TMET-13. SPATIAL METABOLOMIC CHANGES OF NUCLEOTIDE IN THE BRAINS OF ORTHOTOPIC MOUSE GLIOMA MODEL AFTER BORON NEUTRON CAPTURE THERAPY (BNCT)

Abstract Glioblastoma is the most lethal primary brain tumor. Boron Neutron Capture Therapy (BNCT) is a tumor-selective particle radiation therapy, in which high-LET α-particles and recoil 7Li are produced by the capture reaction between 10B and thermal neutrons and it has extended the prognosis of glioblastomas [Kawabata S, et al., Neuro-Oncology Advances 3(1), 1–9, 2021]. Augmented synthesis and use of nucleotide triphosphates is critical and universal metabolic dependency of tumor cells [Mullen, N.J., Singh, P.K. Nat Rev Cancer 23, 275–294 (2023)]. However, the effects of BNCT on metabolism of purine and pyrimidine in brain tumors and the surrounding normal brain are unknown. We spatially investigated metabolomic change in brains of orthotopic mouse glioma model, before and 2, 7, and 14 days after BNCT using mass spectrometry imaging (MSI). By separating tumor and non-tumor areas and performing Partial Least Squares Regression calculations, we have successfully visualized tumor-specific metabolites including adenine (ATP, ADP) and uridine (UTP, UDP-glucose, UDP-GlcNAc) with MSI. Of note, the signal of top-scored tumor specific metabolite, UDP-GlcNAc dramatically decreased and disappeared as the tumor regressed. Furthermore, the signal of ADP which was supposed to be released from tumor, colocalized with invading tumors along with corpus callosum. The value of adenylate energy charge, ([ATP]+0.5[ADP]/[ATP]+[ADP]+[AMP]) in the surrounding normal brain of the untreated tumor-bearing mouse increased up to 0.37 and decreased gradually down to 0.32 with BNCT, approaching to the value of normal control mouse brain, 0.27. These metabolomic changes reflected the tumor-killing effect and restoration of energy charge of surrounding normal brain by BNCT and have potential significance for development of biomarker or diagnosis.