Project Summary/Abstract Isocitrate dehydrogenase (IDH) mutant glioma are mostly non-enhancing, which makes it difficult to distinguish the boundaries of infiltrative lesions from normal tissue and edema in both newly diagnosed and post-treatment settings. The standard efficacy endpoints of response rate or overall survival are also challenging for such slow growing tumors. These limitations have led to the consideration of innovative imaging approaches to improve the characterization of tumor burden and early assessment of treatment response. Expanding imaging capabilities to include robust metrics to describe the biological properties of lesions could be important to assess the population of IDH mutant glioma that are associated with specific metabolic reprogramming, slow growth rate, and high risk of malignant transformation. The proposed project will leverage our experience in the clinical implementation of hyperpolarized [1- 13C]pyruvate imaging for glioblastoma in the previous cycle to assess dynamic metabolism in IDH mutant glioma. Metabolic reprogramming in IDHm tumors specifically results in the conversion of alpha-ketoglutarate (⍺-KG) to a novel oncometabolite 2-hydroxyglutarate (2HG), with a concomitant decrease in conversion of ⍺-KG to glutamate. Dynamic metabolic conversions in IDHm glioma can, therefore, be measured using novel imaging probes HP [2-13C]pyruvate and [1-13C] (⍺-KG). We will first establish the preclinical utility of using [2-13C]pyruvate and [1-13C] ⍺-KG as a non-invasive imaging biomarker of treatment response and tumor burden in Aim 1. In Aim 2, we will take advantage of ongoing clinical trials at UCSF that specifically target the metabolism of IDH mutant glioma to assess the impact of using dynamic hyperpolarized [2-13C]pyruvate imaging to assess early metabolic changes in patients undergoing treatment. Aim 3 will improve the characterization of tumor burden in newly- diagnosed and recurrent IDH mutant glioma patients using hyperpolarized [1-13C] ⍺-KG metabolic imaging with correlation to tissue characteristics. Ultimately, we plan to translate dynamic, non-invasive metabolic imaging biomarkers to enhance the evaluation of novel therapies and assist in the optimal management of IDHm patients.