Using Function to Inform Genomics

Recently, I was asked to evaluate a charming young woman with an unusual gynecologic primary. She had received numerous forms of therapy and surgery for her low-grade carcinoma. Her most recent surgery provided tissue to our laboratory for analysis. The results were consistent with the clinical presentation, revealing relative resistance to virtually all conventional chemotherapeutic drugs, but a very striking pattern of sensitivity to three compounds associated with the insulin like growth factor signaling pathway.

As all three compounds pointed to activity in this pathway, I reasoned that the patient had a mutation upstream, as I wrote in my report to her physician. I suggested that they should investigate this pathway.

I was subsequently apprised that, upon my recommendation and at the request of patient’s husband, an analysis had been submitted to a laboratory that identified a mutation in PI3K, the very pathway that I had identified in our functional analysis. Thus, this patient’s resistance to chemotherapeutics and sensitivity to PI3K inhibitors reflected the profound survival signal provided by this mutation. Of interest, when the family originally requested a molecular profile be conducted in parallel with our functional profile, the commercial lab in Arizona did not include PI3K mutational studies. It wasn’t until the functional results pointed to the PI3K pathway that the specific mutational analysis was undertaken and found positive.

This experience is very similar to our original work with the EGFR inhibitors gefitinib and erlotinib. Several years before the EGFR mutation was identified and long before the mutational analysis was commercially available we identified activity in patients using the functional platform. Patients were then treated based upon the EVA-PCD results under protocol with every one of these patients responding, as we reported (Nagourney Proc ASCO, 2007). This speaks to the robustness of the functional platform and to its capacity to guide drug development.

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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