with generation,” Lotan explains. stroke, and dementia. recurrent and metastatic prostate cancer.” prostate cancer who tests positive for a poor prognosis.” In other words, instead of shutting down deleted CDKN1B gene might be encouraged In a study of 49 patients with Gleason So established, in fact, is ADT that the hormones that help drive the cancer, Many studies of prostate cancer patients to seek surgery or radiation, rather than score 9 and 10 carcinoma (the most although there are other forms of and then waiting for ADT to fail in these worldwide have been done on groups of undergo active surveillance. “These aggressive Gleason grade), Lotan and treatment for advanced and metastatic men, they are cutting right to the chase: entirely or primarily Caucasian men; but deletions were more common in younger colleagues found that 34 percent of prostate cancer – including androgen going after the bad genes that caused the the Hopkins scientists have learned that the men with higher-grade and -stage disease.” patients had at least one mutation in a receptor blockers, , new cancer in the first place. Without ADT. genetic markers that can signal aggressive For this work, Faisal received the Physician DNA damage repair gene, and more checkpoint-blocking prostate cancer in men of one race don’t Scientist Award at the 2019 Young than half of these patients had germ- drugs, and platinum chemotherapy drugs “We are using two PARP inhibitors, always apply to men of other races, and Investigators’ Day at Johns Hopkins. n line mutations. This study was recently – ADT is still the gateway through which olaparib and rucaparib, in two clinical 12 13 WINTER 2020 | DISCOVERY

Amend. “Based on our recent observations, Why not urine? Indeed, says scientist Jun The Keystone to where we observed them as live, functioning Luo, Ph.D., “given that exfoliated cells and Uneven Accuracy in Resistance after cells, we now believe Keystone cells are secretions from the prostate can be found critical operators of resistance.” They found in the urine, it represents an ideal source of IHC Testing Chemotherapy for that when cancer cells are treated with biomarkers for localized prostate cancer.” Immunohistochemical staining (IHC), chemotherapy, the Keystone cancer cells Prostate Cancer Luo, leading a team of investigators to a technique using to detect stop dividing and seem to hibernate. explore novel possibilities of urine testing specific molecules on cells, is an essential Because chemotherapy kills cells that are When cancer cells are in prostate cancer, has developed an tool that pathologists use in diagnosing dividing, “the Keystone cancer cells survive.” innovative procedure to microscopically cancer. But as Brady scientist Angelo M. treated with chemotherapy, After the stress of treatment subsides, identify prostate cells recovered from De Marzo, M.D., Ph.D., and colleagues the Keystone cancer cells stop the Keystone cancer cells wake up, start urine. Using multiplex in situ hybridization recently discovered, there’s a huge dividing again, “and give rise to a generation (a technique that allows scientists to find variation in the quality of IHC tests Brennen, Denmeade, and Isaacs: Protoxin mimics the way immune cells kill cancer. dividing, and seem to hibernate. of now-resistant daughter cells,” Amend precise sequences of DNA or RNA), the available – and this could affect accuracy. Because chemotherapy kills cells colleagues made it prostate-specific. Even continues. “We believe that these Keystone team looked for prostate-specific RNA “IHC is used in thousands of research Special Delivery to though metastatic cancer cells have spread that are dividing, “the Keystone cancer cells are critical to therapy resistance targets. They fluorescently labeled prostate and clinical laboratories,” De Marzo and disease recurrence, and unless they are cells and evaluated RNA sequences at the Metastatic Prostate far from the prostate, they still have PSMA cancer cells survive.” says, “but there is widespread misun- (prostate-specific membrane antigen), eliminated, cancer is going to come back single-cell level, using a method developed derstanding about the two classes of Cancer: PSMA-Targeted a molecule that sits on their surface. Consider, if you will, the Monterey Pine tree. after chemotherapy.” Amend and Pienta by Brady research fellow Jillian Eskra, Ph.D. antibodies used in IHC staining: clinical Poison The PSMA is the address. Metastatic Its cones only open after a fire reaches a certain are now working to learn more about how The results were as exciting as they had grade and research grade. Clinical grade prostate cancer cells also still make PSA, temperature. Its whole survival has adapted these Keystone cancer cells are formed, hoped: “Using this technique, it is possible antibodies are validated for accuracy “so we can learn how to target them, to make to visualize malignant and benign prostate This protoxin is a copycat killer: and here, the PSA acts as the detonator for so that after a wildfire, it will release many prior to their use in hospital pathology the protoxin. seeds at once to repopulate the burnt forest. treatment for advanced prostate cancer cells in urine specimens,” says Luo. labs, but are limited in number,” with like immune cells, it pokes lethal much more effective.” Amend and her Brady scientists Sarah Amend, Ph.D., and Once they had a test, Luo’s team worked about 500 antibodies in use. “On the “Both PSMA and PSA function as molec- colleagues have received an award from The holes in cancer cells. Ken Pienta, M.D., the Donald S. Coffey with urologist Christian Pavlovich, M.D., other hand, the majority of commercially ular scissors, capable of cutting proteins Patrick C. Walsh Prostate Cancer Research Professor of Urology, have found that some- to evaluate how well it worked, in urine available research-grade antibodies When all goes well, the body’s immune cells at specific sites,” explains Isaacs. Using Fund to build on this work. For the next thing similar happens in prostate cancer cells collected from 98 patients. The test are not held to the same standards of should recognize prostate cancer as some- protein engineering, the scientists fused steps of their project, please see page 17. n in response to the stress of chemotherapy. performed like a champ: “When we validation, and there are now more than thing bad that shouldn’t be there, and then the cancer-killing poison to serum albumin “Using an imaging system that allows us to compared the results of the urine test with 3.8 million of these. Overall, we estimate attack the cancer. In effect, they should (a protein made by the liver and carried in track cells over time, we observed prostate clinical and pathological findings,” Luo that at least