Systems approach to personalized molecular medicine.

Abstract

Abstract #MS2-1

The realization of the promise of personalized molecular medicine will require the efficient development and implementation of novel targeted therapeutics. The overall likelihood of response to particular drugs represents the interaction between predictors of sensitivity with predictors of resistance. The phosphatidylinositol 3'kinase (PI3K) pathway is aberrant at multiple levels across a wide variety of tumors making it the most common activating aberration in cancer. This has led to the development and now early clinical testing of drugs targeting multiple components of the pathway. The efficient utilization of these drugs will require the ability to accurately determine mutation and activation status in tumors as well as determining the interaction between the PI3K pathway and other pathways in driving tumor pathophysiology. The PI3K pathway is critically important to cellular function and is thus under exquisite homeostatic control. The feedforward and feedback loops in the pathway determine the response to perturbation of the pathway by mutation or therapeutic intervention. Strikingly inhibition of the pathway at the level of mTOR or AKT results in the activation of potent feedback loops resulting in activation of multiple cell surface tyrosine kinases, PI3K itself and AKT. This may contribute to the observation that mTOR inhibitors appear to make some patient tumors grow more rapidly an unexpected and disappointing consequence. Our preliminary systems biology-based mathematical and experimental models of the PI3K signaling network accurately predict these consequences as well as the biochemical processes involved. Further, the models suggest combinations of targeted therapeutics likely to reverse the negative effects of the mTOR inhibitors converting the outcome from negative to positive in terms of tumor growth.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr MS2-1.