Abstract A105: Establishment, characterization and clinical correlation of a panel of gynecologic patient-derived xenograft (PDX) models.

Abstract

Abstract Background: Ovarian and uterine cancers account for a majority of gynecologic cancer-related deaths in Western countries. Standard treatment for these cancers consists of surgery when appropriate, followed by platinum-based therapy. While the rate of initial response to treatment is high, the majority of patients develop recurrent, chemoresistant disease. Salvage chemotherapy treatment provides benefit to a fraction of these patients, demonstrating the need for identifying additional effective therapies. To assist in identifying new therapies for these cancer types, we have established panels of low passage, patient-derived xenografts (PDX) representing ovarian and uterine cancers and characterized them by mutation and receptor expression. Drug sensitivity studies were performed utilizing platinum and platinum/taxane regimens and compared with clinical outcome prior to and following sample collection. Select screening of targeted therapies was based on model growth factor expression or gene amplifications. Methods: PDX ovarian and uterine models were developed in immune-deficient mice from primary or metastatic patient tissue. Established models were confirmed by histologic comparative analysis and linked with patient treatment and outcome data. For each model, DNA was extracted and subjected to exon sequencing of 207 known oncogenes; growth factor receptor and ligand densities were interrogated using immunohistochemistry. Drug sensitivity studies were performed evaluating models response to chemotherapy and targeted agents. Study endpoints included tumor volume and time from treatment initiation, with tumor growth inhibition, delay and regression reported at study completion. Results: To date we have established and validated 40 ovarian and 25 endometrial low passage PDX models. EGFR staining (1+ to 3+) was reported in over 50% of ovarian models and 86% of endometrial models while HER2 staining was reported in 10% of ovarian and 50% of endometrial models; HER3 expression was found in 43% of all models. Preclinical activity of platinum and platinum/taxane regimens correlated with clinical outcome, with over 80% concordance. High EGFR expression did not correlate with cetuximab sensitivity, even in models with wildtype K-Ras. FGFR inhibitors were effective in endometrial models with amplified but not mutant FGFR1/2. Conclusion: We have established a panel of gynecologic PDX models and characterized mutation status, receptor expression and benchmarked platinum and platinum/taxane treatments and select targeted therapies. These panels can be utilized as a valuable screening tool in early and late-stage oncology drug development. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A105. Citation Format: Michael J. Wick, Abbey Felder, Alyssa Moriarty, Teresa L. Vaught, Anthony W. Tolcher, Drew Rasco, Amita Patnaik, Allen J. White, James Mark, Kyriakos P. Papadopoulos. Establishment, characterization and clinical correlation of a panel of gynecologic patient-derived xenograft (PDX) models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A105.