Chemosensitivity Testing – What It Is and What It Isn’t

Several weeks ago I was consulted by a young man regarding the management of his heavily pre-treated, widely metastatic rectal carcinoma. Upon review of his records, it was evident that under the care of both community and academic oncologists he had already received most of the active drugs for his diagnosis. Although his liver involvement could easily provide tissue for analysis, I discouraged his pursuit of an assay. Despite this, he and his wife continued to pursue the option.

As I sat across from the patient, with his complicated treatment history in hand, I was forced to admit that he looked the picture of health. Wearing a pork pie hat rakishly tilted over his forehead, I could see few outward signs of the disease that ravaged his body. After a lengthy give and take, I offered to submit his CT scans to our gastrointestinal surgeon for his opinion on the ease with which a biopsy could be obtained. I then dropped a note to the patient’s local oncologist, an accomplished physician who I respected and admired for his practicality and patient advocacy.

A week later, I received a call from the patient’s physician. Though cordial, he was puzzled by my willingness to pursue a biopsy on this heavily treated individual. I explained to him that I was actually not highly motivated to pursue this biopsy, but instead had responded to the patient’s urging me to consider the option. I agreed with the physician that the conventional therapy options were limited but noted that several available drugs might yet have a role in his management including signal transduction inhibitors.

I further explained that some patients develop a process of collateral sensitivity, whereby resistance to one class of drugs (platins, for example) can enhance the efficacy of other class of drugs (such as, antimetabolite) Furthermore, patients may fail a drug, then be treated with several other classes of agents, only then a year of two later, manifest sensitivity to the original drug.

Our conversation then took a surprising turn. First, he told me of his attendance at a dinner meeting, some 25 years earlier, where Dan Von Hoff, MD, had described his experiences with the clonogenic assay. He went on to tell me how that technique had been proven unsuccessful finding a very limited role in the elimination of “inactive” drugs with no capacity to identify “active “drugs. He finished by explaining that these shortcomings were the reason why our studies would be unlikely to provide useful information.

I found myself grasping for a handle on the moment. Here was a colleague, and collaborator, who had heard me speak on the topic a dozen times. I had personally intervened and identified active treatments for several of his patients, treatments that he would have never considered without me. He had invited me to speak at his medical center and spoke glowingly of my skills. And yet, he had no real understanding of what I do. It made me pause and wonder whether the patients and physicians with whom I interact on a daily basis understand the principles of our work. For clarity, in particular for those who may be new to my work, I provide a brief overview.

1.    Cancer patients are highly individual in their response to chemotherapies. This is why each patient must be tested to select the most effective drug regimen.

2.    Today we realize that cancer doesn’t grow too much it dies too little. This is why older growth-based assays didn’t work and why cell-death-based assays do.

3.    Cancer must be tested in their native state with the stromal, vascular and inflammatory elements intact. This is why we use microspheroids isolated directly from patients and do not grow or subculture our specimens.

4.    Predictions of response are not based on arbitrary drug concentrations but instead reflect the careful calibration of in vitro findings against patient outcomes – the all-important clinical database.

5.    We do not conduct drug resistance assays. We conduct drug sensitivity assays. These drug sensitivity assays have been shown statistically significantly to correlate with response, time to progression and survival.

6.    We do not conduct genomic analyses for there are no genomic platforms available today that are capable of reproducing the complexity, cross-talk, redundancy or promiscuity of human tumor biology.

7.    Tumors manifest plasticity that requires iterative studies. Large biopsies and sometimes multiple biopsies must be done to construct effective treatment programs.

8.    With chemotherapy, very often more is not better.

9.    New drugs are not always better drugs.

10.   And finally, cancer drugs do not know what diseases they were invented for.
While we could continue to enumerate the principles that guide our practice, one of the more important principles is humility. Medicine is a humbling experience and cancer medicine even more so. Patients often know more than their doctors give them credit for. Failing to incorporate a patient’s input, experience and wishes into the treatment programs that we design, limits our capacity to provide them the best outcome.

With regard to my colleague who seemed so utterly unfamiliar with these concepts, indeed for a large swath of the oncologic community as a whole, I am reminded of the saying “There’s none so blind as those who will not see.”

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.

14 Responses to Chemosensitivity Testing – What It Is and What It Isn’t

  1. patmerwin says:

    Following my own lung cancer dx more than three years ago, I have come to appreciate the role “gut instinct” has played in guiding the many treatment decisions that have enabled me to stay well. As an untreated patient new to the world of cancer, I had no biases to influence my decision to have a cell death assay. In my gut, of course it made sense!

    No disrespect, Dr. Nagourney, but this isn’t rocket science. Patients “get it”, until their oncologists convince them otherwise. If physicians can’t see the simple logic as you have clearly presented above, perhaps they need to get out of their heads long enough to reconnect to their guts. Perhaps the problem isn’t only that they refuse to see, but that, in a landscape of research focused overwhelmingly on genes and clinical trials, they simply “can’t see the forest for the trees”.

    To those physicians I would ask, “which of the 10 statements above do you have a problem with?”. I suspect many would say “none”. So, what does your gut tell you about the value of a cell death assay? What’s not to see?

    • Thanks for your comment. The concept of improving outcomes with the more intelligent use of therapy is appealing to all. Oncologists have been trained that human tissue cannot predict outcome. It sometimes seems that no amount of data will convince them otherwise.

      As we no longer reward physicians for their successes but do very much punish them for their failures, MDs have become risk averse. To a doctor there is little be gained for stepping outside of the NCCN guidelines. For many patients there is little to be gained by remaining within them. Patients are increasingly forced to actively participate in the decision making process. In a way the assay studies that we conduct empower patients to take and active role in at least some the decisions that affect their lives.

  2. Rich says:

    “8. With chemotherapy, very often more is not better.”

    Which seems to be another option for reusing previously “failed” drugs. Do you have the ability to determine dose response differentials?

    Also..in a case with limited “cancer drugs” seemingly possible, can you similarly investigate off label options?

    Thanks

    • Drugs often work because they are the “right drug” not becasue we give a large amount. As to previously failed therapies, we have seen numerous occasions in which a drug used years earlier becomes effective again, once the tumor has been removed from the selective pressure of drug exposure. The tumor loses the capacity to resist. One can test almost any drug in the test tube. Many therapeis in wide use today were originally observed to have activity in our lab, years before they became standard treatments.

      • Rich says:

        Understood. Changes induced by subsequent treatment may bring the tumor back to a point where failed drugs are viable again. But I was referring to using a given drug in ways that (as theory understands it) either “wallops” it (Maximum tolerated dose) or chips away at it via anti-angiogenesis etc (Metronomic).

        This gets my attention:
        “Many therapeis in wide use today were originally observed to have activity in our lab, years before they became standard treatments”

        Makes me wonder what’s identified in your lab but still slogging through phase I “average patient” trials.

        Also makes me wonder if you have investigated drugs that are not active by themselves yet help reverse drug resistance.

      • Yes. Many new drug combinations take years to advance through the trial process. We fist used Cisplatin plus Gemcitabine (under special approval from the FDA) to successfully treat a drug refractory ovarian cancer patient in 1995. The combination of Carboplatin plus gemcitabine did not receive formal FDA approval in this disease until after the publication of the confirmatory European trial by Pfisters in 1996, fully 11 years later. We have tested many small molecules and in the past studied the P-glycoprtein and GST inhibitors to reverse drug resistance.

  3. Rich says:

    I should have referred specifically to metronomic (low dose, continuous) dosing above.

  4. Elaine L. says:

    Rich, interesting question re: off label options. I am finding that many women with ovarian cancer are using Iscador, which is being used in Germany, but not here. It is obtainable and can be ordered in this country. They seem to be getting hopeful results, following a specific protocol and giving themselves self injections. I’m wondering if this type of alternative therapy could be tested for sensitivity, if requested by the patient.

    • We can and have tested many botanical extracts (of which Iscadore is one). In order for us to give useful information, we first must do a series of dose-response studies to examine whether the compound gives a “signal” in our system. We then must calibrate the assay to give a distribution of “sensitive” and “resistant” results for comparison with a given patient’s profile. This can require months of work. It is therefore is important for us to know that a new drug or compound is of real interest and importance to our patients before we embark on the assay development.

  5. Rich says:

    So..you have a number of alternative/off label agents that have gone through the necessary preliminary calibrations? Maybe available off “menu”? 😉

    • We are extremely interested to work with regulatory agencies and pharmceutical companies to help accelerate drug development. This could be a very exciting and highly productive application of our platform.

  6. Sonia says:

    Dear Dr. Nagourney – great thoughts and encouraged to learn that you’re open to evaluating ‘off-label’ and non-conventional treatments.

    Some of the drugs/compounds that are being actively used by many patients across different tumor types (and also are being advocated by many integrative oncologists) are
    1. Curcumin (non-toxic, targeting multiple pathways)

    2. Metformin (I’m aware your lab tests for mTOR inhibitors; wondering if you could test for Metformin having similar activity against IGFR / PI3K influenced tumors ?)

    3. Aspirin / Beta-blockers (used as adjuncts to cytotoxics / targeted agents; which have shown promising results in some pre-clinical / early studies done by Canadian scientists

    either in maintenance setting or used along with cyto-toxic therapies to improve the therapeutic index of therapies / reverse resistance pathways.

    Keen to know your experience with these; either in the lab or with your patients; especially when combined with other cyto-toxics / targeted agents.

    This would be such an exciting area and of extreme help to patients. Thank you very much for continuing to be such a champion of patients.

    • Bill Conrad says:

      I have CLL cancer. Is their a lab that my onacologist could use to find the most efficiant treatment for my cancer? Where can I find a good doctor in CA that would do the test? Bill Conrad

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