What is Personalized Cancer Therapy?

Personalized therapy is the right treatment, at the right dose for the right patient. Like the weather, however, it seems that everyone’s talking about it, but no one is doing anything about it.

In its simplest form personalized care is treatment that is designed to meet an individual’s unique biological features. Like a key in a lock, the right drug or combination opens the door to a good outcome.

When over the years I lectured on the development of the cisplatin/gemcitabine doublet, my two boys were quite young. I would show a slide depicting a doorknob with a key in the keyhole. I likened our lab’s capacity to identify sensitivity to the cisplatin/gemcitabine combination as “unlocking” an individual’s response.

At the time my wife and I would leave the key in the inside of the front door enabling us to unlock it when going out. We reasoned at the time that our 2-year-old would not be strong enough, nor tall enough to turn the key and let himself outside.  We reasoned wrong, for one day our son Alex reached up, turned the key and opened the door right in front of us. Lesson learned: Given the right key, anyone can open a door.

I continued my analogy by saying that even Arnold Schwarzenegger would be unable to open a door given the wrong key, but might, if he continued trying, snap it off in the lock.

The right key is the right treatment, effortlessly unlocking a good response, while the wrong key is the wrong treatment more often than not too much, too late, akin to a solid tumor bone marrow transplant.

In recent years, personalized care has come to be considered synonymous with genomic profiling. While we applaud breakthroughs in human genomics today, there is no molecular platform that can match patients to treatments.  The objective response rate of just 10 percent, almost all in breast and ovarian cancer patients in one study (Von Hoff J Clin Oncol 2010 Nov 20:28(33): 4877-83), suggests that cancer biology is demonstrably more complex than an enumeration of its constituent DNA base pairs. The unilateral focus on this area of investigation over others might be described as “the triumph of hope over experience” (James Boswell, Life of Samuel Johnson, 1791).

But hope springs eternal and with it the very real possibility of improving our patients outcomes. By accepting, even embracing, the complexity of human tumor biology we are at the crossroads of a new future in cancer medicine.

William Withering (1741-1799) the English physician and botanist credited with discovering digitalis as the therapy for dropsy, e.g. congestive heart failure (An Account of the Foxglove and some of its Medical Uses, Withering W. 1785), had absolutely no idea what a membrane ATPase was, when he made his remarkable discovery. It didn’t matter. Cardiac glycosides provided lifesaving relief to those who suffered from this malady for fully two centuries before Danish scientist, Jens Christian Skou, identified these membrane bound enzymes, for which he was awarded a Nobel Prize in 1997.

Similarly, penicillin, aspirin, and morphine were in all use for decades, centuries, even millenia before their actual modes of action were unraveled. Medical doctors must use any and all resources at their disposal to meet the needs of their patients. They do not need to know “how” something works so much as they (and their patients) need to know “that” it works.

The guiding principle of personalized medicine is to match patients to therapies. Nowhere in this directive is there a prescription of the specific platform to be used. Where genomic signatures provide useful insights for drug selection, as they do in APL (ATRA, Arsenic trioxide); NSCLC (EGFr, ROS1, ALK); CML (Imatinib, Dasatanib) then they should be used.

However, in those disease where we haven’t the luxury of known targets or established pathways, i.e. most human malignancies, then more global assessments of human tumor biology should, indeed must, be used if we are to meet the needs of our patients.  Primary culture analyses like the EVA/PCD® provide a window onto human tumor biology. They are vehicles for therapy improvement and conduits for drug discovery.  Scientists and clinicians alike need to apply any and all available methodologies to advance their art. The dawn of personalized medicine will indeed be bright if we use all the arrows in our quiver to advance clinical therapeutics and basic research.

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.

4 Responses to What is Personalized Cancer Therapy?

  1. gpawelski says:

    Dr. Nagourney

    If a genomic signature provides a useful insight for drug selection, as they sometimes do in NSCLC (EGFR, ROS1 ALK), how do they know if the targeted drug even gets into the cancer cell? How do they know if the targeted drug gets pumped out of the cell? Does the cell have ways of escaping targeted drug effects? Can cells repair damage caused by the targeted drug? Do combinations of targeted drugs work in ways which can’t be predicted on the basis of static gene expression patterns? The idea of searching for clinical responders by testing for a single gene mutation seems like a nice “theoretical” idea, but how do they test for the dozens of protein expressions that may be involved in determining sensitivity/resistance to a given targeted drug?

    • At the heart of much scientific discourse is the fundamental priciple of causality. Can we know that a given event occurs based upon our presumed mechanism or gene-mutation? Most often the answer is no. The closest most scientist get is correlation. That is why modern research is so dependent upon statistical analyses, pushing correlations (p values) ever closer to causations, but rarely actually reaching that unobtainable limit. The maturation curve for most scientists starts with certainty and ends with humility, as each, in thier own time, comes to realize how very little we know. The less we know the more we must use the power of observation to explain phenomena at hand. From Tycho Brahe and Johannes Kepler to Gregor Mendel, that which we did not understand came clearer into view as careful observation instructed us with needed insights. I use the study of human tumors as my model precisely because there is so much we do not know or understand. We need the biological signals to guide our subsequent investigations.

      We should be humble in our pursuit of scientific discovery. Medical research has but one true goal, the treatment of disease and alleviation of suffering. I applaud the brilliant discoveries that have been made in recent decades. I am delighted to have access to the many new small molecules that we test daily in our lab. But explorers are only explorers unitl they make a worthwhile discovery. The actions of a VEGF inhibitor (Bevacizumab) or an EGFR TKI (Erlotinib), the finding of a novel SNP or non-coding DNA are all but a weigh stations on our way to better clinical outcomes for our patients. It is perilous indeed for physician-scientists to forget that they are physicians first and scientists second. Those who do, should consider thier career choices carefully, for there is much need for metalurgists and plasma physicists and far too few healers.

  2. Dee says:

    I have just finished reading your most recent posts. As a 7 year epithelial OC survivor with one recurrence I I found your post on platinum resistance and medical tyranny very interesting. I agree personalized medicine should be much more than just studies of our gene profile.

    You mentioned presenting at ASCO. I will be sure to look up when your session is. I would love to hear more about your research. As a survivor, thank you for all that you do to increase our understanding of this disease.

    • Thank you for your nice comment. We are always happy to hear of good outcomes. Patients newly diagnosed with diseases like yours should know that they can do very well. Your words are uplifiting to them all.

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