Abstract 2037: Establishment and characterization of paired mutant B-raf, vemurafenib-sensitive and -resistant patient-derived xenograft models.

Abstract

Abstract Background: Vemurafenib is a recently approved anticancer therapy for B-RafV600E metastatic melanoma. Treatment with this agent increases overall patient survival compared with dacarbazine; however, most patients receiving vemurafenib progress within a year and are left with limited treatment options. Few validated screening tools exist to evaluate potentially beneficial therapies for these resistant/refractory patients. To address this deficiency we have generated a panel of paired mutant B-Raf vemurafenib-sensitive and -resistant patient-derived xenograft (PDX) models of metastatic melanoma and colorectal cancer. Each parent model was screened for activating mutations and all evaluated in vivo against vemurafenib. In addition, select model pairs were subjected to whole genome sequencing and RNA analysis to identify differences in genetic and expression profiles. Methods: Establishment of parent models was previously described. Vemurafenib-resistant PDX models (PDX-VR) were generated by in vivo administration of clinical-grade vemurafenib at increasing concentrations over limited tumor passages. Parental vemurafenib-sensitive models were screened for activating mutations of fifty-two known cancer genes using a PCR-based assay with customized primers. DNA and RNA was extracted from select model pairs and profiled and compared for alterations. Results: To date we have generated six B-RafV600E PDX-VR models (3 melanoma + 3 colorectal) with additional B-RafV600E and B-RafV600K PDX-VR models in development. In vivo studies evaluating vemurafenib in parent models reported notable tumor growth inhibition in all but one colorectal model (ST428), including tumor regressions in melanoma. PDX-VR models reported tumor growth similar to untreated controls at vemurafenib concentrations up to 150 mg/kg/day. Comparative analysis of paired models revealed some differences in DNA and RNA profiles. Conclusion: We have generated a panel of paired mutant B-raf vemurafenib-sensitive and -resistant patient-derived xenograft (PDX) models representing metastatic melanoma and colorectal cancer available as validated screening tools to evaluate potentially beneficial therapies for vemurafenib-resistant/refractory patients. Citation Format: Michael J. Wick, Teresa L. Vaught, Lizette Gamez, Justin Meade, Skylar Carden, Anthony W. Tolcher, Drew W. Rasco, Amita Patnaik, Alexander Miller, Ronald Drengler, Kyriakos P. Papadopoulos. Establishment and characterization of paired mutant B-raf, vemurafenib-sensitive and -resistant patient-derived xenograft models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2037. doi:10.1158/1538-7445.AM2013-2037