title: Pathway-specific engineered mouse allograft models functionally recapitulate human serous epithelial ovarian cancer.
abstract: The high mortality rate from ovarian cancers can be attributed to late-stage diagnosis and lack of effective treatment. Despite enormous effort to develop better targeted therapies, platinum-based chemotherapy still remains the standard of care for ovarian cancer patients, and resistance occurs at a high rate. One of the rate limiting factors for translation of new drug discoveries into clinical treatments has been the lack of suitable preclinical cancer models with high predictive value. We previously generated genetically engineered mouse (GEM) models based on perturbation of Tp53 and Rb with or without Brca1 or Brca2 that develop serous epithelial ovarian cancer (SEOC) closely resembling the human disease on histologic and molecular levels. Here, we describe an adaptation of these GEM models to orthotopic allografts that uniformly develop tumors with short latency and are ideally suited for routine preclinical studies. Ovarian tumors deficient in Brca1 respond to treatment with cisplatin and olaparib, a PARP inhibitor, whereas Brca1-wild type tumors are non-responsive to treatment, recapitulating the relative sensitivities observed in patients. These mouse models provide the opportunity for evaluation of effective therapeutics, including prediction of differential responses in Brca1-wild type and Brca1-deficient tumors and development of relevant biomarkers.
authors.affiliation: Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Szabova
authors.affiliation: Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Sujata
authors.initials: S
authors.lastname: Bupp
authors.affiliation: Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Muhaymin
authors.initials: M
authors.lastname: Kamal
authors.affiliation: Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Deborah B
authors.initials: DB
authors.lastname: Householder
authors.affiliation: Medical Oncology Branch, National Cancer Institute, Bethesda, Maryland, United States of America.
authors.forename: Lidia
authors.initials: L
authors.lastname: Hernandez
authors.affiliation: Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Jerome J
authors.initials: JJ
authors.lastname: Schlomer
authors.affiliation: Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Maureen L
authors.initials: ML
authors.lastname: Baran
authors.affiliation: Advanced Biomedical Computing Center, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Ming
authors.initials: M
authors.lastname: Yi
authors.affiliation: Advanced Biomedical Computing Center, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Stephens
authors.affiliation: Medical Oncology Branch, National Cancer Institute, Bethesda, Maryland, United States of America.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Annunziata
authors.affiliation: Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Martin
authors.affiliation: Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America; Mouse Cancer Genetics Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Terry A
authors.initials: TA
authors.lastname: Van Dyke
authors.affiliation: Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Weaver Ohler
authors.affiliation: Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Simone
authors.initials: S
authors.lastname: Difilippantonio
mesh_terms: D064591:Allografts; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D019313:BRCA1 Protein / Q000235:genetics; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D009154:Mutation; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein
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