The Molecular Basis of Synergism between Carboplatin and ABT-737 in Ovarian Carcinomas
Mathematical Biosciences Institute, The Ohio State University
(February 18, 2010 10:30 AM - 11:18 AM)
Ovarian cancers remain difficult to treat due to the emergence of drug resistance, which may be conferred in part by the expression of anti-apoptotic members of the Bcl-family of proteins. ABT-737 is a recently developed small molecule inhibitor of these proteins, currently in stages I/II of clinical trial. In recent experiments, ABT-737 co-administered with Carboplatin, a Pt-based chemotherapeutic drug used to treat ovarian carcinomas, was found to act in a synergistic manner on cancer cells in vitro. Here we develop a mathematical model to investigate the molecular basis of this synergism. The model is built up of two modules, simulating treatment by each compound as a single agent, and is calibrated versus in vitro cell growth inhibition data. These two components are then integrated to represent combination therapy. Numerical simulations indicate that Carboplatin sensitizes the cells to ABT-737 therapy, due to a diminished ability of cells to withstand DNA damage under lowered Bcl-xL levels. The model predicts the existence of a threshold, so that if intracellular Bcl-xL falls below this, cells with relatively low DNA damage are unable to evade apoptosis. Further, simulations indicate that co-treatment and post-treatment with ABT-737 is an optimal strategy to exploit the synergism of the two drugs. Pre-treatment however displays poor results in comparison, due to their proposed mechanism of action. Such modeling, if developed in conjunction with experimentation, can thus have far reaching effects in the field of anti-cancer drug development.