A decades-long partnership between far-sighted donors and renowned UT Southwestern Medical Center researchers has translated into a urology department that offers one of the country’s most experienced teams in prostate treatment and research.

Led by Chairman Dr. Claus Roehrborn since 2002, the Department of Urology at UT Southwestern has assembled a pre-eminent team that tackles prostate disease with a range of expertise, from biomedical investigations to clinical procedures that include advanced minimally invasive laparoscopic surgery and robotics-assisted surgery with the DaVinci system.

Prostate cancer is the most common malignancy in men and the second-leading cause of death from cancer in men in the U.S. More than 230,000 men in America are diagnosed with the disease each year.

Among the current research projects at UT Southwestern is a search for potential treatment of metastatic prostate cancer. Led by Dr. Ganesh Raj, associate professor of urology, the effort focuses on the androgen receptor, which spurs the expression of genes that help cancer cells proliferate. Since the 1940s, the main treatment strategy for prostate cancer has been prevention of the receptor’s activation. It is known, however, that prostate cancer cells find alternative pathways to activate the androgen receptor.

Dr. Raj has studied the interaction between the androgen receptor and a critical protein co-factor known as FOXA1, which appears to be a key in helping the androgen receptor regulate the expression of many genes critical for prostate cancer cells’ proliferation and growth. “We believe that blocking the interaction between the androgen receptor and FOXA1 may shut down the ability of the androgen receptor to activate the genes,” Dr. Raj said.

In a collaborative effort with researchers at Vanderbilt University and UT Dallas, Dr. Raj helped design a novel protein-like agent known as a peptidomimetic. This specific agent blocks the interaction between the androgen receptor and FOXA1 in prostate cancer. This disruption of receptor activity is a key research finding, and peptidomimetics could become a therapeutic agent against advanced metastatic prostate cancer.

Such discoveries do not happen in a vacuum, however.

The pathway to key findings and clinical accomplishments began four decades ago with the foresight of donors who funded groundbreaking medical research.

DECADES OF RESEARCH

Several biomedical scientists at UT Southwestern have played pivotal roles in various phases of prostate cancer treatment.

In the early 1970s, Dr. Jean Wilson, now professor emeritus of internal medicine, blazed a course for new treatment strategies when he discovered the role of the enzyme 5-alpha reductase in benign prostatic hyperplasia, or enlarged prostate.

In his pivotal 1974 paper in the The New England Journal of Medicine, Dr. Wilson reported that men with a rare genetic disorder – 5-alpha reductase deficiency – did not develop normal prostates or prostatic enlargement. He theorized that reproducing this condition artificially could lead to nonsurgical treatment of an enlarged prostate. He later identified the genes that encode for 5-alpha reductase.

Dr. Wilson’s discovery set in motion a new era of treatment.

The work of UT Southwestern researchers has been greatly supported over the years through endowed chairs, professorships, research funds, fellowships and scholarships, and research and clinical centers that provide essential income to support the research, teaching and patient care missions of UT Southwestern. Endowments provide unique opportunities for programs to flourish, give UT Southwestern critical leverage when competing for national grants, and help substantially in recruiting and retaining outstanding faculty.

In 1982, for instance, Dr. Wilson’s research benefited from endowed funding when he was named holder of the Charles Cameron Sprague Distinguished Chair in Biomedical Science.

Prostate research at UT Southwestern took another critical step forward in the early 1990s when Dr. David Russell cloned the 5-alpha reductase enzyme and published his findings in Nature. He hypothesized that 5-alpha reductase may play a role in preventing prostate cancer.

In 1991, the work of Dr. Russell, UT Southwestern’s vice provost, dean of basic research and professor of molecular genetics, was partially funded by the Eugene McDermott Distinguished Chair in Molecular Genetics.

Building on Dr. Russell’s research, a scientist at the Merck Group developed finasteride, which is manufactured by the pharmaceutical company as Proscar. Finasteride, already proven effective as a therapy for benign prostatic hyperplasia (BPH), also delays or prevents prostate cancer and reduces the risk of urinary problems. It inhibits 5-alpha reductase, significantly lowering the level of the primary male prostate hormone dihydrotestosterone without affecting testosterone levels elsewhere in the body.

UT Southwestern physician-scientists next tested finasteride in a four-year clinical trial that ended in 1998. The drug was shown to shrink the prostate by 20 percent to 30 percent and significantly reduced the need for surgical intervention and the risk of acute urinary retention.

UT Southwestern also participated as a core site in the Prostate Cancer Prevention Trial, a seven-year study involving about 9,500 men. Findings were published in 2003.

“The Prostate Cancer Prevention Trial is the culmination of several decades of work demonstrating the importance of the 5-alpha reductase enzymes and the genetic or medically induced absence thereof in the development and progression of not only BPH, but also prostate cancer,” Dr. Roehrborn said.

CLINICAL RESULTS

The research of Drs. Wilson and Russell – both of whom are among the medical center’s faculty honored as members of the prestigious National Academy of Sciences as well as American Academy of Arts and Sciences – together with funding from endowed chairs, have resulted in numerous clinical accomplishments in prostate treatment at UT Southwestern.

Under the direction of Dr. Paul Peters, then chairman of urology, cutting-edge procedures were adopted beginning in the early 1980s that were designed to preserve male sexual and urinary function following prostate removal. That surgical and oncological care continues under the leadership of  Dr. Roehrborn.

“Cure rates for prostate cancer are high if detected early,” Dr. Roehrborn said. “Men who have a family history of prostate cancer should begin annual screenings and be in the care of a physician who can discern the best course of treatment.”

Before laparoscopic procedures and robotic prostatectomies, open surgery was the only option. Operations typically resulted in substantial blood loss, lengthy recoveries and risk of nerve damage that could lead to incontinence and sexual dysfunction. With less-invasive procedures, UT Southwestern urologic surgeons use the latest technologies to treat patients. A robot named DaVinci assists in the delicate procedures.

Dr. Roehrborn has performed nearly 400 DaVinci robotic surgical removals of the prostate or part of the prostate gland, and hundreds of procedures for benign and cancerous prostate diseases. He is involved in all aspects of basic, translational and clinical research on BPH and prostate cancer and has conducted numerous trials in minimally invasive and surgical treatment for lower urinary tract symptoms and BPH, as well as prostate cancer.

Dr. Roehrborn’s work has been supported by two endowed chairs – the E.E. Fogelson and Greer Garson Fogelson Distinguished Chair in Urology (1988) and the S.T. Harris Family Chair in Medical Science, in Honor of John D. McConnell, M.D. (2000).