DIPG-02. A NOVEL STRATEGY TO RADIOSENSITISE DIFFUSE MIDLINE GLIOMAS VIA DUAL-TARGETING OF GLUCOSE METABOLISM
نویسندگان
چکیده
Abstract Diffuse Midline Gliomas (DMG) is the leading cause of brain tumor-related death in children. Currently, radiation only treatment that offers transient benefit but almost all DMG relapse due to radioresistance. Compared normal tissue, are hypo-perfused with tumor cells being exposed hypoxia, a low oxygen microenvironment serves as potent barrier effective radiotherapy. Biguanides hypoglycemic agents can reduce consumption rate (OCR) mitochondria, thereby sparing more and alleviating hypoxia. Our previous study has shown metformin significantly improves radiosensitivity extends survival patient-derived xenograft (PDX) model. In comparison metformin, phenformin demonstrated greater efficacies anti-proliferation, OCR hypoxia inhibition, radiosensitization panel cultures. These effects were possibly induced by through inhibition mitochondrial complex I cells. The anti-tumor effect was further enhanced combining second drug dichloroacetate simultaneously attenuated phenformin-induced acidification. Specifically, combination higher levels reactive species DNA damage, which subsequently resulted much stronger cell-cycle proliferation arrest, apoptosis, inhibition. Metabolically, co-treatment targeted multiple pathways, reduced ATP production triggered metabolic catastrophe. RNA sequencing significant alterations cell-cycle, repair, unfolded protein response alternative energetic pathways. Furthermore, improved cells, evidenced clonogenic preliminary vivo data possible reduction burden following 4 weeks treatment, no elevation serum L-lactate level phenformin-treated groups. This therapeutic efficacy currently validated orthotopic models optimized schedules.
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ژورنال
عنوان ژورنال: Neuro-oncology
سال: 2023
ISSN: ['1523-5866', '1522-8517']
DOI: https://doi.org/10.1093/neuonc/noad073.049