OVERALL ? SUMMARY The selection of relevant therapeutic agents with optimal pharmacokinetic and pharmacodynamic properties to adequately suppress the intended target across the entire target cell population will be central to the success of genomics-guided precision medicine strategies. Optimal drug therapy for brain tumors is especially challenging due to multiple physical barriers within the vasculature and tumor microenvironment that can result in highly heterogeneous drug delivery. This results in a significant fraction of tumor cells being exposed to sub- therapeutic drug levels that limit the efficacy of therapy and may lead to compensatory cell signaling and emergence of drug resistance. Thus, a central tenet of this proposal is that failure to understand limitations in the physical delivery and distribution of novel therapeutics into brain tumors is a major reason for the collective failure to extend the exciting treatment advances and survival gains realized in peripheral malignancies to the treatment of brain tumors. In this PS-OC, we will focus on understanding physical factors that influence heterogeneous drug distribution and the resulting biology in a highly integrated analysis of patient and animal tumor models using 3-dimensional MR imaging, stimulated Raman scattering (SRS) microscopy, matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), immunohistochemistry (IHC), phosphoproteomics, proximity ligation assays (PLA), and RNAseq. Integration of these data sets across a series of drugs evaluated in multiple tumor models will elaborate critical factors that modulate distribution of these drugs and provide the platform for construction of a multi-scale model that could be used to select a targeted therapeutic with an optimal predicted drug distribution based on MRI features of an individual tumor. In this context, we will directly meet the goal of the Physical Sciences in Oncology Program to integrate physical sciences and cancer research perspectives and approaches to address a complex and challenging question in cancer research. Specifically paraphrased from PAR-14-49, we will address: Physical Dynamics of Cancer: How do physical properties and forces within tumors, disseminating cells, and sites of colonization and metastasis contribute to therapeutic delivery and efficacy? How do these factors affect cancer progression and evolution of therapeutic resistance? Spatio-Temporal Organization and Information Transfer in Cancer: Can the evolutionary dynamics of therapeutic resistance be examined in the context of dynamic spatio-temporal environments to better define mechanisms of progression and resistance and rationally design therapeutic strategies?