half of published studies stab it to death – poking holes in the cancer the blood), “to keep this chimeric protoxin cancer cells responding to chemotherapy says, “we found that the majority of patients using research IHC assays have potentially cells’ surface. Unfortunately, for a variety of from binding to normal cells throughout the Coming Soon: stress,” says Amend. “We found, existing who tested positive for cancer had clinically incorrect staining results due to lack of reasons, so far prostate cancer has proven to body, and to increase delivery to the tumor,” within the larger cancer cell population, a significant disease.” Even better: “Positive validation.” be resistant to immunotherapy. when the drug is administered systemically A New Urine Test for via the bloodstream. This protein is engi- distinctive rare cell subtype,” which they Prostate Cancer detection also correlated with high-risk “A cornerstone of scientific research is So how can we get to metastatic prostate neered to require cutting by PSA to activate have named the Keystone cancer cell. These cancer features” detected in needle biopsy. the ability to reproduce findings of col- cancer cells to kill them? Scientist John Keystone cancer cells are giant and have “These preliminary results indicate the the cell-killing pore forming (hole-poking) Prostate-specific RNA in the leagues’ studies, to either affirm or reject Isaacs, Ph.D., working with colleagues ability of the liberated bacterial toxin.” extra DNA as compared to the other cancer urine test is highly specific for detecting them,” says Brady scientist Karen Sfanos, Nathaniel Brennen, Ph.D., Emmanuel cells. “These cells have been observed by urine may lead to a new test for clinically significant prostate cancer, and M.S., Ph.D., co-author of this study. “The Akinboye, Ph.D., and Samuel Denmeade, In elegant work, Isaacs and colleagues scientists for a century, but have long been holds promise as a tool for distinguishing problem with having many incorrect IHC M.D., has come up with a solution: special modified the protoxin so that when it is dismissed as insignificant, thought to be clinically significant prostate men who harbor aggressive prostate cancer results in the literature is that it makes it delivery. The “package” to be delivered is out for delivery – when it’s circulating in artifacts or dying cells,” adds Pienta. cancer, and may show which men from those with indolent disease.” difficult to rely on prior results, which can chimeric protoxin, a deadly (to cancer!) the blood – it is inactive, and harmless. They seem to be just the opposite: Amend This work was presented at the annual AUA significantly slow down research.” chemical weapon that’s the next best thing But when it reaches cells that have PSMA, have more aggressive disease. and Pienta have discovered that these cells – meeting in May 2019. Results were published to having an army of cancer-killing immune watch out! “It selectively binds to the This work was published in a special issue like the Monterey pine cone seeds after fire Why do we rely so heavily on blood samples in the Journal of Urology, and a second journal cells. “It short-circuits the lack of immune surface of metastatic prostate cancer cells of the Asian Journal of Urology that was – “emerge under therapeutic stress,” says to tell us what’s happening in the prostate? publication is being prepared. n cells by mimicking the way these cells kill that express PSMA, and this binding dedicated to the late Donald Coffey, Ph.D., cancer,” says Isaacs. This protoxin, in other enables PSA to activate the protoxin by longtime Director of the Brady Research words, is a copycat killer: like immune cells, acting as a molecular scissor,” Isaacs says. Labs. In the publication, the Brady it pokes lethal holes in cancer cells. What In other words, the mail bomb only goes scientists provide numerous examples of really matters, Isaacs adds, are the holes off when PSA snips open the package. validated assays, literature and other Did you know you can make a meaningful gift to the Brady Urological – not the hole-punchers. “It comes down “We are accumulating the preclinical resources to help pathologists and scientists to whether enough holes are produced to validation needed for clinical development Institute that won’t affect your income during your lifetime? find the right IHC antibodies and assays. kill the cancer cells. Our approach doesn’t of this PSMA-targeted chimeric protoxin Other authors and contributors included You can help us accelerate lifesaving research and deliver exceptional care for future generations of patients, clinicians, and require the immune cells themselves.” activated by PSA.” Srinivasan Yegnasubramanian, William scientists with a gift through your will, trust, or retirement account. Your gift allows you to leave a lasting legacy to the Brady This work was supported by The Patrick C. Nelson, Tamara Lotan, Ibrahim Kulac, To put the “address” on the package – to Urological Institute while providing you with flexibility today. To learn more, contact the Johns Hopkins Office of Gift Planning. Jessica Hicks, Qizhi Zheng, Charles make sure it goes only to the right cells, and Walsh Prostate Cancer Research Fund and n Bieberich and Michael Haffner. n doesn’t harm normal cells – Isaacs and the Allegheny Fund at Johns Hopkins. 410-516-7954 | Toll-free: 800-548-1268 | [email protected] | giving.jhu.edu/giftplanning

14 15

THE PATRICK C. WALSH PROSTATE CANCER RESEARCH FUND — AWARDEES 2019 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

We are looking for innovative ways to stop lethal prostate cancer and to make life better for men with localized prostate in addition to genetic differences, many may identify whether the biology leading introduce a candidate treatment to cancer: these are the exciting research projects you helped us fund this year. Since its inception in 2005, The Patrick factors contribute to this discrepancy: to aggressive prostate cancer differs eliminate Keystone cells and increase the certainly, issues such as “differences between African American and white chances for long-term survival in patients C. Walsh Prostate Cancer Research Fund has awarded millions of dollars to Johns Hopkins scientists in every discipline in income, education, diet, and access men,” says Trock, “which will help us with aggressive disease.” n with good ideas worth pursuing that can help us understand more about prostate cancer — to help us save lives, to find to medical care,” are important pieces form new hypotheses for reducing risk better ways to treat it at every stage, and even to help prevent it. These awards wouldn’t have been possible without the of this puzzle, Trock notes. “But there and tailoring treatment to the