title: Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas.
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.
authors.affiliation: Department of Mathematics, Florida State University, Tallahassee, Florida,United States of America.
authors.forename: Harsh Vardhan
authors.initials: HV
authors.lastname: Jain
authors.affiliation: Institute for Science and Technology in Medicine, Keele University, Stoke-on-Trent, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Richardson
authors.affiliation: Department of Systems Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany ; Bio Centre for Life Science, Braunschweig University of Technology, Braunschweig, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Meyer-Hermann
authors.affiliation: Oxford Centre for Collaborative and Applied Mathematics, Mathematical Institute, University of Oxford, Oxford, United Kingdom ; Department of Computer Science, University of Oxford, Oxford, United Kingdom.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Byrne
mesh_terms: D000465:Algorithms; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D016190:Carboplatin / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009596:Nitrophenols / Q000494:pharmacology / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D016190:Carboplatin