UT Southwestern. Harold C. Simmons Cancer Center Partners in Progress: Treating GU Cancers

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1 UT Southwestern Harold C. Simmons Cancer Center Partners in Progress: Treating GU Cancers

2 2 Letter 4 GU cancer overview 10 Better bladder cancer detection strategies 12 Transforming prostate care 15 Mutations in kidney cancer 17 MRI innovations 19 Robotics, laparoscopic techniques in urologic surgery 21 Biomarkers and bladder cancer outcomes 24 Novel therapies in prostate cancer treatment 27 Surgery-less surgery 29 Promising SABR technique 32 Holistic approach to care 36 Clinical trials 38 Faculty UT Southwestern is committed to the fight against genitourinary cancers. Through multidisciplinary teamwork, collaborative research, advanced care, and technology, we offer patients and referring physicians partnership in the future of cancer care, today.

3 2 P A R T N E R S I N P R O G R E S S 3 Friends and colleagues We would like to take this opportunity to update you on the many activities and trends taking place within our Genitourinary Cancers Program at UT Southwestern Harold C. Simmons Cancer Center. This program is a partnership that incorporates many departments across UT Southwestern Urology, Pathology, Internal Medicine, Radiology, and Radiation Oncology. Together, we are making a difference in the lives of patients today and working diligently to find the best treatments for the patients of tomorrow. Oncology needs in North Texas are growing. For us, taking care of such a large number of patients with cancer is a privilege and a mandate. The mandate is to work tirelessly as a team to study new ways for prevention, to fine-tune the methods for early detection, and to improve the treatments for both early and late stages of the disease. While the challenges are common for all cancers, there are unique challenges for each GU cancer. In this report, we narrow in on three GU cancers in particular prostate, kidney, and bladder. The research-to-patient-care continuum is so palpable in these areas, and it excites us to be able to share our progress with our patients, the public, and our referring physician partners. At UT Southwestern, the physicians, nurses, and staff across the different departments who are engaged in the treatment of GU cancers are unified in their efforts and come together as a team to provide each patient with the best advice and consultation, leading to the most appropriate treatment plan and outcomes. It gives us great pride to note that this report focuses on those men and women who dedicate their research and clinical careers to the care of the ever growing numbers of patients with cancers of the urinary and male genital systems. Our wish is that the reader whether a health care provider, a patient, or a member of the general public will derive knowledge and comfort from this report, learn more about what we do here, and become our partner as we continue our progress in the research and treatment of cancer. James K.V. Willson, M.D. Director, Harold C. Simmons Cancer Center Claus Roehrborn, M.D. Chair, Department of Urology

4 4 P A R T N E R S I N P R O G R E S S 5 Experience, expertise, and excellence Cancer is, by and large, an illness of the aged. Half of all malignancies of the prostate and the rest of the male genital system, for instance, are diagnosed at age 68 or older; for cancers of the urinary system, the median age is 70. Amplifying that fact within the health care system is the collision of two demographic trends. First, due in great extent to improvements in care for cardiovascular diseases, senior citizens are living longer: Since 1970, life expectancy at 65 has increased by four years, from about age 80 to 84. And in 2011 the massive baby boomer generation, representing about one-quarter of the U.S. population, began entering its golden years. This increasing need for oncology services is further fueled by overall population growth in the U.S. and worldwide including soaring numbers in North Texas. Just between 2000 and 2010, Dallas County s population grew by 6.7 percent, Tarrant County s by 25.1 percent, Denton County s by 53 percent, and Collin County s by 59.1 percent. Combined, those four counties gained more than 1 million people, growing from 4,589,769 residents to 5,622,128. The entire 12-county area that UT Southwestern Harold C. Simmons Cancer Center serves encompasses 6.7 million people. As oncology needs in North Texas expand, so does Simmons Cancer Center. Founded in 1989, the Cancer Center has grown to offer 13 major cancer care programs, including a urologic program providing cutting-edge treatment, guidance, and support for genitourinary malignancies. In addition, in 2010, the Cancer Center earned National Cancer Institute designation, a prestigious accolade that acknowledges excellence in clinical care as well as leadership in research and education. NCI designation recognizes institutional commitment to innovation and collaboration, investment in the latest technologies, and recruitment of nationally recognized research and clinical experts U.S. population data New cancer cases Deaths Prostate 238,590 29,720 Testis 7, Penis & other genital, male 1, Urinary bladder 72,570 15,210 Kidney & renal pelvis 65,150 13,680 Ureter & other urinary organs 2, Estimated 2013 new cancer cases Males Females Prostate 238,590 28% Breast 232,340 29% Lung and bronchus 118,080 14% Lung and bronchus 110,110 14% Colorectum 73,680 9% Colorectum 69,140 9% Urinary bladder 54,610 6% Uterine corpus 49,560 6% Melanoma of the skin 45,060 5% Thyroid 45,310 6% Kidney & renal pelvis 40,430 5% Non-Hodgkin lymphoma 32,140 4% Non-Hodgkin lymphoma 37,600 4% Melanoma of the skin 31,630 4% Oral cavity & pharynx 29,620 3% Kidney & renal pelvis 24,720 3% Leukemia 27,880 3% Pancreas 22,480 3% Pancreas 22,740 3% Ovary 22,240 3% All Sites 854,790 All Sites 805,500 Estimated 2013 cancer deaths Males Females Lung and bronchus 87,260 28% Lung and bronchus 72,220 26% Prostate 29,720 10% Breast 39,620 14% Colorectum 26,300 9% Colorectum 24,530 9% Pancreas 19,480 6% Pancreas 18,980 7% Liver & intrahepatic bile duct 14,890 5% Ovary 14,030 5% Leukemia 13,660 4% Leukemia 10,060 4% Esophagus 12,220 4% Non-Hodgkin lymphoma 8,430 3% Urinary bladder 10,820 4% Uterine corpus 8,190 3% Non-Hodgkin lymphoma 10,590 3% Liver & intrahepatic bile duct 6,780 2% Kidney & renal pelvis 8,780 3% Brain & other nervous system 6,150 2% All Sites 306,920 All Sites 273,430 Death rates for cancer and heart disease Rate per 100,000 population Younger than 85 years Cancer Heart disease 8,000 7,000 6,000 5,000 4,000 3,000 2,000 1,000 Source: CA: A Cancer Journal for Clinicians, Volume 63, Issue 1 85 years and older Heart disease Cancer Total 388,510 60,190 Source: CA: A Cancer Journal for Clinicians, Volume 63, Issue Year of death Year of death Source: CA: A Cancer Journal for Clinicians, Volume 61, Issue 4

