IMAGING TELOMERE MAINTENANCE MECHANISMS IN GLIOMAS

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PROJECT SUMMARY All tumors, including gliomas, need a telomere maintenance mechanism (TMM) in order to proliferate indefinitely and TMMs are, therefore, considered hallmarks of cancer. Primary glioblastomas and low-grade oligodendrogliomas use reactivation of telomerase reverse transcriptase (TERT) expression as their TMM while low-grade astrocytomas use the alternative lengthening of telomeres (ALT) pathway. Due to their essential nature, TERT and ALT are attractive therapeutic targets and, interestingly, studies indicate that TERT inhibition can lead to resistance by induction of the ALT pathway. Our goal is to identify novel, magnetic resonance spectroscopy (MRS)-detectable metabolic biomarkers of TERT and ALT in gliomas that will enable non-invasive imaging of tumor burden and response to therapy. Our scientific premise is that prior studies as well as our preliminary data, indicate that TERT and ALT are associated with significant metabolic reprogramming, resulting in unique MRS-detectable metabolic signatures of TMM status. Our specific aims are as follows: Aim 1- to identify non-invasive 1H- and hyperpolarized 13C-MRS-based imaging biomarkers of TMM status in genetically-engineered and patient-derived glioma cells; Aim 2- to determine the utility of 1H- and hyperpolarized 13C- MRS for metabolic imaging of TMM status in orthotopic glioma xenografts in vivo; Aim 3: to mechanistically validate our imaging biomarkers by identifying the molecular mechanisms by which TERT and ALT alter metabolism in gliomas. This proposal is innovative because: 1) although TMM have been linked to metabolic reprogramming, we are the first to propose to exploit this link for non-invasive imaging 2) we have access to unique genetically-engineered and patient- derived glioma models that differ in TMM status 3) we propose to use unbiased principal component analysis to identify TMM-linked metabolic alterations and 4) we have access to and expertise in the application of innovative, translational hyperpolarized 13C-MRS imaging methods to brain tumors. This research is significant because the metabolic biomarkers identified here will provide a non-invasive means of imaging TMMs, which are molecular features of brain tumors. This will enable clinicians to distinguish tumor from regions of normal brain, edema or necrosis and to monitor tumor recurrence and response to chemotherapy or radiotherapy. Identification of imaging biomarkers tailored to TMM status will also allow detection of tumor response to novel TMM inhibitors and the development of resistance to TMM inhibitors. Importantly, since TMMs are a universal hallmark of cancer, our imaging biomarkers can potentially also be applied to tumor types other than gliomas.