The overall objective of the proposed Minority PDX (patient-derived xenograft) Development and Testing Center (M-PDTC) is directed at improving clinical cancer precision medicine approaches for treating gastric, liver, advanced bladder, and lung cancers. This will be achieved through the large-scale development and comprehensive molecular characterization of over 200 PDX tumor models, with over 60% of the newly developed PDXs derived from minority patients, and to utilize these for in vitro and pre-clinical PDX trials in order to test the efficacy of molecularly-matched therapeutics administered as single agents or in combination regimens. Statistical testing for drug-responsiveness and/or resistance will be performed, as well as the application of data integration strategies that relate treatment responses with molecular characteristics of individual PDXs and patients' tumors. The goal of the UCaMP Bioinformatics Core (UBC) is to provide extensive data analytic support for the proposed studies at multiple stages including study design, molecular characterization of the PDXs, target selection, and statistical correlation and modeling of drug responses. The UBC will be established, and have considerable capabilities, by bringing together key personnel with strengths in genomics, bioinformatics, and biostatistics, and by leveraging the existing infrastructure at the UC Davis Comprehensive Cancer Center, specifically the Biorepository, Genomics, and Biostatistics Shared Resources. The UBC will facilitate the seamless integration of the UCaMP's studies through dynamic interactions with its investigators, and via the implementation of a dedicated UCaMP Bioinformatics Core relational database that will serve as a data repository and interface for linking project design, sample tracking, data analysis, and eventual data sharing. For the comprehensive genetic characterization of the PDX models, and associated patient tumors, we will apply a suite of established bioinformatics analysis pipelines implemented on a high- performance ultra-rapid next-generation sequencing (NGS) data analysis platform for processing whole-exome sequencing and RNA-sequencing data to generate the fundamental results datasets consisting of fully annotated 1) genomic variants and 2) transcripts with corresponding expression values. Additional tumor properties that can figure prominently in guiding therapeutic decisions, such as intratumor heterogeneity (ITH) and mutational signatures, will also be defined. Subsequently, integrative bioinformatics approaches will be applied for target prioritization and treatment matching, which will be followed by biostatistical analyses to evaluate both drug responses and the accuracy of novel molecular biomarkers. The UBC will also collaborate with the four UC Comprehensive Cancer Centers (UCaMP), PDXNet, PDMR, and PDCCC for data sharing and participation in multi-PDTC PDX trials.