5 6 P A R T N E R S I N P R O G R E S S 7 Depth of experience The array of expertise at UT Southwestern is brought to bear every day on a range of cancers, including those of the prostate, kidneys, bladder, ureters, testes, and penis and urethra. Genitourinary cancers accounted for about 388,000 of the 1.6 million estimated cancer cases in the U.S. in 2013, and for about 60,000 cancer deaths. The three most common genitourinary cancers prostate, kidney, and bladder represent the most, fourth-most, and sixth-most common cancers in men, respectively. Furthermore, kidney cancer is the eighth-most common cancer in women. In 2010, prostate cancer was newly diagnosed in more than 11,000 men in Texas including about 2,300 in Dallas, Tarrant, Denton, and Collin counties while about 3,400 patients were diagnosed statewide with bladder cancer and more than 4,100 with kidney cancer. At Simmons Cancer Center, patients benefit not just from the knowledge of the university s renowned clinicians and researchers, but also from the experience that comes with treating hundreds of cases of genitourinary cancer each year. These cancers account for about 25 percent of the total cancer cases seen and treated at UT Southwestern. Overall, from 2008 to 2012, the total number of new cancer cases treated at the center increased from 2,649 to 3,634 while the number of new genitourinary cancer cases treated at the center increased from 658 to 934. As a vital regional hub for treatment of genitourinary cancers, Simmons Cancer Center in 2012 cared for 560 men with prostate cancer, 250 patients with kidney cancer, and 163 people with bladder cancer. Given the large number of oncology providers in North Texas, those percentages translate into a concentration of wellexperienced hands at UT Southwestern. That high volume gives everyone in radiation oncology, oncology, and urology a great deal of expertise in those cancers, says Claus Roehrborn, M.D., Professor and Chair of Urology, adding that UT Southwestern has, for instance, one of the region s highest volumes of patients treated with robotic prostatec tomies. For men considering that procedure, experience is a foremost consideration, he says. The second thing after patients say hello is they ask, How many procedures have you done? Statistics by region of the three most common genitourinary cancers U.S., 2013 Texas, 2010 Expected new cases New cases 12-county catchment area,* 2010 New cases Prostate 238,590 11,016 2,636 Urinary bladder 72,570 3, Kidney & renal pelvis 65,150 4,155 1,004 *Simmons Cancer Center s 12-county catchment area comprises Collin, Dallas, Delta, Denton, Ellis, Hunt, Johnson, Kaufman, Parker, Rockwell, Tarrant, and Wise counties in Texas. GU cancers vs. all cancers at UT Southwestern Number of patients 4,000 3,500 3,000 2,500 2,000 1,500 1, GU cancers by disease site at UT Southwestern Cancer center total Genitourinary Prostate Kidney Urinary bladder Other male genital Other urinary Source: UT Southwestern

6 8 P A R T N E R S I N P R O G R E S S 9 Integrated care As a major referral center, the Cancer Center can offer anything from a consultation or second opinion to a full workup and access to many of the most advanced treatments available, as well as a wealth of supportive care. For referring physicians, UT Southwestern is here to back you up, Dr. Roehrborn says. Whether a malignancy is suspected, or a patient has already been diagnosed with an early, intermediate, or advanced genitourinary cancer, an appointment at Simmons Cancer Center will set into motion a process to best address each patient s needs, enlisting expertise in the departments of Urology, Radiation Oncology, Internal Medicine, Medical Oncology, and Pathology. Those care teams are composed of specialists in genitourinary malignancies. In addition, all these practitioners are fully interconnected with a sophisticated electronic records system, meaning any care provider can readily access treatment, imaging, and other records from any of the university s hospitals or outpatient clinics. That facilitates consultation between disciplines, allowing providers to quickly and simultaneously review a patient s records and other data. The team approach is especially valuable in complex cases, which are formally analyzed at multidisciplinary meetings involving clinicians and researchers with expertise specific to the cancer site. In such cases, sometimes the best option is available only through a clinical trial, an array of which are offered at the Cancer Center. For instance, UT Southwestern investigators, who are at the forefront of identifying novel prostate cancer therapeutic targets, are testing new medicines to treat patients across the disease spectrum. Also, pioneering research at the university could lead to an entirely new class of medicines for prostate and other cancers. Cancer s challenges Even for less-complex cases, specialized expertise is essential to improve cancer outcomes and minimize any negative effects of treatment. In prostate cancer, for instance, a key focus at UT Southwestern is to reduce treatment of harmless cancers and improve identification of aggressive cancers requiring treatment, while developing new approaches, in areas such as highintensity focal ultrasound, that could yield fewer side effects than traditional radiation or surgery. Another key area of progress: the fusion of traditional and advanced imaging to improve the accuracy of prostate biopsies and enable doctors to monitor changes in prostate cancers over time. Ongoing research at the Cancer Center is tackling other challenges in genitourinary cancers, including how best to screen asymptomatic people for bladder cancer and to detect the disease early in symptomatic patients, and how to identify which bladder cancers are likely to recur or become fatal. In kidney cancer, physicianscientists are devising nonsurgical techniques to treat tumors in patients who can t withstand surgery; are identifying new genetic differences among tumors and developing animal models for early testing of targeted drug therapies; and are improving capabilities to noninvasively diagnose and monitor tumors through advanced MRI approaches. Innovations in radiotherapy pioneered at UT Southwestern, meanwhile, may someday help patients with metastatic prostate and kidney cancer. For each individual patient, these efforts mean that the latest scientific knowledge and clinical know-how are marshaled every day to deliver highly personalized care. UT Southwestern has vast resources, and vast experience, Dr. Roehrborn says, and we bring them all together for you. We believe: The only way to care for fellow human beings is in a manner in which oneself would wish to be cared for Every man, woman, and child regardless of cultural, ethnic, and socioeconomic background deserves the very best health education and health care achievable Excellence in clinical medicine is based on excellence in basic and translational research Basic and translational research are inspired by clinical needs Education of students, residents, and fellows, and continuing education of physicians, is the foundation for a healthier tomorrow

