Pictured left are (L to R): Steven Clinton, MD, PhD, prostate cancer specialist and researcher and director of the Prostate and Genitourinary Oncology Clinic; Debra Zynger, MD, urologic pathologist and Periannan Kuppusamy, PhD, director of Ohio State’s Center for Biomedical EPR Spectroscopy and Imaging
Ohio State’s Prostate and Genitourinary Oncology Clinic offers interdisciplinary care backed by research
By Bob Hecker
Photography by Roman Sapecki
Men who have been diagnosed with cancer that is thought to be contained in the prostate are benefitting from an evolution toward integrated multidisciplinary care backed by research that will yield more accurate prognoses and determine better treatment plans.
The Prostate and Genitourinary (GU) Oncology Clinic at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC-James) specializes in evaluating men who are trying to determine their best treatment options. The clinic team particularly focuses on patients who are at high risk for recurrence, and it is a leader in accruing participants to clinical trials that integrate treatment modalities, seek prognostic biomarkers and search for novel approaches to curing the cancer or delaying recurrence.
GU Clinic Director Steven Clinton, MD, PhD, a prostate cancer specialist and researcher, believes many advancements lie ahead as medical scientists identify high-risk biomarkers involving tumor angio-genesis, gene expression, proteomics and microRNAs.
“Prostate cancer is highly heterogeneous,” says Clinton, who is also professor of Medical Oncology and of Public Health and associate professor of Human Nutrition. “We need better tools to predict whether patients have a form that is aggressive, average or indolent so we can better define a course of treatment – surgery, chemotherapy, radiotherapy, hormone therapy or possibly new drugs that target angiogenesis – that is specific to each person’s disease. New bio-markers also will define who has an indolent cancer and can be spared the complications and risks of aggressive therapy.
“In the future,” he adds, “prognosis and treatment of prostate cancer will be defined by molecular signatures that will give us a far better classification of risk for each patient.”
Clinton and colleagues in the GU Clinic – which includes specialists in medical, urologic and radiation oncology – believe interdisciplinary collaboration will help make this a reality.
“The most patient-relevant research advances are achieved only if physicians and scientists with different specialties collaborate,” says urologic pathologist Debra Zynger, MD. “Urologic oncology research at the OSUCCC-James involves team members from multiple disciplines who integrate their clinical expertise and participate in patient-care clinics and conferences to optimize treatment.”
This level of integrative care is relatively new in prostate cancer, Clinton notes.
Historically and nationwide, he explains, patients with confirmed prostate cancer were left to nego-tiate a complex and difficult path-way to choose a treatment plan. Options ranged from watchful waiting to surgery to multiple types of radiation therapy.
“The history of prostate cancer has few examples in which urologists, radiation therapists and medical oncologists got together to conduct randomized studies to compare one treatment with another. There was not that level of collaboration,” Clinton says. “But under the new paradigm, patients with biopsy-confirmed cancer can come to our clinic and on the same day receive assessments from urologists, radiation oncologists and medical oncologists who work together to provide a unified approach toward options for care, which may include clinical trials.”
Patients receive personalized therapy, which can range from watchful waiting, to single modality care for low-risk patients, to multi-modality care for those at higher risk for recurrence. “In high-risk care,” Clinton says, “we may integrate therapies, such as surgery with adjuvant radiation and hormone therapy, or surgery with neoadjuvant chemotherapy and hormone therapy.”
Until risk can be defined by newer molecular signatures, prostate cancer risk of recurrence is determined using tumor grade (Gleason score), stage (amount/size and location), prostate specific antigen (PSA) level and findings on digital rectal exam. This information is plugged into a computerized prostate nomogram – a mathematical model that helps estimate outcomes such as probability of recurrence after treatment, probability of survival after prostatectomy and treatment success for salvage radiation therapy in men whose cancer has recurred after prostatectomy.
“We integrate all of these elements to produce an overall determination of risk,” Clinton says, “but these tools can be greatly improved. In the future we will include data relating to gene expression signatures and other biomarkers such as angiogenesis. We don’t yet have the biomarkers for prostate cancer that we have for breast cancer, which is several years ahead of prostate cancer in that regard, but we’re moving rapidly through basic research and clinical trials.”
