The Clinical Applications of Functional Profiling CSRA: Ovarian Cancer

Ovarian cancer is the leading cause of cancer death for gynecologic malignancies, afflicting 22,000 women in the US each year. The majority of ovarian cancer patients are diagnosed with advanced disease requiring chemotherapy. Experience shows that these patients typically respond well to available drugs, yet there has been no improvement in five-year survival for this disease in decades. And the standard of care — platinum plus taxane — has not changed in more than 15 years.

However, the clinical responsiveness of ovarian cancer renders it an ideal candidate for functional profiling. Using functional profiling, we were the first to use platinum and Gencitabine to treat this disease, showing its efficacy even in platinum-resistant patients. Clinical responses — many very durable — have been observed even in the most heavily pre-treated patients. While there are many drugs active in this disease, microarray gene platforms have been unable to meaningfully distinguish subsets of patients and improve therapy selection. These limitations of DNA-based techniques are not shared by functional profiling, which has the unique capacity to examine complex biological systems in their native state. By incorporating the interaction of tumor cells with their stroma, vasculature and inflammatory elements, functional profiling has been shown to provide highly validated predictive information.

Using functional profiling, we are now exploring novel drug combinations and the introduction of signal transduction inhibitors into the management of advanced ovarian cancer. The failure of large cooperative group clinical trials (like the GOG182) to improve clinical outcomes in the first line setting can now be seen as a failed paradigm of patient randomization. Using functional profiling to examine untreated ovarian cancers, we have shown that no standard combination is best for the majority of patients. Instead, patients manifest unique patterns of sensitivity and resistance that can only be recognized through the individualization of treatment. Functional profiling has the capacity to match patients to available drugs and combinations, thereby improving the odds of good response and minimizing exposure to ineffective and toxic drugs.

About Dr. Robert A. Nagourney
Dr. Nagourney received his undergraduate degree in chemistry from Boston University and his doctor of medicine at McGill University in Montreal, where he was a University Scholar. After a residency in internal medicine at the University of California, Irvine, he went on to complete fellowship training in medical oncology at Georgetown University, as well as in hematology at the Scripps Institute in La Jolla. During his fellowship at Georgetown University, Dr. Nagourney confronted aggressive malignancies for which the standard therapies remained mostly ineffective. No matter what he did, all of his patients died. While he found this “standard of care” to be unacceptable, it inspired him to return to the laboratory where he eventually developed “personalized cancer therapy.” In 1986, Dr. Nagourney, along with colleague Larry Weisenthal, MD, PhD, received a Phase I grant from a federally funded program and launched Oncotech, Inc. They began conducting experiments to prove that human tumors resistant to chemotherapeutics could be re-sensitized by pre-incubation with calcium channel blockers, glutathione depletors and protein kinase C inhibitors. The original research was a success. Oncotech grew with financial backing from investors who ultimately changed the direction of the company’s research. The changes proved untenable to Dr. Nagourney and in 1991, he left the company he co-founded. He then returned to the laboratory, and developed the Ex-vivo Analysis - Programmed Cell Death ® (EVA-PCD) test to identify the treatments that would induce programmed cell death, or “apoptosis.” He soon took a position as Director of Experimental Therapeutics at the Cancer Institute of Long Beach Memorial Medical Center. His primary research project during this time was chronic lymphocytic leukemia. He remained in this position until the basic research program funding was cut, at which time he founded Rational Therapeutics in 1995. It is here where the EVA-PCD test is used to identity the drug, combinations of drugs or targeted therapies that will kill a patient's tumor - thus providing patients with truly personalized cancer treatment plans. With the desire to change how cancer care is delivered, he became Medical Director of the Todd Cancer Institute at Long Beach Memorial in 2003. In 2008, he returned to Rational Therapeutics full time to rededicate his time and expertise to expand the research opportunities available through the laboratory. He is a frequently invited lecturer for numerous professional organizations and universities, and has served as a reviewer and on the editorial boards of several journals including Clinical Cancer Research, British Journal of Cancer, Gynecologic Oncology, Cancer Research and the Journal of Medicinal Food.

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