Abstract 1202: Patient derived xenograft model platform of high grade serous ovarian cancer supporting discovery of targeted therapies and biomarkers

Abstract

Abstract High grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic malignancy in the United States. It is the most common form of ovarian cancer but early detection and effective therapeutics remain elusive and are a major unmet medical need. The current standard of care for ovarian cancer is platinum based therapy, without consideration of histological subtypes. While many patients exhibit an initial response to this standard therapy, few achieve long term remissions or cures. A major limitation in advancing therapeutic development has been a lack of experimental animal models that accurately represent the spectrum of HGSOC, are amenable to assess efficacy of novel therapeutics, are predictive of patient responses in the clinic and can identify patient subsets that will benefit from specific targeted therapeutics. To address this gap, we generated a platform of clinically relevant, early passage, orthotopic HGSOC patient-derived xenograft (PDX) models. These models were established by implanting mice intraperitoneally with fresh human ovarian cancer cells purified from operative or paracentesis samples under an IRB-approved protocol. Implanted mice were sacrificed after showing signs of abdominal distension and ascites development. Fresh mouse ascites-derived ovarian cancer cells were luciferized ex vivo by sophisticated lentivirus based methodologies to allow for non-invasive methods of tumor burden measurement. Luciferized PDX models were further expanded, banked and utilized for drug efficacy and biomarker evaluation studies. Surrogate biomarkers such as plasma CA-125 measured by BioScale AMMP method and circulating human cfDNA by LINE-1 qPCR have been validated and qualified in these models to support secondary methods of tumor burden evaluation. A diverse library of clinically-annotated, HGSOC PDX models has been established that encompass both treatment naïve and treatment refractory HGSOC. Consistent with clinical disease, these orthotopic PDX models exhibit diffusely disseminated peritoneal disease with tissue infiltration to the omentum, ovaries, pancreas and spleen; along with distended abdomens full with ascites. Immunohistochemistry for ovarian specific markers including PAX8 and CK7 were analyzed in these tissues and shown to maintain fidelity to patient material through serial passages in mice. In vivo drug sensitivity studies with platinum and platinum/taxane doublet regimens recapitulate response as expected in HGSOC and, in a model of chemotherapy-resistant disease, demonstrate expected resistance as predicted by the clinical history. A clinically relevant HGSOC PDX model platform, amenable for testing efficacy of novel therapeutics and delineating responder ID has been established. Data will be presented with ongoing additional characterization of this platform. Citation Format: Sangeetha S. Palakurthi, Joyce F. Liu, Qing Zeng, Shan Zhou, Elena Ivanova, Cloud Paweletz, John Murgo, Justin Evangelista, Jennifer Curtis, Huiying Piao, Prafulla Gokhale, Jessie M. English, Paul Kirschmeier, Kwok-Kin Wong, Ursula A. Matulonis, Ronny Drapkin. Patient derived xenograft model platform of high grade serous ovarian cancer supporting discovery of targeted therapies and biomarkers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1202. doi:10.1158/1538-7445.AM2014-1202