Time for Rational Therapy?

At the 2012 American Association for Cancer Research (AACR) meeting recently held in Chicago, I again observed that the AACR presentations continue to diverge from those at the American Society of Clinical Oncology (ASCO). At this year’s meeting, I’m not sure I heard the word “chemotherapy” a single time. That is, all of the alphabet soup combinations that make up the sessions at ASCO are nowhere to be found at the AACR meeting. Instead, targeted agents, genomics, proteomics and the growing field of metabolomics reign supreme.

Over the coming weeks, I will blog about some of the more interesting presentations I attended. However, I note below several themes that seemed to emerge.

First: That cancer patients are highly unique. In one presentation using phosphoprotein signatures to connect genetic features to phenotypic expression, the investigator conducted 21 phosphoprotein signatures and found 21 different patterns. This, he noted, reflected the “uniqueness” of each individual.

Additional themes included the growing development of meaningfully effective immune therapies. There was evidence of a renewed interest in tissue cultures as the best platform to study drug effects and interactions. Although virtually every presentation began with the obligatory reference to genomic analysis, almost every one of them then doubled back to metabolism as the principal driver of human cancer.

Interestingly, the one phrase that cropped up time and time again was rational therapeutics. Although they did not appear to be referring to our group, it was comforting to note that they are at least, finally coming around to our philosophy.

Probing Human Biology

Functional Analyses Unravel The Complexities of Signal Transduction

The application of functional analyses in human tumors is the topic of our upcoming presentation at the American Association of Cancer Research to be held in Washington D.C, in April 2010 (Nagourney, R. et. al, Horizontal and vertical signal pathway inhibition in human tumor primary culture micro-spheroids. Abstract 1764, to be presented Monday, April 19, 2010).

Scientists now realize that cancer biology, indeed all biology, is driven by signaling pathways. Cells speak to each other and the messages they send are interpreted via intracellular pathways known as signal transduction. Many of these pathways are activated or deactivated by phosphorylations on select cellular proteins. Tyrosine kinases, and serine/threonine kinases are among the most important classes of enzymes responsible for these chemical cascades inside the cell. In recent years small molecules have been developed to inhibit these chemical reactions. Hundreds of such compounds are in development for cancer today. While most scientists use genomic or proteomic platforms to detect mutations in these pathways that might result in response to these chemicals, we have taken a different tack. By applying functional analysis, to measure the end result of pathway activation or deactivation, we can predict whether patients will actually respond. Our results in lung cancer patients to date have exceeded the best outcomes using DNA profiles, clearly supporting the predictive accuracy use of functional analyses in this and related areas.

Focusing upon two fundamental pathways, the EGFR and the insulin-like growth factor pathway, we have explored how small molecule inhibitors influence these important survival signaling pathways. This is but one of many applications of functional profiling in the study of human tumor biology.

Chemosensitivity-Resistance Assay as Functional Profiling

Modern cancer research can be divided into three principal disciplines based upon methodology:

1.     Genomic — the analysis of DNA sequences, single nucleotide polymorphisms (SNPs), amplifications and mutations to develop prognostic and, to a limited degree, predictive information on cancer patient outcome.

2.     Proteomic — the study of proteins, largely at the level of phosphoprotein expressions.

3.     Functional — the study of human tumor explants isolated from patients to examine the effects of growth factor withdrawal, signal transduction inhibition and cytotoxic insult on cancer cell viability.

Contrary to analyte-based genomic and proteomic methodologies that yield static measures of gene or protein expression, functional profiling provides a window on the complexity of cellular biology in real-time, gauging tumor cell response to chemotherapies in a laboratory platform. By examining drug induced cell death, functional analyses measure the cumulative result of all of a cell’s mechanisms of resistance and response acting in concert. Thus, functional profiling most closely approximates the cancer phenotype.  Insights gained can determine which drugs, signal transduction inhibitors, or growth factor inhibitors induce programmed cell death in individual patients’ tumors. Functional profiling is the most clinically validated technique available today to predict patient response to drugs and targeted agents.