Abstract 4925: Targeted metabolic profiling of gliomas and glioma stem cells identifies methionine as a differentially regulated metabolite: Proof of principle supporting methionine-pet imaging

Abstract

Abstract Purpose: At present, 18F-Fluorodeoxyglucose(FDG)-positron emission tomography (PET) is the most commonly used diagnostic imaging modality in clinical practice for predicting prognosis in malignant brain tumors. The diffusive nature of glioblastoma (GBM) often makes FDG-PET detection inaccurate and there is no diagnostic gold-standard for GBM. Thus, it is necessary to find new criteria independent of conventional FDG-PET diagnosis to delineate tumor versus normal tissues. Molecular imaging using 11C-Methionine-PET (Met-PET) is one of the most promising approaches to this challenge. Methods: We employed a targeted metabolomic approach to study the extracellular and intracellular levels of methionine in established (ATCC) and patient derived primary glioblastoma (GBM) cell lines, glioma stem cells (GSC) and normal human astrocytes (NHA) to gain a better understanding of methionine uptake. Methylthioadenosine phosphorylase (MTAP) is an enzyme that plays a vital role in polyamine metabolism and methionine salvage. Therefore, we determined the expression profile of MTAP in these cells using RT-qPCR. We then extracted the intracellular and extracellular metabolites of GBM, GSC and NHA to estimate their methionine levels using LC-MS Quadropole Time of Flight (Q-TOF) and LC-MS Triple Quad (QQQ) instruments. Thus, by using metabolic fingerprints of methionine, we quantified methionine accumulation / uptake in GBM, GSC and NHA. Results and Conclusion: PET provides real-time information of metabolism through the behavior of single molecules. Despite clinical trials advocating Met-PET imaging as a superior imaging modality compared to FDG-PET for brain tumors, to date Met-PET has not been widely used in clinical diagnostics. Through this metabolic profiling of gliomas, we have shown for the first time that GBM and GSC accumulate methionine when compared to NHA. Uptake studies through exogenous addition of methionine in GBM, GSC and NHA show a significant uptake of methionine by GBM and GSC when compared to NHA. The results of our study establish the scientific basis for Met-PET imaging in GBM and provide a rationale for incorporating Met-PET imaging in future brain tumor clinical trials to evaluate its prognostic value. Citation Format: Kamalakannan Palanichamy, Thirumoorthy Krishnan, Nikhil Sebastian, Rajbir Singh, Suman Kanji, Arnab Chakravarti. Targeted metabolic profiling of gliomas and glioma stem cells identifies methionine as a differentially regulated metabolite: Proof of principle supporting methionine-pet imaging. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4925. doi:10.1158/1538-7445.AM2014-4925