PROJECT 4: PROJECT ABSTRACT The goal of this project is to improve the management of patients with primary brain tumors by utilizing innovative hyperpolarized carbon-13 MR imaging techniques. These techniques use non-toxic and non- radioactive metabolites to dynamically image metabolic pathways in a matter of seconds. Our team has made significant progress in acquiring, processing, analyzing, and interpreting hyperpolarized carbon-13 MRI during the previous cycle. Our application in high-grade gliomas has also shown that hyperpolarized [1-13C]pyruvate MRI can uncover Warburg-related metabolic dysfunction and regional heterogeneity. Building on these results and our experience in translating different hyperpolarized carbon-13 imaging probes clinically to image glioma subtypes, we aim to challenge the current clinical practice paradigm through the use of dynamic metabolic imaging as opposed to only anatomic imaging in the two most common types of primary brain tumors – glioblastoma and meningioma in this project. In Specific Aim 1, we will explore the impact of using hyperpolarized [1-13C]pyruvate to assess early metabolic changes in patients with recurrent glioblastoma who are treated with novel therapeutic agents. Glioblastoma is the most common malignant primary brain tumor, with a medium overall survival of 14-16 months. Developing and applying noninvasive, easily acquired measures of the pharmacodynamic effect of novel agents in glioblastoma can provide early evaluation of treatment response. In Specific Aim 2, we will evaluate newly diagnosed patients with meningioma prior to surgical resection using hyperpolarized [1-13C]pyruvate and [1- 13C]alanine MRI. This will be used to identify meningioma DNA methylation groups, which have been shown to be more robust classification systems with distinct clinical outcomes and biological drivers across WHO grades. The development of noninvasive imaging techniques for improving risk stratification is a priority for improving patient care. We believe that the results of this study will significantly enhance the management of patients with brain tumors, providing clinicians with a better understanding of the metabolic changes in patients and making early decisions about target modulation in early-phase clinical trials and treatment planning.