Is Cancer a Genetic Disease?

I recently had the opportunity to meet two charming young patients: One, a 32-year-old female with an extremely rare malignancy that arose in her kidney and the other a 33-year-old gentleman with widely metastatic sarcoma.

Both patients had obtained expert opinions from renowned cancer specialists and both had undergone aggressive multi-modality therapies including chemotherapy, radiation and surgery. Although they suffered significant toxicities, both of their diseases had progressed unabated. Each arrived at my laboratory seeking assistance for the selection of effective treatment.

Sarcoma 130412.01With the profusion of genomic analyses available today at virtually every medical center, it came as no surprise that both patients had undergone genetic profiling. What struck me were the results. The young woman had “no measurable genetic aberrancies” from a panoply of 370 cancer-causing exomes, while the young man’s tumor revealed no somatic mutations and only two germ-line SNV’s (single nucleotide variants) from a 50 gene NextGen sequence, neither of which had any clinical or therapeutic significance.

What are we to make of these findings? By conventional wisdom, cancer is a genetic disease. Yet, neither of these patients carried detectable “driver” mutations. Are we to conclude that the tumors that invaded the cervical vertebra of the young woman, requiring an emergency spinal fusion, or the large mass in the lung of the young man are not “cancers”? It would seem that if we apply contemporary dogma, these patients do not have a cancer at all. But nothing could be further from the truth.

Cancer as a disease is not a genomic phenomenon. It is a phenotypic one. As such, it is extremely likely that these patients’ tumors are successfully exploiting normal genes in abnormal ways. The small interfering RNAs or methylations or acetylation or non-coding DNA’s that conspired to create these monstrous problems are too deeply encrypted to be easily deciphered by our DNA methodologies. These changes are effectively gumming up the works of the cancer cell’s biology without leaving a fingerprint.  Slide Detail-small

I have long recognized that cellular studies like the EVA-PCD platform provide the answers, through functional profiling, that genetic analyses can only hope to detect. The assay did identify drugs active in these patients’ tumor, which will offer meaningful benefit, despite the utter lack of genetic targets. Once again, we are educated by cellular biology in the absence of genomic insights. This leaves us with a question however – is cancer a genetic disease?

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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