title: A patient-derived-xenograft platform to study BRCA-deficient ovarian cancers.
abstract: Approximately 50% of high-grade serous ovarian cancers (HGSOCs) have defects in genes involved in homologous recombination (HR) (i.e.,BRCA1/2). Preclinical models to optimize therapeutic strategies for HR-deficient (HRD) HGSOC are lacking. We developed a preclinical platform for HRD HGSOCs that includes primary tumor cultures, patient-derived xenografts (PDXs), and molecular imaging. Models were characterized by immunohistochemistry, targeted sequencing, and reverse-phase protein array analysis. We also tested PDX tumor response to PARP, CHK1, and ATR inhibitors. Fourteen orthotopic HGSOC PDX models withBRCAmutations (BRCAMUT) were established with a 93% success rate. The orthotopic PDX model emulates the natural progression of HGSOC, including development of a primary ovarian tumor and metastasis to abdominal viscera. PDX response to standard chemotherapy correlated to that demonstrated in the patient. Pathogenic mutations and HGSOC markers were preserved after multiple mouse passages, indicating retention of underlying molecular mechanisms of carcinogenesis. ABRCA2MUTPDX with high p-CHK1 demonstrated a similar delay of tumor growth in response to PARP, CHK1, and ATR inhibitors. A poly (ADP-ribose) polymerase (PARP) inhibitor radiotracer correlated with PARP1 activity and showed response to PARP inhibition in theBRCA2MUTPDX model. In summary, the orthotopic HGSOC PDX represents a robust and reliable model to optimize therapeutic strategies forBRCAMUTHGSOC.
authors.affiliation: Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: George
authors.affiliation: Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Hyoung
authors.initials: H
authors.lastname: Kim
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Clemens
authors.initials: C
authors.lastname: Krepler
authors.affiliation: Oncogenomics, Abramson Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Wenz
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Mehran
authors.initials: M
authors.lastname: Makvandi
authors.affiliation: Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Janos L
authors.initials: JL
authors.lastname: Tanyi
authors.affiliation: Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Brown
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Rugang
authors.initials: R
authors.lastname: Zhang
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Brafford
authors.affiliation: Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Jean
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.affiliation: Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Morgan
authors.affiliation: Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Memorial Sloan Kettering, New York, New York, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Soslow
authors.affiliation: Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Ronny
authors.initials: R
authors.lastname: Drapkin
authors.affiliation: Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Johnson
authors.affiliation: Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: George
authors.initials: G
authors.lastname: Cotsarelis
authors.affiliation: Oncogenomics, Abramson Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.affiliation: Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Fiona
authors.initials: F
authors.lastname: Simpkins
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019313:BRCA1 Protein / Q000378:metabolism*; D024682:BRCA2 Protein / Q000378:metabolism*; D063646:Carcinogenesis / Q000378:metabolism; D005260:Female; D064593:Heterografts / Q000187:drug effects / Q000378:metabolism*; D059765:Homologous Recombination; D006801:Humans; D051379:Mice; D057054:Molecular Imaging / Q000379:methods; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins