title: Tumor growth inhibition by olaparib in BRCA2 germline-mutated patient-derived ovarian cancer tissue xenografts.
abstract: OBJECTIVE
  Most patients with ovarian carcinomas succumb to their disease and there is a critical need for improved therapeutic approaches. Carcinomas arising in BRCA mutation carriers display defective DNA double-strand break repair that can be therapeutically exploited by inhibition of PARP-1, a key enzyme in the repair of DNA single-strand breaks, creating synthetic lethality in tumor cells.
  
  
  METHODS
  To investigate synthetic lethality in vivo, we established a BRCA2 germline-mutated xenograft model that was developed directly from human ovarian cancer tissue, treated with the PARP inhibitor olaparib (AZD2281) alone and in combination with carboplatin.
  
  
  RESULTS
  We show that olaparib alone and in combination with carboplatin greatly inhibit growth in BRCA2-mutated ovarian serous carcinoma. This effect was not observed in a serous carcinoma with normal BRCA function, showing a specific antitumor effect of olaparib in mutation carriers. Immunohistochemistry (cleaved caspase-3 and Ki-67 stains) of remnant tissue after olaparib treatment revealed significantly decreased proliferation and increased apoptotic indices in these tumors compared with untreated controls. Furthermore, olaparib-treated tumors showed highly reduced PARP-1 activity that correlated with olaparib levels.
  
  
  CONCLUSIONS
  We established a BRCA2-mutated human ovarian cancer xenograft model suitable for experimental drug testing. The demonstrated in vivo efficacy of olaparib extends on the preclinical rationale for further clinical trials targeting ovarian cancer patients with BRCA mutations.
authors.affiliation: Department of Pathology, British Columbia Cancer Agency and University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ursula
authors.initials: U
authors.lastname: Kortmann
authors.forename: Jessica N
authors.initials: JN
authors.lastname: McAlpine
authors.forename: Hui
authors.initials: H
authors.lastname: Xue
authors.forename: Jun
authors.initials: J
authors.lastname: Guan
authors.forename: Gavin
authors.initials: G
authors.lastname: Ha
authors.forename: Sophie
authors.initials: S
authors.lastname: Tully
authors.forename: Sharaz
authors.initials: S
authors.lastname: Shafait
authors.forename: Alan
authors.initials: A
authors.lastname: Lau
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Cranston
authors.forename: Mark J
authors.initials: MJ
authors.lastname: O'Connor
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D016190:Carboplatin / Q000494:pharmacology / Q000627:therapeutic use; D018267:Carcinoma, Acinar Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D005260:Female; D024522:Genes, BRCA2; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010793:Phthalazines / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017384:Sequence Deletion; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016190:Carboplatin; C531550:olaparib