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

Abstract

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.

• Authors: Olga Karginova, Marni B Siegel, Amanda E D Van Swearingen, Allison M Deal, Barbara Adamo, Maria J Sambade, Soha Bazyar, Nana Nikolaishvili-Feinberg, Ryan Bash, Sara O'Neal, Katie Sandison, Joel S Parker, Charlene Santos, David Darr, William Zamboni, Yueh Z Lee, C Ryan Miller, Carey K Anders
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 14 Issue 4 Pg. 920-30 (Apr 2015) ISSN: 1538-8514 [Electronic] United States
• PMID: 25824335 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• BRCA1 Protein
• Benzimidazoles
• veliparib
• Carboplatin
• Poly(ADP-ribose) Polymerases

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• BRCA1 Protein (genetics)
• Benzimidazoles (administration & dosage, pharmacology)
• Blood-Brain Barrier (metabolism)
• Carboplatin (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cluster Analysis
• Disease Models, Animal
• Drug Synergism
• Female
• Gene Expression Profiling
• Humans
• Mice
• Mutation
• Permeability
• Poly(ADP-ribose) Polymerases (metabolism)
• Triple Negative Breast Neoplasms (diagnosis, drug therapy, genetics, mortality, pathology)
• Xenograft Model Antitumor Assays