7 10 P A R T N E R S I N P R O G R E S S 11 Urologists devise better strategies for detecting bladder cancer sooner When a patient has blood in the urine, it s rarely because of bladder cancer. Still, hematuria the most common presenting sign for bladder cancer occurs in about 90 percent of cases and warrants careful investigation. Balancing the rarity of bladder cancer with the potential importance of hematuria in a way that increases early cancer detection, while minimizing patients exposure to invasive testing, is a critical goal of urologic research and practice at UT Southwestern and Harold C. Simmons Cancer Center. One essential step is to ensure that patients most at risk for bladder cancer are referred for further testing. UT Southwestern research has shown that even when key risk factors for bladder cancer are present age 50 or older and more than 10 years of smoking or 15 years of risky occupational exposure relatively few patients with hematuria are referred for cystoscopy and upper urinary tract imaging, as called for by American Urological Association guidelines. When bladder cancer is finally detected this way, about one-quarter of patients already have muscle-invasive disease, says Professor of Urology Yair Lotan, M.D., Chief of Urologic Oncology. Even after bladder removal, half those patients won t survive five years, he says. Detection biomarkers Researchers at UT Southwestern hope that biological markers molecules detectable in bodily fluids can pinpoint who should undergo further testing. with several other urine-based, noninvasive tests for bladder cancer and to see whether the addition of the aurora kinase A test can enhance the detection capability of BladderChek combined with specific disease features. Several other studies are evaluating novel markers, as well. The real problem, Dr. Lotan says, is there isn t an optimal urine marker to detect bladder malignancies. We re trying to further study more sophisticated markers than the current FDA-approved ones and to improve the likelihood that patients are appropriately evaluated. Screening challenges Focusing on patients with blood in their urine, Cancer Center researchers are combining use of a urine test called BladderChek, which detects higher levels of the protein NMP22, with patient characteristics that signal a higher risk of bladder cancer: male gender, advanced age, Caucasian heritage, presence of visible versus microscopic blood in the urine, and a smoking history. The researchers hope to see whether a physician could combine NMP22 results with that high-risk profile and determine who should be referred to a urologist without delay. The team has enrolled almost 400 patients across three centers. Timely bladder cancer detection is essential because no reliable, broad-based screening test is yet recommended. The key is to focus on at-risk populations to increase the yield of screening and reduce the number of patients who have to be tested. One UT Southwestern project to develop a screening procedure, which used BladderChek to test 1,500 at-risk men and women who smoked, found only three people with bladder cancer not enough of a yield to know whether this is a good idea to apply to the general population, Dr. Lotan says. Other detection efforts at UT Southwestern are helping to compare fluorescence in situ hybridization testing for an overabundance of the aurora kinase A gene Yair Lotan, M.D., was the first in North Texas to perform a robotic cystectomy. He and other UT Southwestern researchers are looking for ways to increase early detection of bladder cancer.

8 12 P A R T N E R S I N P R O G R E S S Researchers are now designing a larger study with a focus on male smokers with at least a 30 pack-year history and will probably look for previously undetected blood in the urine, and use a panel of urine-based tumor markers as a secondary test. Currently, three times as many men develop bladder cancer as women. This gender difference in bladder cancer is not understood, Dr. Lotan says. There s some increased occupational exposure in men, but not enough to explain a threefold difference in cases. Meanwhile, the message for patients especially men who have smoked or had a job involving industrial chemicals is that blood in the urine should always be investigated until its cause is found. Researchers at UT Southwestern hope that biological markers, molecules detectable in bodily fluids, can pinpoint who should undergo further testing Leading-edge technologies transforming prostate care Innovations using magnetic resonance imaging and ultrasound are bringing new levels of precision to prostate cancer care. That precision starts with the biopsy. Currently, most biopsy procedures are guided by the use of transrectal ultrasound (TRUS), which yields only limited images of the prostate. But a new technique combining TRUS with advanced MRI is providing clearer, three-dimensional views of the gland and helping urologists single out potentially cancerous areas. Better ways to biopsy In the past, MRI has not been used widely to assess prostate cancer because standard morphological imaging, with T2-weighted sequences alone, doesn t provide enough information to diagnose or stage tumors, says Associate Professor of Radiology Ivan Pedrosa, M.D. But two new approaches have entered the picture. One is diffusion-weighted imaging, which detects differences in the movement of water molecules in different tissues. Prostate cancer tends to restrict the motion of water molecules, compared with benign prostate tissue, and these differences allow doctors to identify cancerous areas in the prostate. The Daniel Costa, M.D. (left), and Rajiv Chopra, Ph.D., are radiologists helping to develop techniques for more accurate diagnosis and precise treatment of prostate cancer. other, dynamic contrast-enhanced imaging, is a rapid-fire series of images that capture how a contrast agent washes in and out of the prostate. Cancers tend to wash in and wash out rapidly, whereas normal prostatic tissue washes in and out slowly, Dr. Pedrosa says. Based on those contrast kinetics, we can distinguish between benign prostatic tissue and cancer. More parameters, better targeting Physicians at UT Southwestern and Simmons Cancer Center are uniting these strategies in a multiparametric approach. The combination of the three techniques T2-weighted, diffusion-weighted, and contrast-enhanced images has a much higher sensitivity and specificity to detect and stage a tumor, Dr. Pedrosa says. The radiologists use a powerful 3 Tesla field and an endorectal coil to maximize the MR signal and produce higher-resolution images. For biopsies, Dr. Pedrosa and colleagues including Professor and Chairman of Radiology Neil Rofsky, M.D., and Assistant Professor of Radiology Daniel Costa, M.D., have worked with the Department of Urology to implement a technology to fuse those MRI images, with suspicious areas annotated, to the foggier ultrasound images. This approach allows you to see the target area during the TRUS biopsy even when ultrasound images do not show the lesion, Dr. Pedrosa says. This provides the urologists with the opportunity to sample such areas in addition to regions they

9 14 P A R T N E R S I N P R O G R E S S 15 would routinely sample, in some cases detecting tumors missed by repeated, standard biopsies. MRI-TRUS fusion biopsies for the first time allow us to perform targeted biopsies of areas of high suspicion rather than randomly biopsying the entire prostate, notes Professor and Chairman of Urology Claus Roehrborn, M.D. Such cutting-edge approaches to identifying and monitoring prostate cancers are of growing importance as more and more men seek minimally invasive treatments, or active surveillance and treatment postponement, he says. High-intensity focal ultrasound Another innovation, a minimally invasive treatment using ultrasound, might someday be an alternative to radical therapies for low-risk disease. The approach, called high-intensity focal ultrasound (HIFU), could also benefit patients too frail to withstand other therapies. Unlike radiation, ultrasound energy can be focused in the body to heat cancerous tissue and kill it, while sparing surrounding normal tissue. Twenty degrees [Celsius] above normal is all you need to kill cells, says Associate Professor of Radiology Rajiv Chopra, Ph.D. HIFU can target the whole prostate, or be focused on areas of the gland where tumors are identified with imaging. That potential for focal therapy is where a lot of the excitement is, Dr. Chopra says. Furthermore, HIFU treatments are single session, and typically performed in an outpatient fashion. The transurethral advantage Phase III trials have been investigating HIFU delivered to the whole prostate via the rectum. Dr. Chopra s work focuses on a newer approach, through the urethra. Studies so far are preliminary, but it appears the transurethral approach will prove more efficient, with treatment times of 20 to 30 minutes instead of several hours. Also, because the transurethral approach delivers treatment from inside the prostate, it may be likelier than some other treatments to avert damage to sensitive tissues around the prostate, minimizing side effects like incontinence and erectile dysfunction. While transrectal HIFU is aided by ultrasound imaging, Dr. Chopra is developing the use of 3 Tesla MRI to better guide transurethral HIFU increasing the accuracy of the treatment to the order of millimeters. Further, performing the transurethral procedure in the MRI also enables the diagnostic power of MRI to be harnessed for locating tumors in the gland for treatment. But the best uses of the technology are still being determined, Dr. Chopra notes. This is an evolving field, but clearly headed in the direction of merging diagnostic information into treatments for a more targeted approach to cancer treatment. Discoveries prompt new kidney cancer treatments Among the 3 billion letters in the human genome, some 3,000 to 6,000 are amiss in renal cancer. But merely five to 10 misspellings in critical genes trigger kidney cancer development. Research groups worldwide are working to identify these. As part of that quest, investigators at UT Southwestern and colleagues have discovered one of the mutated genes, BAP1. In a manuscript published in 2012 in Nature Genetics, Associate Professor of Internal Medicine and Developmental Biology James Brugarolas, M.D., Ph.D., leader of the Kidney Cancer Program at Harold C. Simmons Cancer Center, reported that BAP1 mutations define a new type of renal cancer. BAP1-mutated tumors account for 15 percent of kidney cancers. Interestingly, these tumors tend not to have mutations in another gene, PBRM1, which is mutated in 50 percent of renal cancers. In a study published in Lancet Oncology, Dr. Brugarolas team reported that these mutations are associated with markedly different outcomes. BAP1-mutated tumors are aggressive: Life expectancy is about half that of patients with PBRM1-mutated tumors. These discoveries set the foundation Discoveries in the lab of James Brugarolas, M.D., Ph.D., are bridging the gap between research and personalized medicine for kidney cancer patients.

