Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas.
KAUST Grant NumberKUK-C1-013-04
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AbstractPlatinum 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.
CitationJain HV, Richardson A, Meyer-Hermann M, Byrne HM (2014) Exploiting the Synergy between Carboplatin and ABT-737 in the Treatment of Ovarian Carcinomas. PLoS ONE 9: e81582. Available: http://dx.doi.org/10.1371/journal.pone.0081582.
SponsorsFunding came from a National Science Foundation grant DMS 0931642 and Award No. KUK-C1-013-04 made by the King Abdullah University of Science and Technology (KAUST). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PublisherPublic Library of Science (PLoS)
PubMed Central IDPMC3882219
CollectionsPublications Acknowledging KAUST Support
Except where otherwise noted, this item's license is described as This is an open-access article distributed under the terms of the , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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