OVERALL: PROJECT ABSTRACT The overall goal of this renewal P01 proposal is to identify imaging and genomic signatures of brain tumor heterogeneity and evolution to optimize patient management of the two most common primary brain tumors in adults: glioblastoma and meningioma. The hallmark of glioblastoma is resistance to standard treatment with rapid progression at the time of recurrence. Although meningioma can be slow growing, a major proportion recur following standard surgery and radiation with a significant adverse impact on survival. A new, prognostically distinct, classification of meningioma based on DNA-methylation was recently developed. This renewal P01 will establish non-invasive imaging correlates of mechanistic genomic drivers of tumor evolution and intra-tumoral heterogeneity (Projects 1 and 2), to uniquely identify new therapeutic targets that can be rapidly evaluated by biologically relevant imaging metrics to assess early response to treatment (Projects 3 and 4). Building upon the demonstration of genomic heterogeneity in these lesions along with the recent technical advances in 1H and hyperpolarized 13C metabolic imaging that have facilitated the successful translation of [1- 13C] and [2-13C]-labeled pyruvate and enabled the development of a new imaging probe ([1-13C]alpha- ketoglutarate) we will: i) elucidate spatial and temporal imaging correlates of genomic underpinnings of intratumor heterogeneity and their functional impact in glioblastoma that confounds therapies (Project 1); ii) characterize meningioma evolution and heterogeneity by defining genomic mechanisms and therapeutic vulnerabilities that underlie imaging features of intratumor molecular heterogeneity (Project 2). 3-D imaging models of genomic data will be generated in both Projects 1 and 2 with additional synergistic interactions based approaches applied. Using 1H- and hyperpolarized 13C- MRS markers of NF2 loss and FOXM1 expression, Project 3 will identify metabolic imaging biomarkers in the preclinical setting that can stratify molecular groups of meningiomas. Project 4 will expand on Projects 1, 2 and 3 to develop and optimize novel 1H and 13C metabolic imaging methods in patients in order to monitor early response to targeted therapy in recurrent glioblastoma, and determine metabolic features of meningioma gene-expression groups, including with the development of a new [1-13C]alanine probe. The Administrative & Clinical Services, Biospecimen & Biomarker, and Imaging Tumor Heterogeneity & Metabolism Cores will be critical for directing and supporting all of the projects. Leveraging the expertise, unique infrastructure at UCSF, translational strengths of the investigators, and achievements to date from the current P01 and other NCI grants, the pioneering fundamental and translational cancer research described in this proposal will accelerate the implementation of innovative experimental genomic and metabolic imaging techniques. This rapid translation of non-inv...