10 16 Immunohistochemical sections of kidney tumors show (A) a typical kidney tumor, with dot-like brown staining indicative of P A R T N E R S I N P R O G R E S S 17 normal expression of the BAP1 protein in cell nuclei; and (B) a lack of the protein, as depicted by absence of brown staining, in BAP1-mutated tumors, which are more aggressive. A for a modern classification of kidney cancer in which risk is assessed by the genetic mutations. Of 60,000 Americans diagnosed each year with kidney cancer, about one-third present with metastatic disease. Another third who initially present with cancer localized to the kidney will, despite surgery, have a recurrence or develop metastases all pointing to an urgent need for better drugs. Until 2005, just one drug was available for metastatic kidney cancer. But important discoveries about mutations in kidney tumors have led to the development and approval of seven drugs since. From a historical perspective, the progress has been incredible, Dr. Brugarolas says. Genetic underpinnings Five of the newer, targeted therapies are rooted in the landmark identification two decades ago of a gene called VHL, which is mutated in the majority of kidney cancers. Discovery of a second pathway, governed by a protein called mtor, paved the way for two additional drugs. B Patients can have the genetics of their tumors analyzed and interpreted The UT Southwestern BAP1 study is the latest milestone on kidney cancer s molecular map. The discovery that kidney cancer can be divided into two different subtypes (based on BAP1 and PBRM1 status) is likely to have a major impact, Dr. Brugarolas notes. This finding paves the way for the development of the next generation of treatments. Work spearheaded by Payal Kapur, M.D., Associate Professor of Pathology and Urology, has led to the development of a clinical laboratory test that identifies patients with BAP1-mutant tumors. Meanwhile, Dr. Brugarolas team has shown that another gene, TSC1, is also mutated in kidney cancer. While TSC1 mutations are infrequent, occurring at a rate of about 5 percent, they appear to identify patients who will derive the greatest benefit from drugs that target mtor. Improving preclinical models Dr. Brugarolas lab is also honing animal models of kidney cancer to ensure that more than just a fraction of drugs in development turn out to be successful. We don t have good models that reproduce what happens in patients, he says. Currently, fewer than 10 percent of anticancer drugs that score well in preclinical models and are taken into clinical trials show activity in humans and are eventually approved. The researchers are implanting kidney tumor samples from patients into kidneys of immune-compromised mice. The samples grow to form tumors with identical features to the source tumors. As reported in Science Translational Medicine last year, Dr. Brugarolas team found that the tumors in the mice respond to treatment in the same way that tumors in patients do. All this research has clear clinical benefits for patients at UT Southwestern, allowing them to profit from the latest discoveries. They can have the genetics of their kidney tumors analyzed and interpreted, and their tumors can be studied in mice. These approaches may complement personalized therapy in the future. MRI innovations help determine renal tumors threat Small renal masses are commonly found on routine imaging, but up to 20 or 30 percent are benign. Currently, imaging can t differentiate malignant from benign tumors. But innovations in magnetic resonance imaging (MRI) may provide a noninvasive way to help physicians discern which patients renal tumors are probably malignant, possibly warranting surgical removal, and which are more likely to be benign and could be biopsied first. For localized cancers, UT Southwestern radiologists are varying imaging parameters for MRI and the way contrast agents are administered to capture different characteristics of the cancer. Some sequences will detect fluid better; others, fat; still others, blood products or other features such as the amount of blood flow in the tumor. A B (A) Patient with metastatic clear cell renal cell carcinoma to the left posterior abdominal wall demonstrating very high blood flow (see arrow) on arterial spin labeling (ASL). (B) One week after combination therapy with sorafenib and bevacizumab, the mass is stable in size but demonstrates marked decrease in blood flow on ASL imaging (see arrow), indicative of the successful antiangiogenic effect of the therapy.

11 P A R T N E R S I N P R O G R E S S 19 Ivan Pedrosa, M.D. [pictured with MRI technician Elizabeth Murray, A.R.R.T. (R)(M)(MR)] is studying the use of MRI as a noninvasive way to help determine malignancy in renal tumors. The combination of those MRI sequences provides us with a number of features of these tumors, says Associate Professor of Radiology Ivan Pedrosa, M.D., Chief of MRI at UT Southwestern and a member of Harold C. Simmons Cancer Center. When we combine all those features into patterns, we can provide information about the renal masses that we didn t have before and can suggest histological diagnosis. The diagnostic advantages of MRI Such feature analysis might allow physicians to triage patients sparing those who are more likely to have a benign kidney tumor the rush to surgery while sparing others the cost, time, and pain of a biopsy when their malignant tumors would need surgery anyway. Another advantage of MRI is that it can analyze an entire tumor, not just small samples of it, as a biopsy does. For this reason, although biopsy remains the reference standard for providing a histopathologic diagnosis, MRI can play a complementary role in the diagnosis of some tumors. For metastatic tumors, an MRI technique called arterial spin labeling (ASL), which measures blood flow into tissue, is helping to gauge the efficacy of antiangiogenic drugs, which starve a tumor by inhibiting the growth of blood vessels nourishing it. For one such drug, examined in a study in which Dr. Pedrosa was a co-investigator, tumor changes detected by ASL within a month of treatment predicted response at four months. Work is proceeding with other, similar drugs, Dr. Pedrosa says. Besides its immediate potential benefit to patients, Dr. Pedrosa says the research gives us the opportunity to better understand the heterogeneity of renal cancer and the genetic alterations that drive growth and aggressiveness of these tumors. Innovations in magnetic resonance imaging (MRI) may provide a noninvasive way to help physicians discern which patients renal tumors are probably malignant Robotics, laparoscopic techniques enhancing urologic surgical options In the quest for greater surgical precision, robots with highly flexible limbs and sophisticated eyes are lending urologic surgeons a hand and enabling the most minimally invasive procedures ever. The latest generation of robots can provide high-definition, three-dimensional views from inside the body, filter out hand tremors, and make minuscule maneuvers possible, all through just a few incisions about an inch long. Instead of our hands controlling surgical instruments, the robot controls the instruments, and we control the robot, says Vitaly Margulis, M.D., Assistant Professor of Urology, one of six surgeons at UT Southwestern and Harold C. Simmons Cancer Center who use robotic systems in urologic surgery. The use of smaller incisions translates into quicker recovery, allowing people who need further treatment, such as chemotherapy, to get it sooner. That can have a real impact on the overall success of treatment, Dr. Margulis says. Other UT Southwestern surgeons who perform minimally invasive and robotic

