title: Conventional chemotherapy and oncogenic pathway targeting in ovarian carcinosarcoma using a patient-derived tumorgraft.
abstract: Ovarian carcinosarcoma is a rare subtype of ovarian cancer with poor clinical outcomes. The low incidence of this disease makes accrual to large clinical trials challenging. However, studies have shown that treatment responses in patient-derived xenograft (PDX) models correlate with matched-patient responses in the clinic, supporting their use for preclinical testing of standard and novel therapies. An ovarian carcinosarcoma PDX is presented herein and showed resistance to carboplatin and paclitaxel (similar to the patient) but exhibited significant sensitivity to ifosfamide and paclitaxel. The PDX demonstrated overexpression of EGFR mRNA and gene amplification by array comparative genomic hybridization (log2 ratio 0.399). EGFR phosphorylation was also detected. Angiogensis and insulin-like growth factor pathways were also implicated by overexpression of VEGFC and IRS1. In order to improve response to chemotherapy, the PDX was treated with carboplatin/paclitaxel with or without a pan-HER and VEGF inhibitor (BMS-690514) but there was no tumor growth inhibition or improved animal survival, which may be explained by a KRAS mutation. Resistance was also observed when the IGF-1R inhibitor BMS-754807 was combined with carboplatin/paclitaxel. Because poly (ADP-ribose) polymerase inhibitors have activity in ovarian cancer patients, with and without BRCA mutations, ABT-888 was also tested but found to have no activity. Pathogenic mutations were also detected in TP53 and PIK3CA. In conclusion, ifosfamide/paclitaxel was superior to carboplatin/paclitaxel in this ovarian carcinosarcoma PDX and gene overexpression or amplification alone was not sufficient to predict response to targeted therapy. Better predictive markers of response are needed.
authors.affiliation: Division of Gynecologic Surgery, Mayo Clinic, Rochester, MN, United States of America.
authors.forename: Gretchen
authors.initials: G
authors.lastname: Glaser
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, United States of America.
authors.forename: S John
authors.initials: SJ
authors.lastname: Weroha
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, United States of America.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Becker
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, United States of America.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Hou
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, United States of America.
authors.forename: Sergio
authors.initials: S
authors.lastname: Enderica-Gonzalez
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, United States of America.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Harrington
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Haluska
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology; D002296:Carcinosarcoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D020714:Maximum Tolerated Dose; D051379:Mice; D058990:Molecular Targeted Therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016190:Carboplatin; D017239:Paclitaxel