New Drugs Are Not Always Better Drugs

The most common form of renal carcinoma is the clear cell variant. These tumors are driven by mutations in the VHL gene and are associated with hyper-vascularity. Understanding the pathogenesis of this disease has enabled researchers to develop new classes of drugs that target VEGF, both at the protein level (Bevacizumab) and at the tyrosine kinase level (sorafenib, sunitinib, etc.). An additional class of drugs targets the intracellular metabolic pathway known as mTOR. Patients newly diagnosed with renal cell carcinoma of the clear cell type are treated with drugs that target these pathways. However, responses occur in the minority of patients. It is unclear why some patients respond to these interventions while others fail.

The EVA-PCD™ analysis is equally applicable to classic cytotoxic drugs and the newer classes of targeted agents, which include Sunitinib and Sorafenib and the rapalogs like Everolimus and Temsirolimus. This enables our lab to explore whether renal cell carcinoma patients are likely to respond to vascular or mTOR targeting classes of drugs. Interestingly, patients who do not respond to these classes of drugs may nonetheless have sensitivity to cytotoxic chemotherapeutic agents. One example currently undergoing therapy is a 51 year old male who was presented in February 2009 with widely metastatic renal cell carcinoma, and a destructive lesion of the right femur requiring open surgical stabilization. Tissue removed from the patient’s femur at the time of the orthopedic surgery was submitted for an EVA-PCD™ analysis. The results were highly instructive, indicating clear resistance to the VEGF targeting agents and the rapalogs but substantial sensitivity to a novel combination of cytotoxic drugs. The patient received an opinion from a renowned renal cell expert who immediately placed him on sunitinib (Sutent™). When he failed sunitinib he was then placed upon Everolimus (Afinitor). Again the patient failed to respond. Progression of his disease was heralded by brain metastases that required both neurosurgery and cranial irradiation. He then revealed rapidly progressive pulmonary metastases as well as large painful bilateral axillary lymphadenopathy and large painful subcutaneous lesions. In light of the patient’s failure of targeted agents, he was treated with a three-drug combination identified to be active in the EVA-PCD™ analysis. The response to date has been dramatic, with complete resolution of subcutaneous lesions and lymph nodes , and objective improvement in the pulmonary metastases by CT scan. The patient remains on therapy, with continued excellent response.

This is but one example of an unexpectedly good response to classic cytotoxic drugs following a failure to respond to the newest classes of targeted agents. These experiences reinforce the need for cancer therapies to be individualized. They also remind us, as physicians, that it is the good outcome of the patient not the therapy applied that constitute successful application of the healing arts.

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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