biological tremendous and amazing generosity of our patients and friends. also appear to be unexplained differences aggressiveness of the tumor.” n What Happens at the between African American and white Beginning of Metastasis? For 2019, we asked scientists to submit one of two types of research proposals: for pilot projects, as in previous years, men in the biology of prostate tumors. Many, but not all, men diagnosed with Although some differences in gene Keystone Cells and Resistance and for team science awards. These team projects are aimed at developing the necessary preliminary data and team low-risk prostate cancer can be safely expression or mutations have been and Lethality of Prostate Cancer monitored without treatment. There’s structure needed to apply for NIH program project grants (such as P01 or U01), or similar funding from other sponsors. identified, they don’t provide a clear still some uncertainty, because we don’t Applications were reviewed by nine separate investigators with appropriate expertise related to each project. Projects indication of how biological functions “We will test the ability of have a way to tell who is truly low-risk, in the prostate may contribute to the -particle irradiation to eradi- were scored on a scale of 1 to 10 (1 being the best possible score) and then ranked, based on their adjusted average α and whose risk might go up over time. excess risk in African American men.” (the highest and lowest scores were eliminated before taking the average of the remaining seven scores). cate these Keystone cancer cells.” Much needed, says Hui Zhang, Ph.D., Metabolites may provide a new window is “a new test that could distinguish for discovery. “Unlike genes and proteins, On page 15, we talked about “Keystone” patients with truly low-risk disease from 2019 AWARDEES mutated BRCA1/2 genes, who may do pilot efforts will lead to a NCI PO1 project, metabolites reflect the actual workings cells – so named by scientists Sarah patients with high-risk features.” Such of cells and organs,” says Trock; in other Jun Luo, Ph.D., better on PARP inhibitors than other men. “with the overall goal of realizing precision Amend, Ph.D., and Ken Pienta, M.D., a test, she adds, would provide peace of n words, what makes the prostate the The Virginia and Warren “The treatment landscape for men with medicine in prostate cancer.” because they seem to play a pivotal mind to men who choose active surveil- prostate. Another advantage of studying Schwerin Scholar advanced prostate cancer is rapidly evolv- role in advanced prostate cancer that lance, and allow doctors to recommend metabolites is that many metabolic patterns Department of Urology ing,” says Brady scientist Jun Luo, Ph.D., defies treatment. These Keystone cells – this strategy with greater confidence. Could Metabolomics Explain can be modified – by changing diet, distinctive, large cells that emerge after Bruce J. Trock, M.P.H., Ph.D who adds that “disruptive changes are being Some Racial Differences in exercise, other behaviors, or . chemotherapy – “have been recognized The Ambrose Monell Foundation introduced by multiple treatment modalities. “A urine test that could Men with Prostate Cancer? “Comparing patterns of metabolism for more than 100 years, but are often Scholar, Department of Urology Although progress has been made in prostate between African American and white distinguish patients with cancer genetics and genomics, there dismissed as unimportant, thought to Sarah R. Amend, Ph.D., Many metabolic patterns can men with prostate cancer may reveal remains a critical knowledge gap that limits be artifacts or dying cells,” says Amend. truly low-risk disease from The Carolyn and Bill Stutt Scholar, differences in the underlying biology. the impact of these advances on the overall be modified – by changing diet, “However, our preliminary data suggest patients with high-risk Department of Urology Identifying key metabolic differences goal of prostate cancer control.” that, in fact, Keystone cells are the Hui Zhang, M.S., Ph.D., exercise, other behaviors, or could, in turn, provide clues about changes critical mediators of therapy resistance. features would provide peace The Beth W. and A. Ross Myers Scholar, “We will use our team science medications. “Identifying key that may help to lower the risk in African Therefore, unless they are eradicated, of mind to men who choose Department of Pathology American men. This type of approach is cancer will recur in treated patients.” award to develop genetic metabolic differences could an example of precision urology.” active surveillance.” In a team project with Brady scientist marker tests and characterize provide clues about changes With their grant from The Patrick C. Angelo De Marzo, M.D., Ph.D., and With co-investigator Alan W. Partin, Walsh Prostate Cancer Research Fund, Stavroula Sofou, Ph.D., a biomolecular Precision Medicine in Prostate subsets of patients with distinct that may help lower the risk in M.D., Ph.D., Director of the Brady Trock and De Marzo will be comparing engineer at the Johns Hopkins Whiting Cancer: Finding Subsets of Urological Institute, Zhang will work on treatment responses. Such tests African American men.” metabolic patterns in the prostatic fluid School of Engineering, Amend will build developing a urinary test to determine Patients taken from men who underwent radical on this work. “We will determine how could help choose treatment Metabolomics is the study of metabolites: cancer risk using urinary glycoproteins, We’ve known for many years that prostate prostatectomy at Johns Hopkins. and when Keystone cells are formed small molecules found inside cells, which have proven to be useful biomarkers cancer fine-tunes itself from patient to at critical disease states along “This fluid is secreted by glands with- during prostate cancer progression,” body fluids, or tissues. Could it help in detecting prostate cancer from blood. patient. This is why, although two men in the prostate – and these glands are Amend says. “We will also explore the prostate cancer spectrum.” explain racial differences in prostate Zhang and Partin have identified four may appear to have identical prostate the structures where prostate cancer how they survive anti-cancer therapy cancer? Bruce Trock, M.P.H., Ph.D., and likely candidate glycoprotein biomarkers. cancer, with the same Gleason grade and Luo, with Brady scientists William Isaacs, originates.” The scientists believe these by exiting the cell cycle and how they co-investigator Angelo De Marzo, M.D., Says Zhang: “We will determine the same stage, one man may respond to a Ph.D., and Shawn Lupold, M.D., Ph.D., metabolites “should closely reflect the repopulate a therapy-resistant population. Ph.D., believe it might. clinical