Functional Profiling

This is an excellent question. Caris is a member of a group of molecular profiling companies. These groups extract protein, DNA or RNA and measure the genetic information present in fixed tissue. Their intent is to match patients to therapy based on this static data. That is, the presence of a gene should, according to their reasoning, confer sensitivity to a drug. The proof of this concept, however, is sorely lacking. If we examine one publication in the literature (VonHoff D et al, J Clin Oncol Nov 2010), we find an objective response rate (measurable benefit in 66 patients treated using molecularly selected drugs) of 10%. Indeed, the positive results reported in this study reflected not a response rate but instead a 30% improvement in the time to disease progression, associated with molecular drug selection, compared with the patients prior, most recent (unsuccessful) therapies. To put this in context, a patient could arguably fail a physician-selected treatment after 1 month, and then receive a Caris selected therapy. If they responded for 1 month plus 10 days (a 30% improvement), they were counted as a success. The clinical relevance of that degree of improvement seems questionable.
While we fully understand the excitement surrounding genetic analyses, the more sophisticated researchers in the field are beginning to appreciate that the complexity of human biology demands more global (functional) analytic platforms that encompass all of the mechanisms of response and resistance. In this light, the presence of a gene cannot predict whether that gene will be expressed, active, counter-acted by a complementary gene, or functional.
We believe that human biology must be taken at face value in its most complex state. This is known as the phenotype and must be examined for the biological features that these interconnected cellular systems create. This field now known as biosystematics, or systems biology, recognizes the redundancies and uncertainties that separate the genotype (molecular profiling) from the phenotype (functional analyses) are not trivial. Our laboratory conducts phenotype analyses. Caris conducts genotype analyses.

One might imagine three platforms for the study of human tumor biology. Genomics studies information at the level of DNA, while proteomics examines protein expression. Functional analyses approximate the living organism by examining the behavior of cancer cells in their own environment. This allows heretofore unrecognized complexities to be examined in real time. A growing number of investigators around the world are beginning to recognize the important and clinical application of these techniques.

Please visit our website at www.rational-t.com for additional information and references. In addition, the Ralph Moss’ book, “Customized Chemotherapy” Equinox Press 2011, is an excellent source regarding the history and application of these techniques.