The overall goal of this P01 proposal is to improve the management of patients with different molecular subgroups of glioma, focusing on novel neuroimaging surrogates associated with metabolic and physiologic changes in each group. The delineation of histopathological and molecular subgroups of glioma has revolutionized the field of neuro-oncology by improving diagnosis and prognosis. Interrogating metabolic and physiologic signatures of these subgroups will be one of the next critical advances in the field of neuroimaging. In the previous cycle of our P01, we acquired a large dataset of image-guide tissue samples matched with MR diffusion, perfusion, and spectroscopy scans. We now seek to combine these techniques using sophisticated data analysis tools to more efficiently predict tumor burden and malignant behavior by subgroup. Our preliminary data also indicate that there are differences in metabolism associated with changes in IDH status and TERT expression that have the potential for being used in developing in vivo signatures for specific molecular subtypes. In this new proposal, we will identify multi-parametric imaging markers that are specific to each subtype; use novel gene editing tools to elucidate mechanisms that influence the regulation of mutant TERT promotor in subgroups with divergent molecular and clinical features; define metabolic signatures of TERT expression; and implement novel 1H and 13C metabolic imaging strategies for monitoring individual patients during the course of their disease. This would set the stage for developing clinical 1H and hyperpolarized 13C metabolic imaging assays that could provide early assessment of tumor recurrence and treatment response. These integrated studies will be supported by specialized resources from the Administrative and Clinical Services Core and the Biospecimen and Biomarker Core. To translate our mechanistic findings and novel imaging technologies into clinically relevant actions, we will use the unique infrastructure that our group has established over the prior cycles of this P01 to perform studies in cells, pre-clinical models, and patients. The innovative research described in this proposal will take advantage of the exceptional resources assembled by the well-established, collaborative group of clinical, biological and imaging scientists at UCSF.
The objective of the proposed program project grant is to improve the management of patients with different molecular subgroups of glioma defined by their 1p19q co-deletion, IDH mutation, and TERT promotor mutation status. This will be achieved by identifying multi-parametric imaging markers that are specific to each sub-type, elucidating mechanisms that influence the regulation of mutant TERT promotor in subgroups with divergent molecular and clinical features, defining metabolic signatures of TERT expression, and implementing novel 1H and 13C metabolic imaging strategies for monitoring individual patients during the course of their disease.
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|Vareth, Maryam; Lupo, Janine; Larson, Peder et al. (2018) A comparison of coil combination strategies in 3D multi-channel MRSI reconstruction for patients with brain tumors. NMR Biomed 31:e3929|
|Li, Yan; Lafontaine, Marisa; Chang, Susan et al. (2018) Comparison between Short and Long Echo Time Magnetic Resonance Spectroscopic Imaging at 3T and 7T for Evaluating Brain Metabolites in Patients with Glioma. ACS Chem Neurosci 9:130-137|
|Gordon, Jeremy W; Chen, Hsin-Yu; Autry, Adam et al. (2018) Translation of Carbon-13 EPI for hyperpolarized MR molecular imaging of prostate and brain cancer patients. Magn Reson Med :|
|Choi, Serah; Yu, Yao; Grimmer, Matthew R et al. (2018) Temozolomide-associated hypermutation in gliomas. Neuro Oncol 20:1300-1309|
|Park, Ilwoo; Larson, Peder E Z; Gordon, Jeremy W et al. (2018) Development of methods and feasibility of using hyperpolarized carbon-13 imaging data for evaluating brain metabolism in patient studies. Magn Reson Med 80:864-873|
|Hayes, Josie; Yu, Yao; Jalbert, Llewellyn E et al. (2018) Genomic analysis of the origins and evolution of multicentric diffuse lower-grade gliomas. Neuro Oncol 20:632-641|
|Zhang, Chenan; de Smith, Adam J; Smirnov, Ivan V et al. (2017) Non-additive and epistatic effects of HLA polymorphisms contributing to risk of adult glioma. J Neurooncol 135:237-244|
|Autry, Adam; Phillips, Joanna J; Maleschlijski, Stojan et al. (2017) Characterization of Metabolic, Diffusion, and Perfusion Properties in GBM: Contrast-Enhancing versus Non-Enhancing Tumor. Transl Oncol 10:895-903|
|Anwar, Mekhail; Molinaro, Annette M; Morin, Olivier et al. (2017) Identifying Voxels at Risk for Progression in Glioblastoma Based on Dosimetry, Physiologic and Metabolic MRI. Radiat Res 188:303-313|
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