Recurrent Small Cell Cancer of the Lung: A Therapeutic Challenge

I recall as a junior medical oncology Fellow, one of my senior Fellows describing small cell cancer of the lung as “leukemia of the lung.” The reason he used this description was because leukemia is among the most rapidly progressive and aggressive forms of cancer.

Arising in the bone marrow, an afflicted patient’s white blood cell count can double every day, a remarkable achievement when one considers the hundreds of billions of cells involved. What this doctor meant was that the lung cancer of small cell type (also known as oat cell), grew so rapidly that in untreated patients, survival can be measured in weeks to months. With the discovery of effective chemotherapy this disease became a comparatively easy mark for the treating oncologist. Ironically, where it was the worst form of lung cancer during the 70s, by the 1990s it was the best form to have. Most patients responded to treatment and some lived years. The problem is, treating patients who recur.

For unknown reasons this otherwise chemosensitive disease has a tendency to recur with a vengeance. Attempts to control recurrent disease with second line therapies have characteristically been unsuccessful. Drug combinations that are generally quite active in the first line setting, are almost universally inactive in second line use.

As a result, recurrent small cell lung cancer is tantamount to a death sentence.

Two months ago, a slender woman arrived at Rational Therapeutics carrying a biopsy kit and a bottle filled with straw-colored fluid. She explained that her husband had recurrent small cell lung cancer and his surgeon had inserted a chest tube. He then provided us with both biopsy material and fluid. She went on to say that she herself was a laboratory scientist and was familiar with laboratory techniques.

We processed the specimen, which provided amble cells for analysis. Not surprisingly, the tumor was resistant to many (most) of the drugs tested. However, the class of drugs known as alkylating agents revealed persistent activity. More importantly, the combination of an alkylating agent and topotican revealed activity and synergy.

Having published a paper on this topic several years ago, (Nagourney et al, British Journal of Cancer 2003) I was quite familiar with this combination. Referencing work by investigators at Yale University, using the combination of cytoxan and topotican, I provided my recommendation to a colleague who administered this combination with a very tolerable weekly dose schedule.

The patient responded immediately. So much so, that between cycle one and cycle two he took a vacation to San Diego with his wife.  Further response was documented following cycle two.  Most gratifying has been the very limited amount of toxicity in the treatment itself.

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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