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.