EXTH-03. TRIPTOLIDE, A NOVEL THERAPEUTIC AGENT FOR IDH1-MUTATED GLIOMA. (11th November 2019)

• Record Type: Journal Article
• Authors: Yu, Di; Liu, Yang; Xu, Guowang; Yang, Chunzhang
• Is Part Of: Neuro-oncology. Volume 21(2019)Supplement 6
• Page Start: vi82
• Page End: vi83
• 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/noz175.337
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: BACKGROUND: Isocitrate dehydrogenase ( IDH1/2 ) mutations are common genetic abnormalities in human malignancies, which result in neomorphic enzyme activity that catalyzes 2-hydroxyglutarate (2-HG) production. While IDH mutations are recognized as critical cancer-associated genetic changes, the therapeutic options for IDH -mutated cancers remain limited. METHODS: In the present study, we investigated the reactive oxygen species (ROS) scavenging pathways in patient-derived IDH1 -mutated cells. Further, we investigated the protective role of glutathione de novo synthesis for IDH1 -mutated cancer cells. Finally, we evaluated triptolide, a diterpenoid epoxide derived from Tripterygium wilfordii, as an experimental therapeutic for IDH1 -mutated cells and xenografts. RESULTS: We discovered that the neomorphic activity of IDH1 mutant enzyme triggers metabolic depletion and a substantial elevated burden of ROS scavenging in cancer cells. The nuclear factor erythroid 2-related factor 2 (NRF2)-guided antioxidant pathway plays a key role in maintaining redox homeostasis for IDH1 -mutated cells. Triptolide serves as a potent inhibitor of NRF2 through enhancing the NRF2 ubiquitination and subsequently proteasomal degradation. Additionally, triptolide compromises the de novo synthesis of glutathione via suppression of NRF2-guided transcription of SLC7A11, which encodes cystine/glutamate transporter (xCT). Reduced availability of glutathione results in overwhelming oxidative damage in DNA and lipid, which translates into severe cytotoxicity and reduced xenograft expansion of IDH1 -mutated cells. CONCLUSION: Overall our findings highlight triptolide as a valuable synthetic lethality approach for IDH1 -mutated malignancies by targeting NRF2-guided redox homeostasis.