performance of detecting drug, and the other will not. Thanks to biological activity giving rise to prostate Then we will test the ability of -particle will use a team science award to develop α patients with different levels of high- advances in prostate cancer genetics – As we discuss elsewhere in Discovery cancer.” They will compare prostatic irradiation to eradicate them.” Amend genetic marker tests and characterize risk tumors, using mass spectrometry many of them made right here at the (see page 12), African American men are fluid metabolites between closely and colleagues believe the results of this subsets of patients with distinct treatment as well as immunoassays for these four Brady – we now know that men with responses. Such tests could help choose more likely to develop prostate cancer, matched African American and white project “will fundamentally change candidates from urine.” n prostate cancer can be divided into subsets. treatment “at critical disease states along and to die of it, than men of European prostate cancer patients whose tumors our understanding of how and when One subset, for example, is men with the prostate cancer spectrum.” These descent. There’s no simple explanation: did, or did not, recur after surgery. “This therapeutic resistance arises, and will 16 17 WINTER 2020 | DISCOVERY

more brady urology cancer news we don’t know if these same biomarkers can predict chemotherapy benefit” if Evaluating alternatives Can Biomarkers Hahn’s leadership of a clinical trial of these tumors are located elsewhere – an immune checkpoint-inhibitor drug, to BCG: Is combination Predict Who Will Benefit namely, in the ureter or renal pelvis; durvalumab, in patients with metastatic these are upper tract urothelial cancers chemotherapy the next from Chemotherapy in bladder cancer. “This study led to (UTUCs). the FDA approval of durvalumab and frontier? Bladder Cancer? Urologist Philip Pierorazio, M.D., and provided bladder cancer patients with Maintenance dosing of intraves- New tests could identify who will another much-needed therapy option,” Hoffman-Censits are collaborating with says Bivalacqua, Director of Urologic other investigators to establish a re- ical combination chemotherapy benefit from chemotherapy, and search-based Center of Excellence at the Oncology. Recently, a team of Hopkins “leads to more durable responses spare those who will not. investigators led by Hahn, including Brady and the Greenberg Bladder Can- Bivalacqua, Luigi Marchionni, Kellie cer Institute. In the recently completed than induction treatment alone.” Imagine a room full of patients with Smith, Woonyoung Choi, Alex Baras, Eastern Cooperative Oncology Group’s muscle-invasive bladder cancer. If you are diagnosed with early-stage Marianna Zahurak, Gary Rosner, David Phase II clinical trial, they and other Which of them should get presurgical bladder cancer, you will probably be McConkey, and Drew Pardoll, received a Hopkins investigators demonstrated that (neoadjuvant) chemotherapy? The given a locally delivered immunotherapy $3.2 million R01 award from the National neoadjuvant chemotherapy has clinical answer right now is, “all of them” – called BCG. Soon, there may be other Cancer Institute for their novel clinical benefit in patients with UTUCs. Now, but that’s not the best answer. and translational work proposed within in a project supported by philanthropic options, as well. Previously, Brady “Although neoadjuvant chemotherapy the ADAPT-BLADDER trial. donation from Jim and Pam Harris, they scientists Max Kates, M.D., and Trinity are performing molecular genetic studies Bivalacqua, M.D., Ph.D., showed that is recommended for everyone with “Within this study, bladder cancer patients to identify biomarkers that can help BCG’s success is largely due to an influx muscle-invasive bladder cancer, it only with BCG-relapsing and BCG-unresponsive, of T cells into bladder tumors. “A single benefits a subset of those patients,” Hahn: “Neoadjuvant multi-agent chemotherapy”– using a triple punch of cisplatin, gemcitabine, and predict which patients with UTUCs are non-muscle invasive bladder cancer will says David McConkey, Ph.D., the Erwin docetaxel – before cystectomy is helping sarcomatoid bladder cancer patients. “Our initial results are very most likely to benefit. These studies are supplier in the United States is cur- be treated with a number of novel immu- encouraging.” being performed in close collaboration rently unable to meet demand for the and Stephanie Greenberg Professor notherapy combination approaches,” with urologist Surena Matin, of MD treatment” notes Kates. “However, BCG of Urology and Director of the Johns cancer, Hahn and urologist Trinity says Hahn, “including durvalumab plus DISCOVERY IN BLADDER CANCER Anderson. (To read more about our is not the only effective treatment for Hopkins Greenberg Bladder Cancer Bivalacqua, M.D., Ph.D., began offering BCG, and durvalumab plus radiation work on UTUCs, please visit https:// this disease.” Institute; he is also Chair for Transla- “neoadjuvant multi-agent chemotherapy” therapy.” The award will also fund novel tional Medicine in the genitourinary Sarcomatoid Bladder www.hopkinsmedicine.org/greenberg- Over the past five years, and with the – using a triple punch of cisplatin, gemcit- genetic and functional immunology inves- division of the Southwest Oncology bladder-cancer-institute/utuc.) n help of collaborators from the Center for Cancer: Encouraging abine, and docetaxel – before cystectomy tigations, using patient samples collected Group (SWOG). Together with Nanomedicine at Johns Hopkins, Kates to sarcomatoid bladder cancer patients within the study. “The ADAPT-BLADDER Woonyoung Choi, M.S., Ph.D., McConkey Responses to New and his colleagues have designed novel seen at Johns Hopkins who were eligible trial is one of the first studies to bring is leading a nationwide effort to chemotherapy approaches to enhance Regimen for cisplatin-based chemotherapy. “Thus urology, medical oncology, radiation Bladder Immune validate several panels of biomarkers. drug absorption into the bladder wall. far, six patients have been treated with oncology, pathology, and translational The biomarkers test for basal and “Four out of six patients Cells May Determine Following the lead of colleagues from this more intense approach, followed by medicine together to create a new luminal molecular subtypes of bladder the University of Iowa, the team has demonstrated a complete cystectomy,” says Hahn. “Our initial multidisciplinary care model for cancer, and also for mutations in DNA Response to begun to offer intravesical combination results are very encouraging, with four non-muscle invasive bladder cancer,” damage repair genes, in tumors that response, with