Highly Productive Targeted Therapies

The introduction of targeted therapies now provides select patients the opportunity to receive first-line therapies with these new classes of drugs. The recognition that epidermal growth factor tyrosine kinase inhibitors are most effective in patients with EGFr mutations (codons 19-21) has enabled us to apply the EGFr mutation analysis as a biomarker for response. Despite the high response rates (up to 70% in mutation positive patients), approximately 30% of patients with the appropriate biomarker do not respond. In addition, patients who do not carry EGFr mutations can nonetheless respond to these classes of drugs. This reflects the complexity, redundancy and promiscuity of signal pathways, such that, pathway cross talk has the capacity to salvage cancer cells from the lethal effects of these inhibitors. The EVA-PCD™ platform has the unique capacity to identify all of the operative mechanisms of response and resistance by gauging the result of drug exposure at its most important level: cell death. Our earliest work, gefitinib conducted in 2001, identified non-small lung cancer as an important target disease. As we continued this work with gefitinib (Iressa) and erlotinib (Tarceva), we have had the opportunity (under IRB-approved protocol) to treat patients with first line Tarceva. To date, we are tracking a 100% response rate to Tarceva in the select populations; even patients who have not been found to carry recognized mutations. More interesting, patients not expected to respond such as one multiply recurrent male, smoker has remained in a 4 year remission on Tarceva as a third line therapy. As predicted by EVA/PCD analysis, the emerging study of combined signal inhibitors provides the opportunity to examine favorable combinations for effect and synergy. The rational combination of signal inhibitors is a highly productive avenue of research under investigations in many centers, including our laboratory. Consistent with our presentation at the recent meeting at the American Association for Cancer Research (Nagourney, R. et. al, Horizontal and vertical signal pathway inhibition in human tumor primary culture micro-spheroids. Abstract 1764, proceedings AACR 2010), the dual inhibition of the PI3k and EGFr pathways may prove highly productive. This work is ongoing at our center.

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.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

%d bloggers like this: