The TEDx Experience

On Saturday July 16, I had the opportunity to present at the TEDxSoCal conference held here in Long Beach. The overall theme for this event was “thriving,” and appropriately, I presented in the afternoon session called, “well-being.” My lecture was entitled “The Future of Cancer Research Lies Behind Us.”

I chose this topic in light of the growing recognition that genomic analyses are not providing the therapeutic insights that our patients so desperately need. As I have written before in this blog, the Duke University lung cancer gene program, which has received much attention recently, is emblematic of the hubris associated with contemporary genomic analytic platforms.

I reviewed the contemporary experience in clinical trials, examined the potential pitfalls of gene-based analysis, and described the brilliant work conducted by biochemists and cell biologists, like Hans Krebs and Otto Warburg, who published their seminal observations decades before the discovery of the double helix structure of DNA.

I described insights gained using our ex-vivo analytic platform, that lead to treatments used today around the world, all of which were initially discovered using cell-based studies. More interesting still will be the opportunity to use these platforms to explore the next generation of cancer therapies – those treatments that influence the cell at its most fundamental level – its metabolism.

Many attendees stopped me after my lecture to thank and congratulate me for my presentation. Fearing that my topic might have been too esoteric, I was delighted by the reception and more convinced than ever that there are many enlightened individuals who thirst for new approaches to cancer treatment. It is these people who will forge the next generation of therapy.

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 The TEDx Experience

  1. Gary Brutsch says:

    Enlightened conversations,often dull with time. Please continue to inspire those individuals capable of continuing the quest for future solutions to historic problems

  2. Elaine L. says:

    Dr. Nagourney,

    I was very disappointed with the The ASCO’s Guideline on Tests to Help Choose Chemotherapy.

    Recommendations:

    Very few research studies suggest that tests to help choose chemotherapy improve treatment. In addition, there are no tests available for many types of cancer. Therefore, ASCO recommends the following for using chemotherapy sensitivity and resistance assays:

    Chemotherapy sensitivity and resistance assays should not be used to select chemotherapy for patients who are not participating in a clinical trial.

    Chemotherapy should be recommended based on research on the specific drug(s) and a patient’s health and treatment preferences.

    Isn’t this a shot in the heart of Assay Testing?

    • The ASCO article is not a shot “in” the heart of these techniques, it is a shot “at” the heart of these techniques. Fortunately their aim is not true. What these reviewers have forgotten is that Evidence Based Medicine, is not simply the application of the results of “Phase III, Randomized, double-blinded, controlled clinical trials” in the practice of medicine. Rather “it involves tracking down the best external evidence with which to answer our clinical questions. To find out about the accuracy of a diagnolstic test, we need to find proper cross sectional studies of patients clinically suspected of harboring the relevant disorder, not a randomized trial”…”some questions do not require randomised trials (successful intervention for otherwise fatal conditions) or cannot wait for the trials to be conducted. And if no randomized trial has been carried out for our patient’s predicament, we must follow the trail to the next best external evidence and work from there.” (Sackett, DL et al BMJ, 312, 1996).

      On every level we meet the criteria outlined by this recognized expert in the field. While we would welcome the opportunity to conduct a formal,cooperative group trial to prove our points, it has been the entrenched forces at these groups who have consistenty failed to allow us to put it to the test. The CATCH-22, of not being allowed to prove the merit of the work and then being told that in the absence of the proof, you can’t use it, is wearing a bit thin.

  3. What is it that ASCO is saying? Chemotherapy sensitivity and resistance assays should not be used outside the confines of a clinical trial setting. The same people who maintain that assay-directed therapy should not be used until proven in prospective randomized clinical trials, are the same people whose entire careers are utterly dependent upon mega-trials funded by pharmaceutical companies (that, plus fees from speeches they give for these companies), are the same people who control the clinical trials system, the grant review study sections, and the journal editorial boards. Why else would they want this technology tested under the clinical trial setting?

  4. Gary Brutsch says:

    If these guidelines were followed Tina would be history. MB Anderson’s DR wolf followed this protocal and sent Tina home to prepare to pass. We are now 3.5 years past that event. Thank you Dr Nagourney opinion

  5. Rich66 says:

    i thought it was a very good and accessible presentation. On the plus side, you were not clearly pimping sensitivity testing. On the negative side, you were not clearly pimping sensitivity testing. I know..the theme was to some degree about humility in the face of cancer. I give you credit while at the same time growing extremely frustrated by ASCO’s rigidity at the expense of patients dying after lab sustaining, incremental, yet ultimately fruitless dabbling.
    Regarding the metabolics of cancer, there are rumblings of a return to activity in this arena. Warburg lives on……..

    • It is always my intent to provide a balanced discussion of these topics. I believe that the data is compelling and, if reviewed with an open mind, should provide ample support for the use of these technologies. As to the rumblings of metabolism, there is no question that is true. What the genomics investigators have found is that their gene platforms are leading them right back to biochemistry, where they would have stayed in the first place, if they hadn’t gotten so smart.

  6. Linda S. says:

    Dr. Nagourney–
    Thought this was a riveting presentation!
    I was wondering how chemosensitivty testing relates to recent trends toward dose dense treatment?

    More specifically, dose dense taxol is recommended for “platinum resistant” ovarian cancer per NCCN guidelines. But what if the patient is resistant to Taxol, given as front line, which seems just as likely as being “platinum resistant?” Is there some magic to dose dense that overcomes the chemoresistance, or does dose dense just confer a temporary anti-angiogenic effect?

    Linda S.

    • Dose Density and the earlier iteration Dose Intensity, are predicated upon the dictum “If some is good, more is better”. The problem is the obverse, namely “If some is bad, more is worse”. Your point is very well taken. While I believe that the dense-dose approach has merit and actually teach the principle in my second year medical student pharmacology classes, I try wherever possible to use it in conjunction with the prior selection of the best drugs. This would be “Rational Dose Density”. In the example cited, simply giving more Taxol may not be the best strategy, yet in the absence of assay-guidance, that ‘s all you’ve got. As to the anti-angiogenic component, that is actully more often ascribed to low dose, chronic administrations via the metronomic approach, not the high dose, dose dense approaches.

      • Rich66 says:

        I don’t know if it applies to Linda’s situation. But I remember coming across some information where “dose dense” was actually referring to a metronomic approach. I can’t remember all the details but came away with the idea that there is occassional variability in the definition.

    • The dose-dense chemotherapy protocol is not the same as the low-dose chemotherapy protocol.

      Dose-dense chemotherapy shortens the treatment cycle while maintaining roughly the same chemotherapy dosage as conventional chemotherapy (the process reduction of time gap between two regular doses).

      Low-dose chemotherapy not only shortens the treatment cycle but lowers the dosage of treatment a patient can withstand during shorten administration of the drugs.

      Since the endothelial cells (involved in angiogenesis) are the first in the tumor to undergo cell death (apoptosis), the more frequent, lower-dose therapy can have an impressive anti-angiogenic and anti-tumor effects. Blood vessel cells are less likely than tumor cells to become resistant to chemotherapy and should still be able to shrink tumors by destroying their blood supply.

      The main targets of dose-dense chemotherapy are proliferating tumor cells. The main targets of low-dose chemotherapy are the endothelial cells of the growing vasculature of a tumor. In other words, chemotherapeutics can be used as anti-angiogenic agents.

  7. Elaine L. says:

    Linda-
    This is an excellent question.

  8. Linda S. says:

    Thanks Rich.

    Specific to my situation, after I flunked first line taxol/cisplatin therapy, and recurred within three months (and therefore was deemed “platinum resistant” by the large, distinguished research hospital where I was being treated), I was offered a Taxol “dose dense” trial (not metronomic) with a chance of also receiving MORAB (or not).

    In my feeble little brain, I thought why would I pursue a dose dense trial of a drug that obviously did not work ? And how did they know I was platinum resistant and not taxol resistant? (or both)

    I asked about assay testing but was told that did not work.

    And so I walked out.

    Linda

  9. Good. Medical centers will learn who they actually work for, when patients vote with their feet.

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