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

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- ¹³ C]-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 ¹³ C imaging using δ-[1- ¹³ C]-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- ¹³ C]-gluconolactone metabolism. We performed in vivo imaging to assess the ability of hyperpolarized δ-[1- ¹³ C]-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- ¹³ C]-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- ¹³ C]-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- ¹³ C]-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.
Competing Interests: The authors have no conflicting interests to disclose.
(© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)