With the discovery of a number of new molecular targets and exponential increase in the number of anti-cancer agents, it has become imperative to optimize preclinical models in order to design rational clinical trials. Recognizing the unique advantage of the patient-derived xenografts (PDXs) models in drug testing and personalized medicine, physicians and researchers at Washington University School of Medicine (WUSM) and the Siteman Cancer Center have been actively generating and utilizing PDX models for cancer research and the evaluation of molecularly targeted agents. Building on our strength and existing infrastructure, we propose to establish the Washington University PDX Development and Trial Center (WU-PDTC), as part of PDXNet program, to promote preclinical testing in a collaborative nation-wide effort. The PDX core within WU-PDTC will develop and characterize at least 1000 new pathogen-free PDX models across major tumor types. The PDX models will be genomically and phenotypically characterized using the latest ?omics technologies and expertly analyzed using the most current data analysis pipelines that have been deployed for other large scale NCI programs. The Bioinformatics Core will integrate these analyzes with clinical annotation from the originating patient to include patient treatment history and tumor response (Aim 1). Our two research projects will conduct PDX clinical trials using single agent and combinational agents using drugs under NCI-IND (Aim 2). Project 1 will test pan- or beta isoform specific class I PI3K inhibitors in over 100 breast PDX models while Project 2 will study combinatorial approaches that overcome tumor intrinsic and extrinsic mechanisms to ERK inhibition in over 100 already available pancreatic PDX models. Proteogenomic and clinical response data will be collected in 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). All relevant information, including proteogenomic features of PDX models and treatment/response history, will be tracked in a dedicated relational database that will be accessible to PDXNet and PDMR-FNLCR. The goal is to identify candidates for human clinical trials for the ET-CTN.
In Aim 4, the WU-PDTC will leverage existing expertise and programs from the NCI-designated Comprehensive Siteman Cancer Center, Institute of Clinical and Translational Research (ITCS), McDonnell Genome Institute, Mallinkrodt Imaging Research Center, and Early Therapeutic Clinical Trials Network (ET-CTN) to support the goals of developing and utilizing PDX models to test and improve cancer treatment, in collaboration with other components of the PDXNet. Finally, WU-PDTC, through coordination by the Administration Core, will support pilot research projects utilizing the PDX resources and fostering collaboration across PDTCs, PNMR-FNLCR, and other NCI programs. The goal is 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. Our demonstrated capability in generating and utilizing PDX models, extensive existing infrastructure, and strong institutional commitment set a solid foundation for a successful PDTC that will help achieve goals set by NCI in advancing the use of PDX models in preclinical testing.
Cancer is a complex disease. A single cancer type may be result from alterations in various distinct molecular pathways. It is likely that combination therapies will be needed to significantly improve the outcomes of patients with advanced malignancies. It is unrealistic to test all possible combinations in human clinical trials. PDX models provide means to test various combinations. Apart from selecting the ideal therapies for clinical testing, these models will also provide material for molecular testing to identify mechanisms underlying responses to therapy.
| Devarakonda, Siddhartha; Govindan, Ramaswamy (2018) Targeting Resistance to Targeted Therapies: Combating a Resilient Foe. Clin Cancer Res 24:6112-6114 |