no identifiable chemotherapy, including gemcitabine/ out of the six patients (67 percent) notes Hahn. “In this respect, it stands Chemotherapy were collected from patients enrolled docetaxel, for patients who do not have residual tumor seen at the demonstrating a complete response, with to serve as a transformative study for the in the SWOG’s Phase 2 clinical trial Scientist Woonyoung Choi, Ph.D., who access to or are not candidates for BCG. no identifiable residual tumor seen at the bladder cancer field.” n comparing gemcitabine/cisplatin and time of surgery.” led genomic studies that identified the time of surgery.” The news was good for Recent work by Kates and colleagues MVAC chemotherapy. basal and luminal molecular subtypes of the other two patients, as well: “Neither has shown that “maintenance dosing of New hope for patients with a rare, bladder cancer, has discovered that the “If the tests are validated, they will of the patients who had residual tumor in this combination leads to more durable extremely aggressive form of bladder immune system plays a powerful role in enable clinicians to use pretreatment the surgery specimen, had growth of their Upper Tract Urothelial responses than induction treatment cancer: “very encouraging responses” how patients respond to chemotherapy. biopsies to identify the subset of cancer on treatment, and neither had any alone,” he says. “We are in the midst of to an intense, triple-drug, neoadjuvant Cancers: Who Will Benefit patients who will receive benefit, severe, unexpected surgical complications.” “Differences in the numbers and character- a new wave of interest in combination chemotherapy approach, followed by sparing the ones who will not,” from Chemotherapy? istics of the immune cells – in particular, intravesical chemotherapy for bladder cystectomy (surgical removal of the Now, the scientists are examining the McConkey notes. “This would dramatically the T lymphocytes – that are present in cancer. Our current efforts are focused bladder). pre-treatment tumor samples from these change clinical practice.” n When it comes to chemotherapy for bladder cancers strongly influence their patients “to examine the genetic basis on sequencing these tumors to identify Medical oncologist Noah Hahn, M.D., urothelial cancer, does location matter? sensitivity to neoadjuvant chemotherapy,” of these encouraging responses,” says predictors of response to these new presented results of the Johns Hopkins Hopkins scientists are working to find out. she says. With a $1.5 million grant from Hahn, “to help guide physicians in and exciting therapies.” For these experience in treating sarcomatoid bladder “Recent studies have led to the identification the Department of Defense, she is deciding whether all or only a portion discoveries, the American Cancer cancer at the International Bladder of genetic biomarkers, including molecular collaborating with a co-investigator in of patients with sarcomatoid bladder Society has given Kates’s lab a five- Cancer Network’s Annual Meeting in subtypes, that can be used to predict benefit Texas to develop a new molecular cancer should be treated with this new, year Clinical Scientist Development Aarhus, Denmark, in October. Based from presurgical (neoadjuvant) chemo- subtyping test, and to perform mechanistic multimodality approach.” Award. This work was published in on a complete response to in urothelial cancers located in studies to determine whether T lympho- Clinical Cancer Research and Cancer chemotherapy in a patient who initially Grant from National Cancer Institute: the bladder,” says medical oncologist cytes are required for bladder cancers to Immunological Research. n was considered to have unresectable Previously in Discovery, we reported on Jean Hoffman-Censits, M.D. “However, respond to chemotherapy. n 18 19 Bivalacqua has made numerous contributions in two areas of urology: sexual dysfunction and urologic WINTER 2020 | DISCOVERY oncology. The coveted Gold Cystoscope Award was presented by AUA President Robert Flanigan.

characteristics,” says urologist Trinity “We found that luminal tumors were less of bladder tumor (TURBT). They com- Bivalacqua, M.D., Ph.D., Director of likely to have spread outside the bladder pared clinical and pathologic information Bivalacqua Wins Gold Cystoscope Award Urologic Oncology. compared with basal tumors.” n from patients whose urothelial carcinoma These subtypes can be classified as either was considered ambiguous to samples “Trinity Bivalacqua defines a translational surgeon-scientist.” basal or luminal. “Basal tumors, while from patients with muscle-invasive more aggressive, show the greatest disease and from patients diagnosed with Brady urologist Trinity Bivalacqua, M.D., success, the AUA Care Foundation now Blue Light Shows improvements in survival outcome, with superficial bladder cancer who underwent Ph.D., the R. Christian B. Evensen Professor, encourages residents to apply for platinum-based neoadjuvant chemo- Urothelial Cancer radical cystectomy (surgery to remove has received this year’s Gold Cysto- postdoctoral fellowships. the bladder). “We found that the great therapy (NAC),” Bivalacqua continues. Have you ever gone to an event and had scope Award, one of the highest honors majority of patients who have ambiguous After his fellowship, Bivalacqua joined Luminal tumors, in contrast, “tend to be your hand stamped? The stamp may not awarded by the American Urological invasion on initial TURBT turn out to the Brady faculty. With a K08 Career less aggressive, but may also receive less show up at all unless someone shines a Association. The award recognizes the have advanced disease” when the removed Development Award from the NIH/ benefit from NAC” – and here is where black light on it, and then there it is, plain young urologist who has made the most bladder specimen is examined. “This NIDDK, he studied next-generation understanding molecular subtypes may as day! Pathologist Andres Matoso, M.D., contributions during the first 10 years emphasizes the need for early repeat therapies for nerve regeneration following provide valuable insight. and colleagues have discovered something after completing residency. Bivalacqua believes his greatest TURBT – or even consideration of early radical prostatectomy – research that led similar by changing the color of light – from accomplishment – so far – has been the cystectomy to lower the risk of worse Bivalacqua is in very good company: to discoveries in the field of peripheral “In the field of bladder cancer, white to blue – used during cystoscopy. successful development and completion pathological findings, and to prolong recipients of this award have a distin- nerve biology and highlighted the “Carcinoma in situ (CIS; abnormal cells