Jump Starting Cancer Drug Development

The April 12 issue of PNAS (Proceedings of the National Academy of Sciences) features a lead article by investigators at NYU, Cornell and Rational Therapeutics, on the identification of three compounds that inhibit the important cell signaling pathway known as WNT.

The WNT pathway was originally described in fruit flies as a determinate of wing shape. It was subsequently shown to be an important factor in human stem cell differentiation. Thereafter, its role in cancer was described. Certain colon cancers associated with a familial syndrome have a mutation in the WNT pathway. This results in an extremely high incidence of colon cancer. We now know that lung cancers, breast cancers, leukemias and lymphomas may share this pathway.

To date, there have been no clinical therapies available to treat WNT-driven tumors. Recognizing the importance of this pathway, the investigators at NYU and Cornell used a technology known as small interfering RNA (SIRNA) to shut down the WNT signal. They then screened 14,000 know chemicals for activity that mimicked the SIRNA effect. Three compounds were identified.

When the compounds showed activity in cell-lines that were WNT addicted, the investigators at NYU provided the compounds to Rational Therapeutics where we applied the EVA-PCD technique to measure activity in human tumor samples. The results confirmed activity and showed that several colon cancers, as well as other tumor types, had favorable profiles. The compounds were not uniformly effective, indicating that they were not simply toxins. Instead, they appeared to selectively injure cells that we assume are driven by WNT-related events.

The beauty of this study represents the introduction of a new paradigm of drug development. Following the elegant and highly sophisticated high throughput method employed by investigators at NYU and Cornell, these compounds were put to the very practical test of human relevance. The identification of activity in human tissues at concentrations similar to those associated with other classes of drugs, suggest that these novel compounds may have promise with these heretofore-untreatable cancers. This highly productive collaboration could prove a new model for the development of effective new therapies.

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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