Metabolic Deuterium Imaging Reports on TERT Expression and Early Response to Cancer Treatment | Clinical cancer research
Maintenance of telomeres is a hallmark of cancer. Most tumors maintain telomere length via reactivation of telomerase reverse transcriptase (TERT) expression. Identification of clinically translatable imaging biomarkers of TERT may allow noninvasive assessment of tumor proliferation and response to therapy.
We used RNAi, doxycycline-inducible expression systems, and pharmacological inhibitors to mechanistically delineate the association between TERT and metabolism in preclinical patient-derived tumor models. Deuterium Magnetic Resonance Spectroscopy (2H-MRS), which is a novel translational metabolic imaging modality, has been used for TERT imaging in tumor-bearing cells and mice live.
Our results indicate that TERT expression is associated with elevated NADH in several cancers, including glioblastoma, oligodendroglioma, melanoma, neuroblastoma, and hepatocellular carcinoma. Mechanically, TERT works through the metabolic regulator FOXO1 to upregulate nicotinamide phosphoribosyl transferase, which is the key enzyme in NAD+ biosynthesis, and the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, which converts NAD+ to NADH. Since NADH is essential for the flux of pyruvate to lactate, we show that 2H-MRS based assessment of lactate production [U-2H]-reports of pyruvate on TERT expression in preclinical tumor models live, including clinical field strength (3T). Above all, [U-2H]-pyruvate reports an early response to treatment in mice with patient-derived orthotopic gliomas at early time points before radiographic alterations can be visualized by MRI.
Elevated NADH is a metabolic consequence of TERT expression in cancer. Above all, [U-2H]-pyruvate reports early response to treatment, before anatomical alterations, providing clinicians with a new tool for assessing tumor burden and response to cancer treatment.