Zynger agrees. “If we can identify biomarkers that will stratify prostate tumors and predict their behavior, many men may be able to delay treatment or completely avoid it, while others will be steered toward more aggressive and effective multimodality care.”
Angiogenesis may offer one example. A recent study led by the OSUCCC-James in collaboration with the Harvard School of Public Health suggests that prostate cancer behavior is predicted by the size, shape and number of tumor blood vessels.
The study, published in the Journal of Clinical Oncology, analyzed microvessel morphology as a predictor of prostate cancer mortality in 572 men with localized disease who underwent prostatectomy. Researchers immunostained tumor block sections for endothelial marker CD34 and assessed microvessel density, vessel size (area and diameter) and irregularity of vessel lumen using computer-assisted image analysis.
“They first determined how to more accurately measure angiogenesis in prostate tumors,” Clinton says. “Typically, the approach has been to manually count the vessels we see using a microscope. But we wanted a more precise and consistent assessment of tumor blood vessels. We chose computerized digital analysis, which gives better quantitation of vascular architecture and more objective data.”
After an average follow-up of 10 years, 44 of the 572 men had developed metastatic cancer or died of their disease. Men whose tumors had smaller vessel diameters were six times more likely to have aggressive cancer and die from it, and those with the most irregularly shaped vessels were 17 times more likely to develop lethal cancer. The findings were independent of traditional markers (Gleason score, stage, PSA level).
The investigators concluded that aggressive tumors “form vessels that are primitive in morphology and function, with consequences for metastasis.”
“It’s as if aggressive prostate cancers are growing faster, and their blood vessels never fully mature,” Clinton says.
If these findings are validated, particularly in biopsy specimens, the measurement of tumor blood vessel architecture might help patients determine their optimal choice of therapy and improve long-term survival. “It really is about personalized health care,” Clinton says.
Pleased as PUNCH
The “Pre-surgical Study Using Neoadjuvant Chemotherapy (PUNCH)” is a national, randomized, phase III clinical trial that compares progression-free survival in men with high-risk localized prostate cancer who undergo prostatectomy with or without six months of presurgical chemohormonal therapy (docetaxel and the androgen-deprivation agents leuprolide acetate or goserelin).
Clinton notes that Ohio State leads the nation with nearly 30 accruals to this Cancer and Leukemia Group B (CALGB) clinical cooperative group study. “This trial should determine the benefits of aggressive combination chemotherapy and hormonal therapy prior to surgery in patients who have a 40 percent or more five-year risk of recurrence,” he says. Five to 10 years of follow-up will be needed to learn if the treatment improves survival, he adds, although “some short-term outcomes may be determined sooner, such as how the grade and stage were affected by the neoadjuvant therapy.”
Clinton attributes Ohio State’s success in PUNCH accruals to the GU Clinic’s multidisciplinary structure, in which patients are quickly informed of their options, and to the skill and reputation of colleagues such as Ronney Abaza, MD, director of Robotic Urologic Surgery. “Dr. Abaza is now a major referral center for robotic prostate surgery, so we’re seeing a larger number of high-risk candidates for this trial,” Clinton says.
The basic laboratory of Periannan Kuppusamy, PhD, a member of the Experimental Therapeutics Program at the OSUCCC-James, develops imaging technologies for tumor oxygenation and therapeutic drugs that target hypoxic tumors.
Along with OSUCCC-James researchers Tim Eubank, PhD, and Clay Marsh, MD, Kuppusamy’s lab has shown how in vivo imaging of tumor oxygenation (tissue pO2) can be used as a marker of tumor-growth inhibition by anti-angiogenic therapy.
Published in the journal Cancer Research, this study “was performed using a mouse model of breast cancer with the administration of granulocyte macrophage colony-stimulating factor (GM-CSF) as an anti-angiogenic agent,” Kuppusamy says. “We used a nanoprobe-based electron paramagnetic resonance (EPR) imaging technology developed by my group to monitor reduction in tumor oxygenation following GM-CSF treatment.”
Kuppusamy, who directs Ohio State’s Center for Biomedical EPR Spectroscopy and Imaging, also is developing EPR oximetry for clinical applications.
