CBMT-30. TARGETING NICOTINAMIDE ADENINE DINUCLEOTIDE BIOSYNTHESIS IN CNS TUMORS. (11th November 2019)

• Record Type: Journal Article
• Authors: Lindsay, Ken; Brenner, Charles; Hockenbery, David; Paddison, Patrick
• Is Part Of: Neuro-oncology. Volume 21(2019)Supplement 6
• Page Start: vi39
• Page End: vi39
• Publication Date: 2019-11-11
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noz175.152
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Nicotinamide adenine dinucleotide (NAD) metabolic pathways have been shown to be critical targets in many cancers, including brain tumors. However, inhibiting nicotinamide metabolism has had limited efficacy in the clinic to date due to on-target side effects. To identify new metabolic vulnerabilities in human Glioblastoma, we performed a chemical library screen using 250 inhibitors of metabolic enzymes in Glioblastoma stem-like cells (GSCs) (0131 and 0827) and control hNPC-CB660 cells. Among the screen hits, we identified FK866, an inhibitor of the NAD salvage enzyme NAMPT, as having GSC-selective cytotoxicity. Taking an advantage of an alternative NAD precursor salvage pathway, we show that cytotoxicity with inhibitors of the NAMPT salvage enzyme for neural stem cells was abrogated by media addition of nicotinamide riboside (NR), while certain glioblastoma stem-like cells (GSCs) remained exquisitely sensitive. Examining our GSC isolates, we observed that hypersensitivity correlated with low/absent expression of NMRK1, a kinase required for utilization of NR. We find that 5–20% of most tumor types (CNS, non-CNS) exhibit comparably low NMRK1 mRNA expression. In looking for associations with oncogenic drivers, we noted significant negative correlation with MYCN and MYC expression for multiple tumors. We have additional data suggesting that MYC/MYCN induces the NMRK1 low state via transcriptional repression. These results suggest that NAMPT inhibitors, already in clinical trials, can be administered with NR to widen the therapeutic index for NMRK1 low tumors. This combined theranostic approach could protect NMRK1-proficient normal cells without compromising treatment efficacy in NMRK1 low tumor cells.