Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas

Jain, HV; Richardson, A; Meyer-Hermann, M; Byrne, HM

Abstract

Platinum drug-resistance in ovarian cancers mediated by anti-apoptotic proteins such as Bcl-xL is a major factor contributing to the chemotherapeutic resistance of recurrent disease. Consequently, concurrent inhibition of Bcl-xL in combination with chemotherapy may improve treatment outcomes for patients. Here, we develop a mathematical model to investigate the potential of combination therapy with ABT-737, a small molecule inhibitor of Bcl-xL, and carboplatin, a platinum-based drug, on a simulated tumor xenograft. The model is calibrated against in vivo experimental data, wherein xenografts established in mice were treated with ABT-737 and/or carboplatin on a fixed periodic schedule. The validated model is used to predict the minimum drug load that will achieve a predetermined level of tumor growth inhibition, thereby maximizing the synergy between the two drugs. Our simulations suggest that the infusion-duration of each carboplatin dose is a critical parameter, with an 8-hour infusion of carboplatin given weekly combined with a daily bolus dose of ABT-737 predicted to minimize residual disease. The potential of combination therapy to prevent or delay the onset of carboplatin-resistance is also investigated. When resistance is acquired as a result of aberrant DNA-damage repair in cells treated with carboplatin, drug delivery schedules that induce tumor remission with even low doses of combination therapy can be identified. Intrinsic resistance due to pre-existing cohorts of resistant cells precludes tumor regression, but dosing strategies that extend disease-free survival periods can still be identified. These results highlight the potential of our model to accelerate the development of novel therapeutics such as BH3 mimetics.

• Acceptance Date: Oct 23, 2013
• Publication Date: Jan 6, 2014
• Journal: PLoS One
• Print ISSN: 1932-6203
• Publisher: Public Library of Science
• Pages: e81582 - ?
• DOI: https://doi.org/10.1371/journal.pone.0081582
• Keywords: algorithms, animals, biphenyl compounds, carboplatin, cell line, tumor, computer simulation, disease models, animal, drug resistance, neoplasm, drug synergism, female, humans, mice, models, biological, nitrophenols, ovarian neoplasms, piperazines, sulfona
• Publisher URL: http://dx.doi.org/10.1371/journal.pone.0081582