Abstract IA20: Linking tumor genomics to patient outcomes through a large-scale patient-derived xenograft (PDX) platform.
Authors: Gandara David R. , Li T. , Lara P.N. , Kelly K. , Cooke D.T. , Gandour-Edwards R. , Yoneda K. , Goodwin N. , Kuslak-Meyer S. , Mack P. 
Published: August 2014

Background: Preclinical models have generally proven suboptimal for directing clinical application of new anti-cancer therapies. Here we detail an integrated research platform engaging core resources at JAX-WEST and the clinical research and genomics facilities at UCDCCC. Pilot studies using this platform are focusing on non-small cell lung cancer (NSCLC) due to molecular targets of interest, such as epidermal growth factor receptor (EGFR), heterogeneity in NSCLC tumor biology and the complexity of related cancer signaling pathways.

Methods: Clinically and demographically annotated cancer patients (pt) seen at UCDCCC and collaborating facilities undergo tumor biopsy of various types which are implanted into JAX Nod Scid Gamma (NSG) mice to develop PDXs. Pt tumors and subsequent PDXs are assessed by histomorphology, clinically applicable molecular biomarkers, gene expression arrays and genome-wide technologies (NGS). NSCLC PDXs are grouped as panels (EGFR mutant (MT), KRAS MT ALK+). PDX panels of interest undergo multi-regimen drug testing for differential efficacy, together with pre- and post-therapy NGS and timed tumor pharmacodynamics (PD) assessment, to determine mechanisms of primary and acquired resistance in individual PDX models and how to overcome them.

Results: As of November 2013 over 1,200 cancer pt tumors have been xenotransplanted into NSG mice (~175 from NSCLC), including successful PDX formation from small FNA and, cell pellets and transportability of specimens by overnight shipping for implantation. NSCLC PDXs show excellent histomorphologic, gene expression and mutational fidelity to host pt tumors, including mutation status for KRAS, EGFR and gene expression levels. Pilot studies in a panel of EGFR MT PDXs with TKI-acquired resistance demonstrate differential drug activity which mimics that of the host pt to the same therapy, and tumor PD at baseline and timed intervals post-therapy provide the basis for subgrouping resistance mechanisms

Conclusion: This UCDCCC-JAX collaboration has established a large resource applicable to multi-drug testing and tumor PD in a wide range of clinically and genomically characterized tumors, including PDX panels for representative oncogene-driven NSCLCs. An EGFR-directed pilot project supports the feasibility of systematically integrating data derived from these models in order to optimize drug development and treatment strategies to address drug resistance mechanisms. This approach to PDX development and testing will be prospectively integrated into a developing multi-institution clinical trial of the Southwest Oncology Group (S1403), designed to advance understanding of differences in inter- and intra-patient tumor biology and hasten the transition to personalized cancer therapy.

Citation Format: David R. Gandara, T. Li, P.N. Lara, K. Kelly, D.T. Cooke, R. Gandour-Edwards, K. Yoneda, N. Goodwin, S. Kuslak-Meyer, P. Mack. Linking tumor genomics to patient outcomes through a large-scale patient-derived xenograft (PDX) platform. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr IA20.