Project 3: Preclinical metabolic imaging of molecular alterations of meningiomas

PROJECT 3: PROJECT ABSTRACT Meningiomas are the most common primary brain tumors in adults. Integrated genomic, epigenomic and proteomic analyses of patient biopsies have identified biological groups of meningiomas with distinct clinical outcomes and molecular drivers. Merlin-intact meningiomas have the best outcomes with the least risk of recurrence and are distinguished by expression of the tumor suppressor NF2. Immune-enriched tumors undergo loss of NF2 and have an intermediate risk of recurrence. NF2 loss combined with expression of the transcription factor FOXM1 is observed in aggressive hypermitotic tumors with the highest risk of recurrence. Identifying biomarkers of NF2 loss, alone or combined with FOXM1 expression, has the potential to enable non-invasive stratification of meningioma patients according to their risk of recurrence. Many oncogenes and tumor suppressors, including NF2 and FOXM1, rewire cellular metabolism in a manner that can be non-invasively visualized by magnetic resonance spectroscopy (MRS). 1H-MRS quantifies steady- state metabolite concentrations and is in clinical use. Hyperpolarized 13C-MRS enables in vivo imaging of dynamic metabolic activity and is in clinical trials in brain tumor patients. In combination, 1H- and hyperpolarized 13C-MRS provide a comprehensive view of the metabolic state of tumor tissue in vivo. Our preliminary studies in isogenic models identify NF2 and FOXM1 driven differences in amino acid, glucose, and phospholipid metabolism that can be interrogated using 1H-MRS, hyperpolarized [1-13C]-pyruvate and hyperpolarized [1-13C]- alanine. Based on these studies, we propose to identify 1H-MRS (Aim 1) and HP 13C-MRS (Aim 2) biomarkers of NF2 loss and FOXM1 expression in patient-derived meningioma cells, tumor xenografts, and patient biopsies. We will then mechanistically validate our metabolic biomarkers by delineating the molecular pathways that link NF2 and FOXM1 to meningioma metabolism (Aim 3). Our studies are innovative because we will, for the first time, leverage metabolic reprogramming for non-invasive imaging of meningiomas. Our proposal is significant because our biomarkers have the potential to non-invasively discriminate between clinically relevant molecular groups of meningiomas. By doing so, they will provide physicians with the ability to determine whether an individual patient’s tumor is likely to recur and tailor the treatment plan accordingly. In essence, our studies will enable precision imaging that has the potential to enhance outcomes and quality of life for meningioma patients.