Abstract 1471: Establishment, characterization, and clinical correlation of a platform of ovarian patient-derived xenograft (PDX) models

Abstract

Abstract High grade serous ovarian carcinoma (HGSOC) is the most common form of ovarian cancer; effective therapeutics for HGSOC remains elusive and is major unmet medical need. Standard treatment for these patients is surgery followed by platinum- based therapy. While the majority of patients exhibit an initial response to this standard therapy, many develop disease recurrence. In order to advance therapeutic development we have established a panel of low passage, well characterized, orthotopic, luciferized HGSOC patient derived xenografts (PDXs) that accurately represent the disease characteristics and are amenable to assess efficacy evaluations of novel therapeutics. Ovarian PDXs 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 lentivirus based methodologies to allow non-invasive methods of tumor burden measurement. Luciferized PDX models were further expanded, banked and utilized for drug efficacy and biomarker evaluation studies. DNA from patient material and matched established PDX models was extracted and subjected to CNV on the Affymetrix CytoscanTM HD microarray platform and BROCA cancer risk panel targeted sequencing. Data from these analyses indicated that the PDXs are molecularly diverse and faithfully maintain the genetic alterations and copy number variation profiles of the patient tumors. Consistent with clinical disease, these orthotopic PDX models exhibit diffusely disseminated peritoneal disease with tissue infiltration to the omentum, ovaries and pancreas, along with ascites and abdominal distention. Immunohistochemical analysis of PDX tumor tissues infiltrated in major organs for ovarian specific PAX8, p53 and WT1 markers confirmed the high grade serous type of ovarian tumors. Orthotopic PDXs have been validated and are shown to be robust and amenable for drug efficacy evaluations by Bioluminescent Imaging. Their response to standard carboplatin mirrors the response in the patients from which they were derived. 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. Conclusion: A platform of HGSOC PDX models that retain histologic and molecular characteristics of primary tumors that are expected to be predictive of clinical outcomes and amenable for efficacy testing of novel therapeutics is established. These models are being utilized for hypothesis driven combination efficacy and biomarker studies for translation to the clinic. Citation Format: Sangeetha S. Palakurthi, Joyce F. Liu, Qing Zeng, Shan Zhou, Wei Huang, Elena Ivanova, Cloud Paweletz, John R. Murgo, Justin Evangelista, Melissa Buttimer, Jennifer Curtis, Huiying Piao, Prafulla Gokhale, Colin Pritchard, Jessie M. English, Paul Kirschmeier, Kwok-Kin Wong, Ursula A. Matulonis, Ronny Drapkin. Establishment, characterization, and clinical correlation of a platform of ovarian patient-derived xenograft (PDX) models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1471. doi:10.1158/1538-7445.AM2015-1471