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Efficacy of Carboplatin Alone and in Combination with ABT888 in Intracranial Murine Models of BRCA-Mutated and BRCA-Wild-Type Triple-Negative Breast Cancer.

Publication ,  Journal Article
Karginova, O; Siegel, MB; Van Swearingen, AED; Deal, AM; Adamo, B; Sambade, MJ; Bazyar, S; Nikolaishvili-Feinberg, N; Bash, R; O'Neal, S ...
Published in: Molecular cancer therapeutics
April 2015

Patients with breast cancer brain metastases have extremely limited survival and no approved systemic therapeutics. Triple-negative breast cancer (TNBC) commonly metastasizes to the brain and predicts poor prognosis. TNBC frequently harbors BRCA mutations translating to platinum sensitivity potentially augmented by additional suppression of DNA repair mechanisms through PARP inhibition. We evaluated brain penetrance and efficacy of carboplatin ± the PARP inhibitor ABT888, and investigated gene-expression changes in murine intracranial TNBC models stratified by BRCA and molecular subtype status. Athymic mice were inoculated intracerebrally with BRCA-mutant: SUM149 (basal), MDA-MB-436 (claudin-low); or BRCA-wild-type (wt): MDA-MB-468 (basal), MDA-MB-231BR (claudin-low). TNBC cells were treated with PBS control [intraperitoneal (IP), weekly], carboplatin (50 mg/kg/wk, IP), ABT888 (25 mg/kg/d, oral gavage), or their combination. DNA damage (γ-H2AX), apoptosis (cleaved caspase-3, cC3), and gene expression were measured in intracranial tumors. Carboplatin ± ABT888 significantly improved survival in BRCA-mutant intracranial models compared with control, but did not improve survival in BRCA-wt intracranial models. Carboplatin + ABT888 revealed a modest survival advantage versus carboplatin in BRCA-mutant models. ABT888 yielded a marginal survival benefit in the MDA-MB-436, but not in the SUM149 model. BRCA-mutant SUM149 expression of γ-H2AX and cC3 proteins was elevated in all treatment groups compared with control, whereas BRCA-wt MDA-MB-468 cC3 expression did not increase with treatment. Carboplatin treatment induced common gene-expression changes in BRCA-mutant models. Carboplatin ± ABT888 penetrates the brain and improves survival in BRCA-mutant intracranial TNBC models with corresponding DNA damage and gene-expression changes. Combination therapy represents a potential promising treatment strategy for patients with TNBC brain metastases warranting further clinical investigation.

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Published In

Molecular cancer therapeutics

DOI

EISSN

1538-8514

ISSN

1535-7163

Publication Date

April 2015

Volume

14

Issue

4

Start / End Page

920 / 930

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Triple Negative Breast Neoplasms
  • Poly(ADP-ribose) Polymerases
  • Permeability
  • Oncology & Carcinogenesis
  • Mutation
  • Mice
  • Humans
  • Gene Expression Profiling
  • Female
 

Citation

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Karginova, O., Siegel, M. B., Van Swearingen, A. E. D., Deal, A. M., Adamo, B., Sambade, M. J., … Anders, C. K. (2015). Efficacy of Carboplatin Alone and in Combination with ABT888 in Intracranial Murine Models of BRCA-Mutated and BRCA-Wild-Type Triple-Negative Breast Cancer. Molecular Cancer Therapeutics, 14(4), 920–930. https://doi.org/10.1158/1535-7163.mct-14-0474
Karginova, Olga, Marni B. Siegel, Amanda E. D. Van Swearingen, Allison M. Deal, Barbara Adamo, Maria J. Sambade, Soha Bazyar, et al. “Efficacy of Carboplatin Alone and in Combination with ABT888 in Intracranial Murine Models of BRCA-Mutated and BRCA-Wild-Type Triple-Negative Breast Cancer.Molecular Cancer Therapeutics 14, no. 4 (April 2015): 920–30. https://doi.org/10.1158/1535-7163.mct-14-0474.
Karginova O, Siegel MB, Van Swearingen AED, Deal AM, Adamo B, Sambade MJ, et al. Efficacy of Carboplatin Alone and in Combination with ABT888 in Intracranial Murine Models of BRCA-Mutated and BRCA-Wild-Type Triple-Negative Breast Cancer. Molecular cancer therapeutics. 2015 Apr;14(4):920–30.
Karginova, Olga, et al. “Efficacy of Carboplatin Alone and in Combination with ABT888 in Intracranial Murine Models of BRCA-Mutated and BRCA-Wild-Type Triple-Negative Breast Cancer.Molecular Cancer Therapeutics, vol. 14, no. 4, Apr. 2015, pp. 920–30. Epmc, doi:10.1158/1535-7163.mct-14-0474.
Karginova O, Siegel MB, Van Swearingen AED, Deal AM, Adamo B, Sambade MJ, Bazyar S, Nikolaishvili-Feinberg N, Bash R, O’Neal S, Sandison K, Parker JS, Santos C, Darr D, Zamboni W, Lee YZ, Miller CR, Anders CK. Efficacy of Carboplatin Alone and in Combination with ABT888 in Intracranial Murine Models of BRCA-Mutated and BRCA-Wild-Type Triple-Negative Breast Cancer. Molecular cancer therapeutics. 2015 Apr;14(4):920–930.

Published In

Molecular cancer therapeutics

DOI

EISSN

1538-8514

ISSN

1535-7163

Publication Date

April 2015

Volume

14

Issue

4

Start / End Page

920 / 930

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Triple Negative Breast Neoplasms
  • Poly(ADP-ribose) Polymerases
  • Permeability
  • Oncology & Carcinogenesis
  • Mutation
  • Mice
  • Humans
  • Gene Expression Profiling
  • Female