12 20 P A R T N E R S I N P R O G R E S S About 400 to 500 robotic surgeries are performed at UT Southwestern each year for genitourinary cancers surgery are Professor and Chairman of Urology Claus Roehrborn, M.D.; Professor of Urology and Radiology Jeffrey Cadeddu, M.D.; Chief of Urologic Oncology Yair Lotan, M.D.; Associate Professor of Urology Ganesh Raj, M.D., Ph.D.; and of Urology Jeffrey Gahan, M.D. About 400 to 500 robotic surgeries are performed at UT Southwestern each year for genitourinary cancers. Toward greater flexibility, precision Robotic systems are used widely in prostate cancer operations, as well as for many cancers of the kidney, bladder, and adrenal gland, and can also be used in early cases of testicular cancer, says Dr. Margulis. Even partial kidney removal, a highly complex procedure, can now be done robotically. According to Dr. Margulis, the robotic instruments have almost unparalleled flexibility. The standard laparoscopic instruments are like chopsticks; they can move in two dimensions. The robotic instruments can bend or contort to pretty much any angle you want, he says. In skilled surgical hands, that flexibility equals precision, which can mean less collateral damage: for instance, a speedier return of continence and sexual function after prostatectomy. Or, in a kidney tumor resection, the preservation of more healthy tissue. Where no robot has gone before Still, robotic surgery isn t always an option. Open surgery is necessary, for instance, if scar tissue is present from extensive prior surgery. Surgeons at UT Southwestern are experienced in all approaches. UT Southwestern is also a leader in single-port surgery, conducted by robot or by hand with a few incisions at the navel. Dr. Cadeddu was the first U.S. surgeon to remove a patient s kidney using that approach. The procedure, usually used for conditions other than cancer, leaves virtually no noticeable scars, which is important to many patients, says Dr. Cadeddu. Meanwhile, other cutting-edge technologies deployed robotically are shedding new light on kidney operations. Jeffrey Cadeddu, M.D., pictured with Taffy Boggan, R.N., is one of many UT Southwestern urologists performing robotic-assisted surgery to treat genitourinary cancers. In one procedure, a green dye visible with the robot s fluoroscopic camera is given to the patient intravenously. The dye helps surgeons distinguish tumor tissue from healthy tissue more clearly. The technology also helps minimize blood loss by allowing surgeons to see that blood flow to the targeted area of the organ is cut off. Dr. Margulis says that despite such technology, in the end, it s not about the robot; it s about the surgeon. You want to have a surgeon who knows how to treat the disease, not just how to use the robot. Biomarkers may improve prediction of bladder tumor recurrence A set of biological markers studied at UT Southwestern is providing a glimpse into how patients with bladder tumors may fare. If the biomarkers prove their value in larger, multicenter trials, they may help further the goal of personalized treatment for each patient based on molecular characteristics specific to each cancer.

13 22 Molecular markers such P A R T N E R S I N P R O G R E S S 23 as marker of cell growth (Ki-67) can identify characteristics of tumors that increase risk of recurrence. Currently, bladder cancer care is tailored according to tumor grade and stage. But there s more work to do for instance, learning more about bladder tumor molecular characteristics to customize treatments more precisely, says Professor of Urology Yair Lotan, M.D., Chief of Urologic Oncology at UT Southwestern. One crucial treatment decision that biomarkers could someday guide is which patients most need chemotherapy. Such systemic treatment is routine for patients whose bladder cancer has spread to the lymph nodes or has clearly metastasized because in those cases the disease can t be cured by surgery alone. But among patients with muscle-invasive bladder cancer, 25 to 30 percent will experience a recurrence after bladder removal, even if the disease was confined to the bladder wall. They might benefit from chemotherapy, but how do you know? Dr. Lotan says. Are you going to give toxic chemotherapy to every patient to try to help 25 percent? So the question is, can we identify patients whose tumors are more likely to recur? Payal Kapur, M.D. (left) and Yull Arriaga, M.D., along with other researchers at UT Southwestern, are studying bladder tumor molecular characteristics to help customize treatment for bladder cancer. Biomarkers might do just that. Researchers at UT Southwestern and Harold C. Simmons Cancer Center have been studying a set of five molecular markers comprising tumor protein 53; cyclin-dependent kinase inhibitors 1A and 1B; antigen identified by monoclonal antibody Ki-67; and cyclin E1, all cell cycle- or proliferation-related proteins to see if they can independently distinguish whose cancers are more advanced and predict whether the disease will later recur or prove fatal. The merits of immunohistochemical expression H&E Previous research into the biomarkers had looked back in time, comparing known patient outcomes with testing in tumor tissue collected earlier. That research showed associations between the biomarkers and recurrence and mortality. The new study represented the first prospective look at biomarkers in bladder cancer. Testing malignant tissue obtained during surgery to remove the cancer, the researchers evaluated the five-biomarker panel. After adjusting for variables known to predict outcomes, such as tumor stage, lymphovascular invasion, surgical margin status, and lymph node involvement, the investigators found that immunohistochemical Ki-67 expression of these proteins could improve prediction of recurrence as well as death from the cancer. Associate Professor of Pathology and Urology Payal Kapur, M.D., notes immunohistochemistry is used in routine diagnostics. This panel of immunohistochemistry assays can be performed in most laboratories, she says. But the research team has taken the process further, using image analysis for scoring the immunostains to reduce variability among pathologists assessing the findings. In sum, she says, we have demonstrated the utility and feasibility of routine clinical assessment of these markers in bladder carcinoma. Further study is suggesting the biomarkers might be informative when doctors initially scrape the bladder to diagnose the cancer. But the panel doesn t yet inform decisions to give chemotherapy to patients with muscle-invasive bladder cancer, says of Internal Medicine Yull Arriaga, M.D., a coinvestigator on the project, along with Drs. Lotan and Kapur. Well-designed, prospective, randomized clinical trials are needed to evaluate the role of biomarker testing as a predictive factor of response to chemotherapy, Dr. Arriaga says.