“Oxygen concentration is an important determinant of treat-ment outcome in radiation and chemotherapy in solid tumors, including prostate cancer,” he says. “Since vascularity and angiogenesis are directly related to tumor oxygen levels, our goal has been to use oxygen concentration as a surrogate endpoint to assess anti-angiogenic therapy. We believe this would help us make better prognostic decisions and monitor treatment.”
Prostate cancer researchers at the OSUCCC-James also are developing and testing drugs to delay recurrence in high-risk patients or to treat more advanced disease.
In 2008, investigators led by Ching-Shih Chen, PhD, and Clinton reported in the journal Cancer Research that a drug designed by Chen blocks prostate cancer progression in an animal model with an aggressive form of the disease.
The agent, called AR-42 (OSU HDAC42) is a histone deacetylase inhibitor that has been shown in animal studies to reactivate epigenetically silenced tumor-suppressor genes. It prevented mice with prostatic intraepithelial neoplasia from developing advanced prostate cancer. “This study showed that an agent with a specific molecular target can dramatically inhibit prostate cancer development in a very aggressive model of the disease,” Clinton says.
With one foot rooted in the lab and the other in the clinic, Clinton has a perspective that enables him and his collaborators to expedite science-based care, particularly for high-risk prostate cancer patients.
“Medicine is moving toward therapies that are increasingly individualized,” Zynger says. “If we take steps to further target our therapeutic approach in prostatic adenocarcinoma, we may reduce morbidity while enhancing cure in a large number of men.”
“Our mission is to move promising lab findings into the clinic to help realize our vision of creating a cancer-free world sooner rather than later,” Clinton says. “Over the next decade I believe we will see clear benefits of integrating multidisciplinary treatment plans into a personalized care plan for each patient and increasing our cure rates for high-risk patients.”
OSU ANGIOGENESIS RESEARCH
FURTHER FOLKMAN’S LEGACY
Steven Clinton, MD, PhD, believes researchers at The Ohio State University who study angiogenesis in cancer or other medical disciplines have a special bond with the founder of the field.
“Our work with angiogenesis has an historical link to Dr. Judah Folkman, one of the greatest scientists OSU has produced,” Clinton says. “The field of angiogenesis research owes so much to his pioneering work.”
Folkman, who died in 2008, was a former central Ohio resident who graduated from Ohio State in 1953 and earned his MD at Harvard Medical School. He later became a surgeon and researcher at Harvard and at Children’s Hospital Boston, where he directed the Vascular Biology Program.
In a 1971 paper in the New England Journal of Medicine, Folkman hypothesized that all tumors depend on angiogenesis for sustenance, an idea that opened global avenues of investigation for thwarting this process and inhibiting tumor growth. “But his hypothesis was not widely supported, and it was nearly two decades before his persistent and careful research stimulated an explosive growth in the field,” Clinton says.
In 1998 The New York Times reported that two anti-angiogenesis agents Folkman had developed – angiostatin and endostatin – had eradicated cancer in mice with no toxic effects. This news dramatically elevated public hopes for an imminent cure for human cancers even though Folkman was cautious about the promise of these agents.
“In the mouse models those agents were potent, but such findings don’t always translate immediately to the more complex human system,” says Clinton, who trained at Harvard and served on the faculty from 1988-98.
Clinton, who knew Folkman and often discussed science with him, was first motivated to study angiogenesis through his own observations coupled with those of Folkman. “I noticed in the lab that when cancer was developing in the prostate, there was a large vascular pattern in and around the tumor,” he recalls. “Through my exposure to Dr. Folkman, I realized he had similarly observed this as a surgeon and was making progress toward understanding the process.”
Based on Folkman’s pioneering findings, “We have seen in recent years an evolving approach to using small molecule drugs and antibodies that target angiogenic growth factor signaling,” Clinton says. “Some of these, such as Avastin, have made their way into the clinic, and others are being developed that wholly or partially target angiogenesis signaling.”
Clinton considers Folkman a humble visionary and an outstanding scientist who always encouraged anyone interested in angio-genesis. “He simply wanted to see the field move forward to help more patients. We’ve not yet appreciated the full potential of targeting angiogenesis for prevention and therapeutic purposes. It’s up to us to learn how we can best translate the basic science into clinical care, but certainly Dr. Folkman’s legacy will be seen as a key contributor to a cancer-free world.”