TMET-30. ENHANCED RADIOSENSITIZATION OF GLIOMAS BY METABOLIC TARGETING OF SALVAGE PATHWAY OF NAD SYNTHESIS THROUGH NAMPT INHIBITION

Abstract BACKGROUND Pathway-specific targeted agents have failed to improve outcome in patients with high grade gliomas. Tumor recurrence is driven by glioma heterogeneity and emergence of therapy-resistant subpopulations. We previously reported that metabolic targeting NAMPT, the rate limiting enzyme NAD salvage synthesis pathway, circumvents induces cytotoxicity mitochondrial membrane depolarization generation reactive oxygen species. Based on these data, we examined potential for NAMPT inhibition synergize ionizing radiation enhance vitro vivo. METHODS Using a panel genetically heterogeneous patient-derived stem-like cells (GSC), effects using KPT9274, potent inhibitor, combination cell proliferation clonogenicity Cell Titre Glo assay, colony formation assays secondary sphere formation. Changes DNA damage-related proteins were visualized immunofluorescence assay confocal microscopy. Effects gene expression protein levels assessed western blot, reverse phase array (RPPA) RNA Seq. RESULTS reduced rate, self-renewal clonogenic capacity vitro. Combining KPT-9274 caused synergistic GSC. RPPA RNASeq results showed downregulation several repair which was further confirmed staining indicating crucial role resistance therapies. Results ongoing vivo studies assess PK/PD, drug toxicity survival benefits this therapy orthotopic GSC intracranial mouse model will be reported. CONCLUSIONS Our suggest through sensitizes radiotherapy. Ongoing delineating mechanistic basis their impact as rationale clinical assessment