Washington University PDX Development and Trial Center

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OVERALL PROJECT SUMMARY/ABSTRACT The myriad of both newly-available molecular targets and novel anti-cancer agents has underscored the crucial need to develop preclinical models in order to optimize clinical trial design. Several technical benefits make patient-derived xenograft (PDXs) models particularly attractive for drug testing and personalized medicine. Biologists and physicians at Washington University School of Medicine (WUSM) and the Siteman Cancer Center (SCC) developed and operated the Washington University PDX Development and Trial Center (WU-PDTC) as part of the PDXNet program during a prior funding period (CA224083) from 2017-2022. Based on the success of this program, we propose to renew WU-PDTC funding as a T-PDTC with the goal of continuing our efforts in preclinical testing and prioritizing and studying unmet needs in cancer in this collaborative, nation-wide effort. The PDX Core within WU-PDTC will develop and characterize 400 new PDX models across major tumor types. These models will be characterized using the latest omics technologies and analyzed using the most current bioinformatics pipelines that have been deployed for PDXNet and other large scale NCI programs. Tumors representing unmet needs and priority areas for collection will be emphasized (e.g. treatment resistant cancers). The Bioinformatics Core will integrate these analyses with clinical annotation from the originating patient to include treatment history and tumor response (Aim 1). Our two Research Projects will conduct PDX clinical trials of single and combination agents using drugs in the NCI CTEP portfolio (Aim 2). Project 1 will investigate predictive biomarkers and resistance mechanisms for DS-8201a alone and in combination with DDRi in breast cancer (expanding to GI and lung cancers), while Project 2 will study targeting the onco-inflammatory circuitry in combination with anti-KRAS and chemotherapies in GI and lung cancer (this will expand to breast cancer). Proteogenomic, imaging, and clinical response data will be collected for these models as part of a broader effort of characterizing PDX models and conducting clinical correlation and treatment response analyses by the Bioinformatics Core (Aim 3). Proteogenomic features of PDX models and treatment/response histories will be tracked using our well-established WU-PDXdb that will be accessible to PDXNet and PDMR-FNLCR. In Aim 4, the WU-PDTC will leverage existing expertise and programs from Siteman Cancer Center (SCC), Institute of Clinical and Translational Research (ITCS), McDonnell Genome Institute (MGI), Mallinkrodt Imaging Research Center (MIRC), and Early Therapeutic Clinical Trials Network (ETCTN) to support the goals of developing and utilizing PDX models to test and improve cancer treatment, in collaboration with other components of PDXNet. Finally, WU-PDTC, through coordination by the Administration Core, will support Pilot Projects utilizing these PDX resources to foster collaboration across PDTCs, PDMR-FNLCR, and other NCI programs (Aim 5). In summary, the goals are to increase the spectrum of agents tested in PDX clinical trials and to improve the reliability, validation, utility, and standardization of PDX models through innovative cross-PDXNet research.