of a tissue-engineered conduit that may we are desperately trying to find survival.” guished history of going on to become detrimental effects of neuroinflammation that may become cancerous and spread; one day lead to development of a new leaders in the field. And, over the years, in autonomic nerve degeneration. For biomarkers for the selection of also called stage 0 disease) is difficult to This study was published in the World artificial bladder. The trial, “Phase I Open many Gold Cystoscope awardees have this work, he was awarded the esteemed visualize with white light cystoscopy,” says Journal of Urology. Label Single Center Exploratory Study patients for NAC before sur- been Brady faculty and former residents, AUA Rising Star Award. Matoso, “but blue light cystoscopy, using of Autologous Neo-Urinary Conduits in including: Patrick Walsh, William gery,” Bivalacqua says. photosensitizing agents, improves detection Over time, his clinical and research Subjects Requiring Incontinent Urinary Catalona, Mani Menon, Herbert Lepor, rates” of urothelial cancer, also known as practice shifted to focus on bladder can- Diversion following Cystectomy,” uses “If accurate, they could be used on tumor Louis Kavoussi, Alan Partin, Jeffrey transitional cell carcinoma, the most cer. As the Brady’s Director of Urologic autologous cell-based, engineered tissues obtained at transurethral resection Cadeddu, and William Roberts. common type of bladder cancer. Oncology, Bivalacqua has built a program genitourinary tissue – instead of a of bladder tumor (TURBT) to identify high- “Trinity Bivalacqua defines a translational around multi-disciplinary care of urologic surgically removed section of intestine risk patients who would benefit from In a recent study, Matoso and colleagues surgeon-scientist,” says Partin, Director oncology patients. He heads a translational – to replace the lower urinary tract, to chemotherapy, while low-risk patients might assessed the sensitivity of blue light cys- of the Brady, “and he has made numerous research program in genitourinary cancers reduce complications following surgery. be spared the side effects of chemotherapy.” toscopy, and compared the results with the contributions in two fields – sexual and tissue engineering, using preclinical “This trial was conceived and designed Bivalacqua and Brady urologist Max final pathology diagnoses (see photo). “We dysfunction and urologic oncology.” animal models of disease – in particular, from research performed in the lab, and Kates, M.D., have teamed up with other also focused on cells that looked abnormal transgenic mouse models of bladder cancer was brought to the first in-human clinical After earning a bachelor’s degree in Cell urologists worldwide “to determine in blue light cystoscopy and had a pathology and of . “My research trial in this field,” Bivalacqua says. and Molecular Biology from Tulane whether we can use the molecular diagnosis that was suspicious, but not uses cell culture models of urothelial diagnostic of CIS. We found that blue light University, he entered the M.D./Ph.D. In addition to his clinical and scientific subtypes to help us select patients with carcinoma and genetically engineered cystoscopy allows us to detect CIS that program at Tulane’s School of Medicine. work, Bivalacqua has served on numerous high-risk, non-muscle-invasive bladder rodent models of bladder cancer to study would have been underdiagnosed with the “My Ph.D. thesis described the influence of national committees for the AUA, the cancer who should be offered chemo- the inflammatory and immune responses conventional white light cystoscopy.” Their systemic disease states on dysfunctional Society of Urologic Oncology and Sexual therapy” at the time of radical cystectomy. that mediate development and ultimate results were published in Human Pathology. genes responsible for aberrant vascular Medicine Committee of North America. n “This is necessary,” Bivalacqua explains, progression of urothelial carcinoma.” control of the heart, pulmonary and “because some patients with T1 disease Bladder cancer that invades the muscle penile circulation,” he recalls. Bivalacqua The carcinogen model developed in are actually understaged,” and more wall: Matoso and colleagues recently was the first to show that both gene and Bivalacqua’s lab has led to the first Bladder Immune Molecular or higher-grade cancer is found after completed another study to evaluate the stem cell-based therapies improved preclinical model to study non-muscle the removed bladder is examined by a clinical significance of invasive urothelial penile vascular function in preclinical invasive bladder cancer. Using this Subtypes Can Help pathologist. “This means these patients carcinoma that might be invading the models of erectile dysfunction. model, which has been characterized have more aggressive cancer, and thus muscle wall of the bladder – but again, at the genetic and molecular level, Determine Who May may benefit from chemotherapy prior to “I knew I wanted a career that would allow it might not. “Urothelial carcinoma that Bivalacqua’s team has developed novel radical cystectomy (bladder removal).” Look at the difference a change in light makes! me to combine basic science research with Benefit from Chemotherapy invades the muscle wall has a much intravesical therapies. Recently, they The white light used with conventional cystoscopy clinical responsibilities,” Bivalacqua says. In a study published in European Urology, worse prognosis than cancer that is is on the left; the same views using blue light are developed a genetically engineered, for Urothelial Cancer Urology was a perfect fit, and he “pur- Bivalacqua, Kates, and Hopkins colleagues non-invasive, or that just invades on the right. A and B show a small papillary recombinant BCG that over-expresses a posefully sought out a residency at Johns looked at how various molecular subtypes superficially,” says Matoso. “While most lesion – which really shows up well under blue STING (stimulator of genes) Urothelial cancer, also known as light cystoscopy, highlighted by red fluorescence. Hopkins, due to the Brady’s rich tradition fared when pathologists examined the patients can confidently be diagnosed as agonist, “resulting in enhanced inter- transitional cell cancer, is the most C and D show areas (in red under blue light of training surgeon-scientists in urologic removed bladder specimen – particularly, having either superficial or muscle- feron signaling and greater therapeutic common type of bladder cancer; it’s also cyscoscopy) that need to be biopsied. oncology.” He applied for a postdoctoral at the cancers that turned out to have invasive bladder cancer, there’s a small response than BCG alone.” His work has more complicated, and has more subtle fellowship during his research year in spread beyond the bladder – in a multi- subset of cases that are difficult to classify.” resulted in a patent and licensing of differences from person to person, than residency, and obtained an M.D./Ph.D. institutional cohort of patients with clinical rBCG-STING, “which is soon to be tested scientists used to think. It encompasses In this study, Matoso and colleagues Fellowship from the AUA Foundation T1-T2 bladder cancer who were treated with in a phase 1 clinical trial in patients who several molecular subtypes, “each with looked at invasive urothelial carcinoma – the first resident to do so. In part radical cystectomy. “This study provides have been unresponsive to BCG.” its own distinct clinical and biological that appeared ambiguous for muscle wall because of Bivalacqua’s groundbreaking valuable guidance,” says Bivalacqua. invasion on initial transurethral resection 20 21 WINTER 2020 | DISCOVERY

