Chemosensitivity Testing: Lessons Learned

Like all physicians and scientists engaged in the study of cancer biology and cancer treatment, I had accepted that cancer was a disease of abnormal cell growth. I remember reading the lead article in the New England Journal of Medicine (NEJM) that described the clonogenic assay (Salmon, S. E., Hamburger, A. W., Soehnlen, B. S., et al. 1978. Quantitation of differential sensitivity of human tumor stem cells to anticancer drugs. N Engl J Med 298:1321–1327).

I sat in a laboratory at Georgetown University reading about a lab test that could accurately predict the outcome of cancer patients, without first having to give patients toxic drugs. It seemed so logical, so elegant, so inherently attractive. Sitting there as a medical student, far removed from my formal cancer training, I thought to myself, this is a direction that I would like to pursue.

But I was only a first year student and there were miles to go before I would treat cancer patients. Nonetheless, selecting drugs based on a laboratory assay was something I definitely wanted to do. At the time I had no idea just how difficult that could prove to be.

After medical school I found myself in California. There I met an investigator from the National Cancer Institute who had recently joined the faculty at the University of California, Irvine. He too had read the NEJM paper. Being several years ahead of me in training he had applied the clonogenic technique at his laboratory at the National Cancer Institute. Upon his arrival in California, he had continued his work with the clonogenic assay.

All was going along swimmingly until the NEJM published their report documenting the results of five years experience with the clonogenic assay.  It wasn’t a good report card. In fact the clonogenic assay got an “F.”

Despite the enthusiastic reception that the assay had previously enjoyed, the hundreds of investigators around the world who had adopted it and the indefatigable defense of its merits by leading scientists, it seemed that something was very wrong with the clonogenic assay and I desperately needed to know what that was.

It so happens that in parallel to clonogenic assays, my colleague was working on a simpler, faster way to measure drug effects. Using the appearance of cells under the microscope and their staining characteristics, one could skip the weeks of growth in tissue culture and jump right to the finish line. The simple question to be answered was: Did the drugs and combinations kill cancer cells in the test tube? And if they did kill cancer cells in the test tube, would those drugs work in the patient? The answer was, “YES!”

Despite the clonogenic assay’s supporters, it turned out that killing cancer cells outright in the test tube was a much, much better way to predict patient’s outcomes. It would be years before I understood the depth of this seemingly simple observation and the historical implications it would have for cancer therapy.

FINAL book cover-lo resIn Chapter 7 of my soon-to-be-released book, Outliving Cancer I examine the impact of programmed cell death on human biology.

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.

2 Responses to Chemosensitivity Testing: Lessons Learned

  1. barbaraH says:

    Hmm.. My comment from yesterday never showed up. Forgive me if this turns out to be a double post, or delete one if you can. Here it is again:

    Hi Dr. Nagourney –

    Thanks as always for taking the time to make all this information available. I am so grateful for it.

    I have a couple of questions for you, if you have time to answer. You often say that cancer cells don’t grow too much, they die too little. When I repeat this to people, in my constant proselytizing on behalf of the chemosensitivity test, I haven’t been able to actually articulate what this means. Us laypeople think that chemo has always been designed to kill cells. If anything, we think chemotherapy used to be designed to kill as many cells as possible, and today’s drugs are designed to target individual pathways to their growth.

    I must have something backwards, and so if you could give me a second sound bite to add to the first, I’d be very appreciative!

    Thanks –

    Barbara
    (Still doing well and almost another two years out from when I met you.)

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