14 24 P A R T N E R S I N P R O G R E S S Novel therapies help chart new territory in prostate cancer treatment Bench-to-bedside research at UT Southwestern is developing new options for patients with any stage of prostate cancer and particularly in the late stages, when the cancer is no longer responsive to hormonal treatments. We have terrific clinical strength across disciplines urology, radiation oncology, and medical oncology with a very defined and strong interest in prostate cancer and active, ongoing research, says of Internal Medicine Kevin Courtney, M.D., Ph.D. Outside his own research into mechanisms underlying prostate cancer, Dr. Courtney is fostering a clinical trials program that covers the full spectrum of the disease. We can offer patients clinical trials, novel therapies, and expert care, he says. Open trials Harold C. Simmons Cancer Center has several radiation studies open for patients with localized prostate cancers. One Phase III trial for intermediate-risk patients compares radiation alone, targeting the prostate bed or prostate bed plus lymph nodes, with radiation plus androgen-deprivation therapy. Another Phase III trial, for high-risk patients, packs extra ammunition besides giving radiation and standard androgen-deprivation treatment, the trial is testing an investigational drug, TAK-700, which inhibits androgen synthesis. For patients with newly diagnosed metastatic prostate cancer, the Cancer Center is opening a Phase III randomized trial combining androgen-deprivation therapy, which is the standard-of-care, front-line treatment for metastatic prostate cancer, with either one of two agents: bicalutamide or TAK-700. This study is designed to determine which treatment combination can best control the cancer and extend survival. Additional trials include Phase II options for men with metastatic, castration-resistant disease. One study investigates use of the prostate cancer vaccine Provenge and stereotactic ablative radiotherapy (see page 29). Another tests a potential smart bomb called PSMA-ADC, which is an antibody that targets a protein (PSMA) on the surface of prostate cancer Research Esssenium led tre by con Jer-Tsong deessin Hsieh, actum Ph.D., te, untem has found poeremus that consus malfunction nonorae in a rem particular mis. Befac gene facere is associated acper with feci tam metastatic fadere con prostate deessin cancer. actum te, untem poeremus consus nonorae rem misefac facere. cells, combined with a chemotherapeutic drug. The pairing is designed so the antibody selectively delivers the chemotherapy inside cancer cells. Focusing on DAB2IP Other work at the Cancer Center is charting new territory. Research led by Professor of Urology Jer-Tsong Hsieh, Ph.D., is helping shed light on a new gene, DAB2IP, whose malfunction is associated with metastatic prostate cancer. The research team was first to describe DAB2IP s role in prostate cancer a decade ago. The gene s protein product restricts other players in prostate cancer progression. Retrospective studies have shown that DAB2IP loss is linked to disease progression and shorter survival. In addition, the gene appears related to stem cell-like qualities possessed by a hardy subset of prostate cancer cells that are capable of renewing a cancer after treatment has mostly quelled it. We believe DAB2IP gives those cells an advantage to survive, Dr. Hsieh says. The researchers have also found that with DAB2IP loss, a downstream protein called Clusterin that is important to cell survival becomes associated with drug resistance in prostate cancer. A

15 P A R T N E R S I N P R O G R E S S 27 Ganesh Raj, M.D., Ph.D, and his colleagues are developing a new class of drugs that target proteins that drive aggressive growth in prostate cancer. Harold C. Simmons Cancer Center has several radiation studies open for patients with localized prostate cancers drug already in Phase III clinical testing, OGX-011, specifically targets the gene expression of this protein. At the same time, Dr. Hsieh s team is collaborating with others at the university to develop a small molecule to mimic the function of the DAB2IP protein. Targeting proteins Other molecular research is developing a new class of drugs that mimic the function of peptides. These peptidomimetics represent a novel way of targeting proteins that drive malignant processes within cells, says Associate Professor of Urology Ganesh Raj, M.D., Ph.D., who leads the research. In castration-resistant prostate cancer, androgen receptors on the cell surface adapt and continue to drive aggressive growth, despite the scarcity of androgens. While current drugs for prostate cancer block that receptor, peptidomimetics halt receptor signaling within the cell, regardless of whether the androgen receptor is activated. It s like pulling the wires behind an electrical switch, so turning the switch on won t matter. That s a fundamentally different way to target the androgen receptor, Dr. Raj says, noting his team envisions a peptidomimetic working when traditional androgen-deprivation and anti-androgen therapies fail. These agents are currently in advanced preclinical testing and being developed conjointly with a pharmaceutical company. Dr. Raj and his colleagues are developing a series of peptidomimetic drugs that could impact a number of cancers fueled through other steroid receptors, such as estrogen and progesterone. Progress for patients with castration-resistant prostate cancer is urgent, Dr. Raj adds, because once androgen-deprivation therapy fails, there are only very limited options. The D2 peptidomimetic molecule resembles a helix and can fit into a critical pocket of the androgen receptor and block its function. D2 has biological activity against prostate cancer that is driven by the androgen receptor. Using surgery-less surgery to kill kidney tumors In treating smaller kidney tumors, UT Southwestern urologists have minimized the cutting in cutting edge. Traditionally, localized kidney cancer has required significant cutting open surgery with a large and painful incision, about five days hospitalization, and two months recovery. In recent years, laparoscopic approaches, including use of robotics, have entailed cutting out the cancer through tiny incisions, a couple of days hospitalization, and two or three weeks recovery. But that s still major surgery. Now, says UT Southwestern Professor of Urology and Radiology Jeffrey Cadeddu, M.D., the true revolution is we re not even doing surgery on some patients anymore. A minimally invasive technique called radiofrequency ablation, or RFA, in which a needle probe is inserted to heat a cancer and kill it, is proving itself in an era when renal tumors are being found earlier and more commonly in elderly or ill patients who aren t candidates for surgery. Dr. Cadeddu, a pioneer of leading-edge procedures, was first in Texas to use RFA to eliminate tumors rather than

