GLP1R agonists and vorasidenib converge on peroxynitrite-mediated cytotoxicity in mutant IDH glioma

This preprint reports that GLP1R agonists synergise with vorasidenib in patient-derived and murine models of mutant IDH glioma, through cAMP and protein kinase A signalling, nitric oxide synthase 1-dependent nitric oxide production, and peroxynitrite-mediated cytotoxicity. The Claidex graph holds one IDH1 failure, olutasidenib-idh1-cmml-mds-mpn-mdacc-pi-withdrawal, a Phase 2 of olutasidenib in IDH1-mutated chronic myelomonocytic leukaemia, higher-risk myelodysplastic syndrome and advanced myeloproliferative neoplasms, terminated at principal investigator request. That is an operational termination in a haematological setting and says nothing about mutant IDH inhibition in glioma, so severity is mild. The claim worth tracking is the combination logic rather than the target, because it addresses progression on an inhibitor that engages its target rather than a failure to engage it.