studies have compared these management these kidney tumors. This is because kid- DISCOVERY IN TESTICULAR CANCER options simultaneously,” notes urology ney cancers suppress the body’s immune Conditional Survival resident Ridwan Alam, M.D., who led a system as they grow and spread.” After Kidney Cancer Much-Needed third recent study, published in the British Can what’s happening to the immune “How long am I going to live?” There’s a Journal of Urology International. The study system in kidney cancer be tracked? Are Guidelines for Treating new way to answer this question, and it’s found that all four management options had there biological footprints that might lend called conditional survival. “The term Testicular Cancer excellent oncological outcomes. “Partial themselves to a test? refers to the improving probability of nephrectomy and ablation were generally “Many urologists may go for preferred over radical nephrectomy, as Quite possibly! The Kidney Cancer surviving long-term after the diagnosis they spare kidney function,” he says. Biomarker Group, headed by Pierorazio, of cancer or another .,” years without treating a single examined the urine of 100 patients with Active surveillance was confirmed to be a says Joseph Cheaib, M.D., postdoctoral patient with testicular cancer.” reasonable option for well-selected either benign tumors, benign-behaving researcher in the Brady. kidney cancer, or aggressive kidney can- patients with comparable mental health Cheaib recently evaluated the conditional The long-term survival for a man cer, and found a number of lactose-con- and oncologic outcomes. “We also found survival of patients with kidney cancer, diagnosed with testicular cancer is excellent taining molecules that could differentiate that mental and emotional health im- using the national SEER database and the – about 95 percent – thanks to good these groups. “Importantly, these lac- Allaf and Pierorazio: “Understanding the emotional and psychological stresses involved with having a small proved over time for patients undergoing records of about 3,000 patients in the Johns treatment, including chemotherapy and renal mass are just as important as an assessment of a patient’s physical health.” tose-containing molecules were cell-sur- immediate surgery and active surveillance.” Hopkins database. “We found a stage- retroperitoneal dissections. patients who chose surgery to treat face antigens – tiny sugar molecules used “However, the disease is relatively rare,” DISCOVERY IN KIDNEY CANCER “Understanding the emotional and psycho- specific conditional survival,” he explains. their small renal mass. They generated by the immune system to identify good says Phillip Pierorazio, M.D., Director of logical stresses involved with having a “In particular, patients with advanced kidney a DISSRM Score, incorporating age, from bad cells,” says Pierorazio. the Brady’s Division of Testicular Cancer, Physical, Mental Health small renal mass are just as important as an cancers had a greater probability for long- tumor size, and other medical issues. Scientist Jelani Zarif, Ph.D., and colleagues “with only about 9,000 men diagnosed with assessment of a patient’s physical health,” term survival for every year they survived and Active Surveillance “Importantly,” notes Allaf, who holds the evaluated the role of macrophages in the it in the U.S. every year. Many urologists says Pierorazio, “we want patients to be after the diagnosis of kidney cancer.” Mohamad E. Allaf Directorship in Minimally development of early to aggressive forms may go for years without treating a single for Kidney Cancer confident in their choices. If they choose Cheaib’s findings, recently published in Invasive Surgery, “the DISSRM Score also of kidney cancer. “Macrophages are patient with testicular cancer, and there surveillance, we want them to safely and Seminars in Urologic Oncology, indicate “Half of the patients who chose incorporated how patients felt about their immune cells that engulf and digest has been little guidance on treating testicular assuredly remain in the program.” n that patients with stage I and II kidney own physical health – their ability to cellular debris, bacteria – and, in some cancer for the average urologist.” delayed intervention did so cancer did not experience a conditional perform moderately strenuous activities circumstances, cancer cells,” Zarif explains. survival – because they consistently That’s no longer the case. In May, the because their cancer grew or like pushing a vacuum cleaner or playing But certain types of macrophages, called survive at about 98 percent and 90 percent, American Urological Association (AUA) golf.” Asking patients about their physical M2, can actually promote cancers by changed; the other half decided to Potential Biomarker respectively, no matter how long they are released its first-ever guidelines for the health “may be an important step suppressing the immune system around a followed. Patients with metastatic kidney management of early-stage testicular have surgery because of anxiety in assessing suitability for surveillance,” for Kidney Cancer: malignant cell. Zarif’s study, reported in cancer showed the greatest increase in cancer. The AUA Guidelines include 45 says Patel. “A patient’s perception of European Urology Oncology, found more or uncertainty about their cancer. The Immune System? survival, increasing from 23 percent to statements to direct the diagnosis and physical health takes into account age macrophages and more immunosuppression 59 percent, and 31 percent to 76 percent management of men with early-stage “The good news is that none of and other medical issues, and it’s easy for in kidney cancer cells than in the normal Can what’s happening to the over a five-year period in the SEER and testicular