LAUSR

BACKGROUND The alternative lengthening of telomeres (ALT) pathway is essential for tumor proliferation in astrocytomas. The goal of this study was to identify metabolic alterations linked to the ALT pathway that can be exploited for non-invasive magnetic resonance spectroscopy (MRS)-based imaging of astrocytomas in vivo. METHODS Genetic and pharmacological methods were used to dissect the association between the ALT pathway and glucose metabolism in genetically-engineered and patient-derived astrocytoma models. 2H-MRS was used for non-invasive imaging of ALT-linked modulation of glycolytic flux in mice bearing orthotopic astrocytomas in vivo. RESULTS The ALT pathway was associated with higher activity of the rate-limiting glycolytic enzyme phosphofructokinase-1 and concomitantly elevated flux of glucose to lactate in astrocytoma cells. Silencing the ALT pathway or treating with the poly (ADP-ribose) polymerase inhibitor niraparib that induces telomeric-fusion in ALT-dependent astrocytoma cells abrogated glycolytic flux. Importantly, this metabolic reprogramming could be non-invasively visualized by 2H-MRS. Lactate production from [6,6'- 2H]-glucose was higher in ALT-dependent astrocytoma tumors relative to normal brain in vivo. Furthermore, treatment of orthotopic astrocytoma-bearing mice with niraparib reduced lactate production from [6,6'- 2H]-glucose at early timepoints when alterations in tumor volume could not be detected by anatomical imaging, pointing to the ability of [6,6'- 2H]-glucose to report on pseudoprogression in vivo. CONCLUSIONS We have mechanistically linked the ALT pathway to elevated glycolytic flux and demonstrated the ability of [6,6'- 2H]-glucose to non-invasively assess tumor burden and response to therapy in astrocytomas. Our findings point to a novel, clinically translatable method for metabolic imaging of astrocytoma patients.