16 28 P A R T N E R S I N P R O G R E S S 29 Stereotactic surgically remove them. He notes the technique is appropriate only for select kidney tumors those in a posterior or lateral location and less than 3-4 centimeters in size, depending on where the tumor lies. Nothing like surgical pain Patients who undergo RFA leave the hospital that day. It s like getting a wart burned off, Dr. Cadeddu says, adding that pain afterward ranges from none to mild. It s nothing like surgical pain. For the procedure, a urologist like Dr. Cadeddu teams up with a radiologist in Dr. Cadeddu s case, often Associate Professor of Radiology and Urology Clayton Trimmer, D.O. The whole process takes four to five hours, including about 90 minutes for the ablation. The patient undergoes general anesthesia in a CT scanner, which allows targeting of the tumor, then a needle probe with an array of antennas is inserted through the back or side into the tumor. The array heats the tumor cells just past boiling. A repeat CT scan confirms tumor kill. Then doctors remove the probe and rouse the patient, who stays a couple of hours and goes home wearing a bandage. UT Southwestern urologists and radiologists began groundbreaking RFA work in 2000 and have published several dozen papers on the topic; they have some of the most extensive experience UT Southwestern physicians are using radiofrequency ablation to eliminate localized kidney tumors and are exploring other ablative techniques in multiple types of cancer. with the procedure worldwide, having performed about 400 ablations at UT Southwestern in the past decade. For us, it s a standard option. In the community, people are still learning it, Dr. Cadeddu says. As with other advanced procedures, experience is crucial. For tumors smaller than 3 centimeters, five-year data suggest the efficacy is the same as with partial kidney removal. Another ablative technique, cryotherapy, is similarly effective. But cryotherapy has disadvantages, Dr. Cadeddu says, including a high hemorrhage rate and a higher cost than RFA. Additional ablative techniques Meanwhile, UT Southwestern also is using the latest technology, called irreversible electroporation, to ablate other types of tumors and is exploring its use in the kidney. This technology overcomes key limitations of RFA and cryotherapy namely, that they don t effectively kill all of a large tumor and can injure critical structures nearby. IEP s high-voltage electrical pulses can be tailored around vulnerable tissues. UT Southwestern is also extending RFA s benefits to younger, healthier renal cancer patients, Dr. Cadeddu says. We are leaders in expanding the indications for this promising, truly minimally invasive approach. radiation therapy promising for metastases High-dose radiation could pack a onetwo punch for patients with metastatic genitourinary cancers. Investigators are exploring how this powerful localized treatment might improve the immune system s ability to fight tumors distant from the radiation s target. The work builds on UT Southwestern s pioneering role in developing a therapy called stereotactic ablative radiotherapy, or SABR, which delivers highly focused beams of radiation from different angles at a tumor target, destroying cancer cells with far fewer treatment sessions than traditionally delivered radiation. Multiple studies, including those performed at UT Southwestern and published between 2007 and 2009, have demonstrated that SABR is effective in treating metastatic sites. It is particularly advantageous for larger lesions that tend to be more resistant to chemotherapy, says Raquibul Hannan, M.D., Ph.D., of Radiation Oncology. Although not

17 30 P A R T N E R S I N P R O G R E S S curative for the cancer, a few fractions of SABR can effectively eliminate metastatic lesions in the bones and at other sites with minimal side effects, multiple studies in recent years have shown. In renal cancer, SABR has well more than a 90 percent chance of eradicating the treated brain or spine metastases and a similar chance of eradicating targeted metastases elsewhere in the body, articles published in the past decade have shown. Those are extremely good numbers in the cancer world, Dr. Hannan says. The abscopal effect Radiation also offers a potential additional bonus: As cancer cells die from the treatment, the immune system might become programmed to attack remaining cancer cells elsewhere in the body that are still living and multiplying. Case reports in The New England Journal of Medicine and elsewhere have described cancer patients given high-dose radiation in one site experiencing tumor reduction in other sites, SABR delivers highly focused beams of radiation from different angles at a tumor target. an occurrence called the abscopal effect. But the abscopal effect happens only sporadically, and, when it does, often the patients are receiving immunotherapy. That observation led Dr. Hannan to hypothesize that immunotherapy, administered together with SABR, might produce a supra-additive tumor response, improving the chance of eradicating tumors not only at the treated site but also systemically. His recently published work in mice has elucidated the immuno-stimulatory properties of high-dose radiation and has shown that, when administered together with immunotherapy, the abscopal effect of SABR can happen more consistently. i-sabr trials dual focus Now researchers are translating those findings into clinical trials for genitourinary cancers. Collectively known as the i-sabr trials ( i for immunotherapy ), two Phase II studies led by Dr. Hannan aim to capitalize on the immune-stimulating and antigen-presenting properties of SABR. For prostate cancer, researchers are enrolling patients with metastatic disease for whom surgery, local radiation, and hormone treatment have failed. The study will utilize SABR for up to six metastatic sites, along with an immune boost with the prostate cancer vaccine sipuleucel-t (Provenge). Researchers Findings led by Raquibul Hannan, M.D., Ph.D., are being translated into clinical trials that aim to capitalize on the immune-stimulating and antigen-presenting properties of SABR. hope the addition of SABR will prompt immune targeting of multiple tumorassociated antigens rather than merely the single antigen that sipuleucel-t targets. The second study, for metastatic renal cancers, is enrolling patients for whom surgery has failed. The trial combines high-dose interleukin-2, a highly toxic and nonspecific immune-stimulatory therapy, with SABR in hopes of directing the immune stimulation toward cancer antigens and improving the risk-benefit ratio for IL-2. A multidisciplinary effort An important part of both trials will be correlative laboratory studies. We are going to do extensive studies to explore the specific biological aspects of how SABR interacts with immunotherapy, Dr. Hannan says. The effort taps expertise across UT Southwestern, including the Department of Urology; Robert Timmerman, M.D., Professor of Radiation and Neurological Surgery; David Pistenmaa, M.D., Ph.D., Professor of Radiation Oncology; Nathan Kim, M.D., Ph.D., of Radiation Oncology; Jeffrey Meyer, M.D., of Radiation Oncology and in the Cancer Immunobiology Center; James Brugarolas, M.D., Ph.D., Associate Professor of Internal Medicine and Developmental Biology; Kevin Courtney, M.D., Ph.D., and Yull Arriaga, M.D., s of Internal Medicine; and the Cancer Immunobiology Center, headed by Ellen Vitetta, Ph.D., also Professor of Immunology and Microbiology.