cancer – and each of those patients and physicians to understand.” surrounding kidney tissue. these patients had a recurrence immune system in kidney cancer Johns Hopkins datasets, respectively. statements is supported by evidence Physical health is just one part of the Scientist Richard Zieran, M.D., Ph.D., and from the Evidence-based Practice Center of cancer.” “These data have two important assessment of patients with small renal be tracked? Are there biological colleagues are evaluating nano-vesicles (EPC) at Johns Hopkins, led by Eric Bass, implications for our kidney cancer masses. In another study, published in in the blood and urine of patients with M.D., M.P.H. The EPC team – made up of Who’s the ideal patient for active footprints that might lend them- survivors,” says Phillip Pierorazio, M.D., Urologic Oncology, Mohit Gupta, M.D., kidney cancer. “Traditionally, researchers Bass, Pierorazio, and Brady residents and surveillance for a small kidney cancer? selves to a test? Quite possibly! the study’s senior author. “First, for urologic oncology fellow, and colleagues thought these were the ‘trash cans’ of cells,” fellows – evaluated hundreds of medical “Although we have made significant strides patients with early-stage disease: once evaluated patients who enrolled in active says Zieran. “But we are increasingly manuscripts about testicular cancer and in our understanding of active surveillance There’s no PSA equivalent for detecting or they undergo curative surgery, we can surveillance but later went on to have finding evidence that these nano-vesicles generated five reports, on topics including for these patients, there are no universally monitoring kidney cancer. Brady investi- limit the extent of follow-up imaging surgery. “About 15 percent of patients in actually contain valuable information in the proper diagnostic and staging tests for accepted criteria for selecting patients,” gators, supported by funding from Brady after a relatively short period of time. active surveillance later choose surgery,” the form of proteins and nucleic acids. testicular cancer patients, the comparative says urologist Phillip Pierorazio, M.D., Advisory Board members Patricia and And for patients with advanced cancer, says Gupta. “We found that half of these They are a form of communication effectiveness of surveillance, chemotherapy, who with urologist Mohamad Allaf, M.D., Kevin Kiernan, are hoping to change that. it is very encouraging to see that our Ph.D., began the Delayed Intervention patients who elected delayed intervention between cells.” Zieran’s early work, radiation and surgery, surveillance after They have been building an understanding treatments are getting more and more and Surveillance for Small Renal Masses did so because their small renal mass grew presented at the American Association therapy, and survivorship for men with of kidney cancer biomarkers and, in the effective. This is an incredibly hopeful (DISSRM) Registry at the Brady 10 years or changed in a manner suspicious for for Cancer Research’s meeting in Atlanta, early forms of the disease. process, learning much more about the time for patients with metastatic cancer. But the other half elected to have suggests that cancer cells may produce ago. “However, recent studies led by kidney cancer!” n “This was a much-needed guideline for surgery because of anxiety or uncertainty disease. “When we started looking for Brady trainees have highlighted the more vesicles than healthy cells, and thus the standardization of testicular cancer about their cancer.” The good news is that kidney cancer biomarkers, we thought importance of physical and mental health influence the tumor environment. care in the U.S. and around the world,” none of the patients who underwent we would find sugars and proteins in the as determining factors.” “As we learn more about the immune says Pierorazio. “We are confident delayed surgery had a recurrence of cancer. urine or blood that were released by the In one study, published in the Journal of cancerous cells,” says urologist Phillip system, we believe we are getting closer this will translate into improved care Urology, Brady Chief Resident Hiten Patel, In addition to active surveillance, treatment Pierorazio, M.D. “It turns out, we are more to finding the elusive biomarker that will and outcomes for testicular cancer M.D., and colleagues compared 410 patients options for small renal masses include likely to detect sugars and proteins that help us diagnose and guide treatment patients everywhere.” n who chose active surveillance with 341 partial nephrectomy, radical nephrectomy, describe the immune system’s response to for many patients with kidney tumors,” and thermal ablation of the tumor. “Few says Pierorazio. n 22 23 Discovery is published by THE JAMES BUCHANAN BRADY UROLOGICAL INSTITUTE Johns Hopkins Medicine 600 North Wolfe Street, CMSC 130 Baltimore, Maryland 21287-2101 410.955.8434 www.hopkinsmedicine.org/brady-urology-institute

Patrick Walsh, M.D. University Distinguished Service Professor of Urology Emeritus

Janet Farrar Worthington Writer/Editor Laura LeBrun Hatcher Design & Art Direction Keith Weller Principal Photography

Every Man Needs This Book. Each year, more than 160,000 American men are diagnosed with prostate cancer. The good news is that more men are being cured of this disease than ever before.

Now in a revised fourth edition, this lifesaving guide – Amazon’s #1 Bestseller in Men’s Health for 24 years – by renowned expert Dr. Patrick Walsh and acclaimed science writer Janet Farrar Worthington offers a message of hope to every man facing this illness. Prostate cancer is a different disease in every man—which means that the right treatment varies for each man. Giving you a second opinion from the world’s top experts in surgery, pathology, urology, and radiation and medical oncology, this book helps you determine the best plan for you. Learn: • What causes prostate cancer: your risk factors, including heredity, diet, and environment • Why African American men are more vulnerable, and what they need to know FOURTH EDITION • Which simple changes in your diet and lifestyle can help prevent or delay the disease What you need to know • Why the digital rectal exam and PSA test can save your life—and how newer about prostate cancer: blood tests and imaging make the diagnosis more accurate Revised and updated with • New treatment guidelines that enable many men to safely undergo active surveillance and delay treatment the latest advances in surgery, radiation, and • Advances in radiation and surgery that save lives and reduce side effects precision oncology. • Breakthroughs in the treatment of advanced cancers such as gene- and immunotherapy that are prolonging life and offering new hope