2.50
Hdl Handle:
http://hdl.handle.net/10033/311718
Title:
Exploiting the Synergy between Carboplatin and ABT-737 in the Treatment of Ovarian Carcinomas.
Authors:
Jain, Harsh Vardhan; Richardson, Alan; Meyer-Hermann, Michael ( 0000-0002-4300-2474 ) ; 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:
Exploiting the Synergy between Carboplatin and ABT-737 in the Treatment of Ovarian Carcinomas. 2014, 9 (1):e81582 PLoS ONE
Journal:
PloS one
Issue Date:
2014
URI:
http://hdl.handle.net/10033/311718
DOI:
10.1371/journal.pone.0081582
PubMed ID:
24400068
Type:
Article
Language:
en
ISSN:
1932-6203
Appears in Collections:
publications of the research group system immunology ([BRICS]SIMM)

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.accessioned2014-01-23T08:59:14Zen
dc.date.available2014-01-23T08:59:14Zen
dc.date.issued2014en
dc.identifier.citationExploiting the Synergy between Carboplatin and ABT-737 in the Treatment of Ovarian Carcinomas. 2014, 9 (1):e81582 PLoS ONEen
dc.identifier.issn1932-6203en
dc.identifier.pmid24400068en
dc.identifier.doi10.1371/journal.pone.0081582en
dc.identifier.urihttp://hdl.handle.net/10033/311718en
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.language.isoenen
dc.rightsArchived with thanks to PloS oneen
dc.titleExploiting the Synergy between Carboplatin and ABT-737 in the Treatment of Ovarian Carcinomas.en
dc.typeArticleen
dc.identifier.journalPloS oneen

Related articles on PubMed

This item is licensed under a Creative Commons License
Creative Commons
All Items in HZI are protected by copyright, with all rights reserved, unless otherwise indicated.