Quantitation of nutrient metabolism in brain tumor patients using advanced 13C isotopomer technology

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Project Summary/Abstract Malignant brain tumors are aggressive cancers that have high proliferative rates with much higher energy requirements and high mortality rates. Despite intense clinical and drug development efforts in the last two decades, there has been no improvement in survival. To support the abnormal growth commonly seen in tumors, the cancer cells have altered their metabolism compared to normal cells in healthy tissues. Most of the knowledge to date on cancer metabolism is derived from cultured cell lines. Probing metabolism in intact tumors will be critical to understand how the tumor cells grow in a patient under the complex biological tumor environment. From our pilot study involving a small number of patients, we have demonstrated that gliomas and brain metastases have the capacity to oxidize acetate in the citric acid cycle to meet their bioenergetic requirements, and glucose and acetate together contribute up to 63.0% of the total acetyl-CoA pool in these tumors. The remaining acetyl-CoA that provides carbon sources for biomolecular synthesis, must be derived from other nutrients. The following are the goals of this proposal: (1) determine if acetate and ketone body (beta hydroxybutyrate, BHB) utilization is a common property of all gliomas or specifically linked to high grade GBMs (2) examine whether acetate and BHB provide carbons for 2-hydroxyglutarate (2-HG) synthesis in IDH mutated glioma patients (3) preclinical testing of the effects of small molecule inhibitors of acetate and BHB, in freshly resected tumor tissue slices. We have Institutional Review Board (IRB) approved clinical protocol to infuse non-toxic and non-radioactive 13C-enriched acetate in patients who will be undergoing surgical removal of a brain tumor. Using Nuclear Magnetic Resonance (NMR) spectroscopy and mass spectrometry of these surgically resected tumor tissues, we will investigate the above described aims on energy metabolism of primary brain tumors. The attractiveness of this technology is that no radioactivity is involved. We anticipate that the outcome of this study will generate a detailed understanding of in vivo utilization of acetate and ketone body in brain tumor patients. This knowledge will lead to identification of key metabolic targets that may be further exploited for the development of new therapies. Additionally, it may identify novel biomarkers which may be helpful in designing non-invasive in vivo MRI methods to track acetate utilization by tumors for diagnostic purposes.