Probing Human Biology

Functional Analyses Unravel The Complexities of Signal Transduction

The application of functional analyses in human tumors is the topic of our upcoming presentation at the American Association of Cancer Research to be held in Washington D.C, in April 2010 (Nagourney, R. et. al, Horizontal and vertical signal pathway inhibition in human tumor primary culture micro-spheroids. Abstract 1764, to be presented Monday, April 19, 2010).

Scientists now realize that cancer biology, indeed all biology, is driven by signaling pathways. Cells speak to each other and the messages they send are interpreted via intracellular pathways known as signal transduction. Many of these pathways are activated or deactivated by phosphorylations on select cellular proteins. Tyrosine kinases, and serine/threonine kinases are among the most important classes of enzymes responsible for these chemical cascades inside the cell. In recent years small molecules have been developed to inhibit these chemical reactions. Hundreds of such compounds are in development for cancer today. While most scientists use genomic or proteomic platforms to detect mutations in these pathways that might result in response to these chemicals, we have taken a different tack. By applying functional analysis, to measure the end result of pathway activation or deactivation, we can predict whether patients will actually respond. Our results in lung cancer patients to date have exceeded the best outcomes using DNA profiles, clearly supporting the predictive accuracy use of functional analyses in this and related areas.

Focusing upon two fundamental pathways, the EGFR and the insulin-like growth factor pathway, we have explored how small molecule inhibitors influence these important survival signaling pathways. This is but one of many applications of functional profiling in the study of human tumor biology.

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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