Imaging telomerase reverse transcriptase expression in oligodendrogliomas using hyperpolarized δ-[1-13C]-gluconolactone

Georgios Batsios; Celine Taglang; Anne Marie Gillespie; Pavithra Viswanath

doi:10.1093/noajnl/vdad092

Imaging telomerase reverse transcriptase expression in oligodendrogliomas using hyperpolarized δ-[1-¹³C]-gluconolactone

Neurooncol Adv. 2023 Jul 21;5(1):vdad092. doi: 10.1093/noajnl/vdad092. eCollection 2023 Jan-Dec.

Authors

Georgios Batsios¹, Celine Taglang¹, Anne Marie Gillespie¹, Pavithra Viswanath¹

Affiliation

¹ Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, USA.

Abstract

Background: Telomere maintenance by telomerase reverse transcriptase (TERT) is essential for immortality in most cancers, including oligodendrogliomas. Agents that disrupt telomere maintenance such as the telomere uncapping agent 6-thio-2'-deoxyguanosine (6-thio-dG) are in clinical trials. We previously showed that TERT expression in oligodendrogliomas is associated with upregulation of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP). We also showed that hyperpolarized δ-[1-¹³C]-gluconolactone metabolism to 6-phosphogluconate (6-PG) can be used to probe the PPP in glioblastomas. The goal of this study was to determine whether hyperpolarized ¹³C imaging using δ-[1-¹³C]-gluconolactone can monitor TERT expression and response to 6-thio-dG in oligodendrogliomas.

Methods: We examined patient-derived oligodendroglioma cells and orthotopic tumors to assess the link between TERT and hyperpolarized δ-[1-¹³C]-gluconolactone metabolism. We performed in vivo imaging to assess the ability of hyperpolarized δ-[1-¹³C]-gluconolactone to report on TERT and response to 6-thio-dG in rats bearing orthotopic oligodendrogliomas in vivo.

Results: Doxycycline-inducible TERT silencing abrogated 6-PG production from hyperpolarized δ-[1-¹³C]-gluconolactone in oligodendroglioma cells, consistent with the loss of G6PD activity. Rescuing TERT expression by doxycycline removal restored G6PD activity and, concomitantly, 6-PG production. 6-PG production from hyperpolarized δ-[1-¹³C]-gluconolactone demarcated TERT-expressing tumor from surrounding TERT-negative normal brain in vivo. Importantly, 6-thio-dG abrogated 6-PG production at an early timepoint preceding MRI-detectable alterations in rats bearing orthotopic oligodendrogliomas in vivo.

Conclusions: These results indicate that hyperpolarized δ-[1-¹³C]-gluconolactone reports on TERT expression and early response to therapy in oligodendrogliomas. Our studies identify a novel agent for imaging tumor proliferation and treatment response in oligodendroglioma patients.

Keywords: TERT; hyperpolarized 13C imaging; magnetic resonance spectroscopy; oligodendrogliomas; pentose phosphate pathway.