High grade gliomas HGGs are among the most aggressive primary brain tumors, yielding a median survival time of less than 2 years and a 5-year survival of 2.5%. There has been little in the way of treatments and novel approaches are needed to combat HGG’s poor prognosis. Recent studies have established that HGG cells exhibit metabolic reprogramming to adapt to diverse metabolic gradients within heterogenous tumor microenvironments. Using an unbiased metabolomics approach, we investigated metabolic changes both pre- and post-ionizing radiation across several patient-derived cell lines. Acute dosages of ionizing radiation resulted in significant changes in the synthesis of aminolevulinic acid (ALA), which is known to be converted into the fluorescent metabolite protoporphyrin IX (PpIX) in the porphyrin synthesis pathway. PpIX has been utilized by surgeons in fluorescence-guided tumor resection for clearer visualization of tumor boundaries in recent years. Fractionation of radiation therapy also resulted in dose-dependent changes in the pathway concerning heme synthesis within these cells, especially presenting decreased levels of ALA dehydratase (ALAD) and increased levels of ferrochelatase. As ALAD promotes PpIX accumulation and ferrochelatase catalyzes its conversion to heme, this indicates a decreased favorability for the accumulation of PpIX in the reprogrammed metabolism of HGG cells following radiation. Consequently, we propose that PpIX fluorescence is not a reliable visual aide in surgical re-resection of HGGs post-radiation therapy.

Citation Format: Paras S. Minhas, Aarooran Durairaj, Melanie McReynolds, Katrin I. Andreasson, YooJin Jung, Joshua Rabinowitz. Irradiation of patient-derived high-grade gliomas reduces 5-ALA-induced fluorescence utility during re-resection [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B046.