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

Handle URI:
http://hdl.handle.net/10754/596783
Title:
Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas.
Authors:
Jain, Harsh Vardhan; Richardson, Alan; Meyer-Hermann, Michael; Byrne, Helen M
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.
Citation:
Jain 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.
Publisher:
Public Library of Science (PLoS)
Journal:
PLoS ONE
KAUST Grant Number:
KUK-C1-013-04
Issue Date:
6-Jan-2014
DOI:
10.1371/journal.pone.0081582
PubMed ID:
24400068
PubMed Central ID:
PMC3882219
Type:
Article
ISSN:
1932-6203
Sponsors:
Funding 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.
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Publications Acknowledging KAUST Support

Full metadata record

DC FieldValue Language
dc.contributor.authorJain, Harsh Vardhanen
dc.contributor.authorRichardson, Alanen
dc.contributor.authorMeyer-Hermann, Michaelen
dc.contributor.authorByrne, Helen Men
dc.date.accessioned2016-02-21T08:50:36Zen
dc.date.available2016-02-21T08:50:36Zen
dc.date.issued2014-01-06en
dc.identifier.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.en
dc.identifier.issn1932-6203en
dc.identifier.pmid24400068en
dc.identifier.doi10.1371/journal.pone.0081582en
dc.identifier.urihttp://hdl.handle.net/10754/596783en
dc.description.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.en
dc.description.sponsorshipFunding 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.en
dc.publisherPublic Library of Science (PLoS)en
dc.rightsThis 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.en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subject.meshModels, Biologicalen
dc.titleExploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas.en
dc.typeArticleen
dc.identifier.journalPLoS ONEen
dc.identifier.pmcidPMC3882219en
dc.contributor.institutionDepartment of Mathematics, Florida State University, Tallahassee, Florida,United States of America.en
dc.contributor.institutionInstitute for Science and Technology in Medicine, Keele University, Stoke-on-Trent, United Kingdom.en
dc.contributor.institutionDepartment of Systems Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany ; Bio Centre for Life Science, Braunschweig University of Technology, Braunschweig, Germany.en
dc.contributor.institutionOxford Centre for Collaborative and Applied Mathematics, Mathematical Institute, University of Oxford, Oxford, United Kingdom ; Department of Computer Science, University of Oxford, Oxford, United Kingdom.en
kaust.grant.numberKUK-C1-013-04en

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