Yet Another Study Agrees: Functional Profiling Provides Insight

It was during the last weeks of December that a particularly interesting article crossed my desk. The study done by a group from Toronto, Canada, is entitled Variable Clonal Repopulation Dynamics Influence Chemotherapy Response in Colorectal Cancer. The study examined the proliferative capacity and drug sensitivity in colorectal cancer cells that were tracked using a process known as lentiviral lineage tracking. The investigators showed that despite serial passages, the cell populations remained stable from a genomic standpoint.

What was most interesting was the finding that these genomically related subpopulations became progressively more resistant to oxaliplatin after drug exposure, suggesting what they described as “inherent functional variability.”

As one of several investigators engaged in the field of functional profiling (EVA-PCD), I found the article both interesting and extremely consistent with our laboratory observations. First, cancer cells display biological differences that may reflect environmental (microenvironmental) influences, epigenetics and other drivers not readily identified at the DNA level.

Second, these investigators, using extremely sophisticated molecular techniques, found, as the lead investigator said, “We should not be putting our eggs exclusively in the genetics basket.” This quote from the lead investigator, John Dick, was particularly resonant.

As many of you who read my blogs know, a recurring theme in these pages is the need to broaden our scope and examine the protein, metabolic and functional characteristics of the cancer cells in their native state. Once again we find that as our most accomplished molecular brethren drill down to the bedrock of cancer biology, they are confronted by complexities and crosstalk that can only be effectively studied at the level of cell biology.

I wish all of readers of this blog a happy New Year, and look forward to a healthy and productive 2013.

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.

One Response to Yet Another Study Agrees: Functional Profiling Provides Insight

  1. A New England Journal of Medicine (366:883-892, March 8, 2012) article described how intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized medicine and biomarker development. This intratumor heterogeneity issue is not a new revelation to cell function analysis.

    According to a study published in Molecular Cancer Therapeutics, there is a need to analyze tumor specimens at the time of ovarian cancer recurrence, because they found significant changes in molecular characteristics for some biomarkers. This type of profiling does not take into account changes that can occur in recurrent ovarian tumors. This had been published in 1983, 1984, 1986 by cell function analysis.

    A study published in the journal Cell Stem Cell uncovered a case of mistaken identity that may have a significant impact on future breast cancer treatment strategies. They were able to distinguish four kinds of breast cancer that were distinct on the basis of their genetic makeup. These were rough categories and there were divisions within them.

    What’s more important than what genes are in the DNA is what genes are actively making RNA, which RNA is actively making protein, which protein is being turned off or turned on, and how all of the proteins in the cell are interacting with each other.

    The only way to get the latter information, which is ultimately what you want, is to treat the patient with phenotype analysis. In drug selection, phenotype analysis doesn’t dismiss DNA testing, it uses all the information, measuring the interaction of the entire genome, to design the best treatment for each individual.

    I like the analogy of Dr. Scott L. Shreeve about functionality. Anyone familiar with cellular biology knows that having the genetic sequence of a known gene (genotype) does not equate to having the disease state (phenotype) represented by that gene. It requires specific cellular triggers and specialized cellular mechanisms to literally translate the code into the work horse of the cellular world – proteins.

    As a result, while genomics provides a methodology to understand the sheet music of life, there is more interest in the proteomic symphony that results by literally bringing the dead notes to life. Since the actual performance of the sheet music can vary, based on the whims of the composer, there is the individual variation or free-lancing of the orchestral performers.

    So while the sheet music is absolutely essential to even contemplate a symphonic performance, no one goes to listen to the sheet music. It is the individual performances, the living-breathing-audible-panoramic-splended-view of the whole chamber coming to life that ultimately stirs the soul.

    In an analogous fashion, the proteins are the cellular accessories that literally add life to an otherwise staid genetic makeup. Infinitely more variable, infinitely more possibilities, and as a result, infinitely more interesting.

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