title: 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.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Olga
authors.initials: O
authors.lastname: Karginova
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Marni B
authors.initials: MB
authors.lastname: Siegel
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Amanda E D
authors.initials: AE
authors.lastname: Van Swearingen
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Biostatistics Core Facility, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Deal
authors.affiliation: Medical Oncology Department, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Barbara
authors.initials: B
authors.lastname: Adamo
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Sambade
authors.affiliation: Department of Radiology, University of North Carolina, Chapel Hill, North Carolina. Department of Biomedical Engineering, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Soha
authors.initials: S
authors.lastname: Bazyar
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Nana
authors.initials: N
authors.lastname: Nikolaishvili-Feinberg
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Ryan
authors.initials: R
authors.lastname: Bash
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Sara
authors.initials: S
authors.lastname: O'Neal
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Katie
authors.initials: K
authors.lastname: Sandison
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Parker
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Charlene
authors.initials: C
authors.lastname: Santos
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: David
authors.initials: D
authors.lastname: Darr
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina. Translational Oncology and Nanoparticle Drug Development Initiative (TOND2I) Laboratory, University of North Carolina, Chapel Hill, North Carolina. Carolina Center of Cancer Nanotechnology Excellence, Chapel Hill, North Carolina. UNC Institute of Pharmacogenomics and Individualized Therapy, Chapel Hill, North Carolina.
authors.forename: William
authors.initials: W
authors.lastname: Zamboni
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Department of Radiology, University of North Carolina, Chapel Hill, North Carolina. Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Yueh Z
authors.initials: YZ
authors.lastname: Lee
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina. Neurology and Neurosciences Center, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: C Ryan
authors.initials: CR
authors.lastname: Miller
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Department of Medicine, University of North Carolina, Chapel Hill, North Carolina. carey_anders@med.unc.edu.
authors.forename: Carey K
authors.initials: CK
authors.lastname: Anders
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000235:genetics*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000378:metabolism; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016000:Cluster Analysis; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D009154:Mutation; D010539:Permeability; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D001562:Benzimidazoles; C521013:veliparib; D016190:Carboplatin; D011065:Poly(ADP-ribose) Polymerases
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