Project Summary The Texas Experimental Cancer Therapeutic Network (TEX-CTN) is comprised of the University of Texas MD Anderson Cancer Center (UT MDACC; Lead Academic Organization, LAO), the UT Health San Antonio Cancer Center (UT Health SA; Affiliate Organization, AO), the UT at Austin (UTA); Affiliate Organization, AO) and the UT Medical Branch at Galveston (UTMB; Affiliate Organization, AO). We propose to advance the development of novel therapeutics using precision oncology approaches and rationally designed clinical trials. The long-term objective is to provide the ETCTN with the joint expertise of the faculty from the four member institutions, expediting translating preclinical discoveries to the clinic, and to provide significant scientific and administrative leadership to the ETCTN. Our hypothesis for the optimal development of novel targeted agents includes testing within a molecularly profiled population, integrating pharmacodynamics markers in early clinical trials and programmatic assessment of predictors of intrinsic sensitivity/resistance and mechanisms of acquired resistance. We are proposing to achieve these goals through the following five specific aims: 1) To study, in an efficient, systematic and collaborative manner, the safety and clinical activity of new agents or hypothesis-driven novel combinations. 2) To molecularly profile tumors and patients (host tissues), to optimize selection of potentially relevant therapies based on the molecular aberrations identified in the tumor and immune environment, where appropriate. 3) To develop and validate clinically relevant of predictors and pharmacodynamic markers of response. 4) To mentor early career faculty, trainees and research personnel in the leadership, conduct, analysis, and reporting of ETCTN trials. 5) To provide scientific and administrative leadership within ETCTN. The TEX-CTN will unite four University of Texas institutions to facilitate access to novel therapies and biomarker-driven trials across the network, for patients with rare as well as common tumors, as well as patients from underserved minority populations. Our team consists of internationally recognized leaders of Phase I and II trials, multidisciplinary disease experts, interventional radiologists, translational pathologists, and diagnostic radiologists. TEX-CTN is well poised to attain a new paradigm for early experimental therapeutic clinical trials.