title: Poly(ADP-ribose) polymerase-1 inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary tumors in vivo and delays tumor relapse in combination with carboplatin.
abstract: Germ-line heterozygosity of the BRCA2 gene in women predisposes to breast and ovarian cancers. Successful therapies targeted specifically at these neoplasms have thus far remained elusive. Recent studies in mice have shown that inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) targets cells lacking Brca2 and xenografts derived from BRCA2-deficient ES cells or Chinese hamster ovary cells. We set out to develop a more relevant preclinical model that will inform and accelerate translation into the clinic. As such, we conditionally deleted Brca2 and p53 within murine mammary epithelium and treated the resulting tumors in situ with a highly potent PARP-1 inhibitor (AZD2281) alone or in combination with carboplatin. Daily exposure to AZD2281 for 28 days caused significant regression or growth inhibition in 46 of 52 tumors. This response was shown to be specific to tumors lacking both Brca2and p53. AZD2281/carboplatin combination therapy for 28 days showed no advantage over carboplatin monotherapy. However, if PARP inhibitor treatment was continued, this significantly increased the time to tumor relapse and death in these mice. This preclinical study is the first to show in vivo hypersensitivity of spontaneously arising Brca2-deficient mammary tumors to PARP-1 inhibition monotherapy or combination therapy. As such, our data add substantial weight to the argument for the use of PARP inhibitors as therapeutic agents against human breast cancers in which BRCA2 is mutated. Moreover, the specificity that we have shown further suggests that PARP inhibitors will be generally effective against tumors caused by dysregulation of components of the homologous recombination pathway.
authors.affiliation: Department of Genetics, School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Trevor
authors.initials: T
authors.lastname: Hay
authors.forename: James R
authors.initials: JR
authors.lastname: Matthews
authors.forename: Lucie
authors.initials: L
authors.lastname: Pietzka
authors.forename: Alan
authors.initials: A
authors.lastname: Lau
authors.forename: Aaron
authors.initials: A
authors.lastname: Cranston
authors.forename: Anders O H
authors.initials: AO
authors.lastname: Nygren
authors.forename: Anthony
authors.initials: A
authors.lastname: Douglas-Jones
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Smith
authors.forename: Niall M B
authors.initials: NM
authors.lastname: Martin
authors.forename: Mark
authors.initials: M
authors.lastname: O'Connor
authors.forename: Alan R
authors.initials: AR
authors.lastname: Clarke
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D024682:BRCA2 Protein / Q000172:deficiency / Q000235:genetics; D016190:Carboplatin / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D024522:Genes, BRCA2; D016158:Genes, p53; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010793:Phthalazines / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics
chemical_list: D024682:BRCA2 Protein; C106711:BRCA2 protein, mouse; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016159:Tumor Suppressor Protein p53; D016190:Carboplatin; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; C531550:olaparib