18 32 P A R T N E R S I N P R O G R E S S 33 Cancer Center taking holistic approach At UT Southwestern, comprehensive cancer care focuses on the whole person, not just the tumor. We re working hard to provide the resources and oncology specialists needed to get patients through their cancer journey with as little life disruption as possible, says Associate Professor of Psychiatry Jeff Kendall, Psy.D., Clinical Leader of Oncology Supportive Services at Simmons Cancer Center. Oncology supportive services help patients and families with disease- or treatmentrelated side effects. Many different professionals are needed to address the physical, emotional, social, and spiritual aspects of cancer and its treatment. For instance, dietitians help patients manage eating challenges that cancer can pose. Rehabilitation professionals help patients maximize physical functioning during treatment and promote recovery afterward. Meanwhile, psychologists and social workers help patients and families adjust to the dramatic changes cancer brings and ensure needed support and resources are available. Integrative care, such as music therapy, is available to improve well-being and aid with stress management. Chaplains focus on emotional and spiritual wellness. Patients will say, I didn t realize how anxious or sad I am; I m so glad you asked, Dr. Kendall says. Many cancer programs don t ask because they don t have the specialists to deal with the problems. They can do something for themselves and for the future, Ms. Beaver says. That s why we have the drugs we have, because people have gone on trials. The Department of Urology also coordinates two support groups, a Manto-Man meeting every other month for prostate cancer, and a bladder cancer group meeting quarterly. Both are open to the public. Sessions typically feature experts answering questions about patients diseases, treatments, side effects, and more. Participants also benefit from the experience of fellow group members, Ms. Beaver says. The camaraderie is awesome. Music therapy administered to patients by trained music therapists is one of many supportive care offerings available at Simmons Cancer Center. (Pictured: Katrina Tabinowski, M.M., M.T. B.C., NICU-M.T.) Clinical trials open doors, offer hope Clinical trials at UT Southwestern offer patients the newest therapies, plus an extra dose of cancer care. We re right there during the trial with them and help them get through a scary time, says Allison Beaver, B.S.N., R.N., Clinical Research Nurse Administrator for the Department of Urology. After enrolling patients, the research support team monitors them closely and helps them navigate complex care needs. Patients have various reasons for entering trials. Some want a treatment that isn t widely available often after other therapies have failed. And some hope to contribute to scientific knowledge. Cancer helpline provides invaluable, free assistance Answers about cancer are just a phone call away. Simmons Cancer Center s free and confidential Cancer Answer Line ( ) fields questions from patients, family members, and others affected by cancer. Questions also can be ed to canceranswerline@utsouthwestern.edu. The service typically is used by people who have just received a cancer diagnosis, are unsure what to expect with testing

19 34 P A R T N E R S I N P R O G R E S S 35 or treatment, or want more information about what their doctors have advised. The answer line provides self-advocacy approaches for people to ask the right questions of their provider and make informed decisions, says Maria Grabowski, M.S.N., R.N., O.C.N., Program Manager for Patient Education and Community Outreach. For urologic cancers, questions about prostate-specific antigen tests, prostate biopsies, active surveillance, and incontinence are common, Ms. Grabowski says. Patients also ask about bladder and renal surgeries, clinical trials, and treatments at UT Southwestern including stereotactic ablative radiotherapy and robotic surgery. The Cancer Center also maintains a speakers bureau, arranging for cancer professionals to share their expertise with local groups. Such efforts are essential to the center s mission, We re working hard to provide the resources and oncology specialists needed to get patients through their cancer journey with as little life disruption as possible Ms. Grabowski says. We re taking clinical research to the bedside, then out into the community. Event marks launch of formal kidney cancer program Simmons Cancer Center has demonstrated its commitment to the care of kidney cancer patients by formalizing a program that brings together the strengths of UT Southwestern in both basic research and clinical medicine to conquer kidney cancer. This occasion was marked with an event including kidney cancer patients and their families, as well as UT Southwestern physicians and researchers, gathering for educational presentations, food, fellowship, professional entertainment, and a talent show. To learn more about the kidney cancer program, visit utsouthwestern. edu/kidneycancer. Geneticists pinpoint crucial cancer links Simmons Cancer Center experts can put together hereditary pieces of a cancer puzzle. Consider a prostate cancer patient with breast cancer in the family. A cancerassociated mutation in the BRCA2, or less commonly BRCA1, gene means other relatives warrant genetic testing and that males with the mutation should start prostate screening early. Renal cancers are another focus. About 4 percent are genetic, says Linda Robinson, M.S., C.G.C., Assistant Director of Clinical Cancer Genetics. One important genetic condition affecting the kidneys (and other sites) is von Hippel-Lindau syndrome. VHL patients should be monitored to find cancers early. We follow lots of families with this rare condition, Ms. Robinson says. Testing also is available for other syndromes linked to renal cancer. One, Lynch syndrome, associated largely with colorectal cancer, is suspected in urologic patients with tumors in transitional cells lining the renal pelvis, bladder, or ureter, says Certified Genetic Counselor Megan Farley, M.S., C.G.C. Simmons researchers, meanwhile, recently described how the gene BAP1 signals kidney tumor aggressiveness and appears linked to some familial cancers. BAP1 s full impact is not yet clear, says Ms. Farley, a research collaborator. We ll learn that only if we follow patients. Genetics counselors Linda Robinson, M.S., C.G.C. (left), and Sara Pirzadeh-Miller, M.S., C.G.C., help patients identify familial cancer risks and discuss options for managing health.

20 36 P A R T N E R S I N P R O G R E S S 37 At a glance: Genitourinary Prostate Bladder Kidney cancer clinical trials at UT Southwestern Phase III prospective randomized trial of dose-escalated radiotherapy with or without short-term androgen deprivation therapy for patients with intermediate-risk prostate cancer Phase III trial of short-term androgen deprivation with pelvic lymph node or prostate bed only radiotherapy (SPPORT) in CAP patients with rising PSA after radical prostatectomy Phase III trial of dose-escalated radiation therapy and standard androgen deprivation therapy with a GNRH agonist versus dose-escalated radiation therapy and enhanced ADT with GNRH agonist and TAK-700 for men with high-risk prostate cancer Phase II trial of Sipuleucel-T and stereotactic ablative body radiation (SABR) for patients with metastatic castrate-resistant prostate cancer Phase II, open-label, multicenter study of PSMA ADC in subjects with castration-resistant metastatic prostate cancer (CRMPC) Phase III randomized trial comparing androgen deprivation therapy + TAK 700 with ADT + bicalutamide in patients with newly diagnosed metastatic hormone sensitive CAP A Phase III surgical trial to evaluate the benefit of a standard versus an extended pelvic lymphadenectomy performed at time of radical cystectomy for muscle invasive urothelial cancer Phase II, randomized, open label, parallel arm study to evaluate the safety and efficacy of rad-ifn/syn3 following intravesical administration in subjects with high grade, BCG refractory or relapsed non-muscle invasive bladder cancer (NMIBC) Clinical, non-intervention study of the Cxbladder urine test for the detection of recurrent urinary tract urothelial carcinoma Surveillance for low-risk muscle invasive bladder cancer - a pilot study comparing AUA and EAU guidelines Evaluation of Xpert Bladder Assay for monitoring recurrence in bladder cancer patients and detection of bladder cancer in symptomatic patients Randomized, double-blind Phase III study comparing gemcitabine, cisplatin, and bevacizumab to gemcitabine, cisplatin and placebo in patients with advanced transitional cell carcinoma Prognostic significance of circulating tumor cells in patients with renal cell carcinoma Neoadjuvant RAD001(everolimus) for advanced RCC before cyto-reductive nephrectomy with correlative tumor studies Phase II trial of high dose IL-2 and SABR for patients with metastatic clear cell renal cancer MRI and renal cell Randomized, open-label, Phase III study of BMS versus everolimus in subjects with advanced or metastatic clear-cell renal cell carcinoma who have received prior anti-angiogenic therapy For a real-time, updated list of GU cancer clinical trials and all cancer clinical trials at UT Southwestern Harold C. Simmons Cancer Center, visit simmonscancercenter.org