Repurposing Vandetanib plus Everolimus for the Treatment of <i>ACVR1</i>-Mutant Diffuse Intrinsic Pontine Glioma.

ABSTRACT: Somatic mutations in ACVR1 are found in a quarter of children with diffuse intrinsic pontine glioma (DIPG), but there are no ACVR1 inhibitors licensed for the disease. Using an artificial intelligence-based platform to search for approved compounds for ACVR1-mutant DIPG, the combination of vandetanib and everolimus was identified as a possible therapeutic approach. Vandetanib, an inhibitor of VEGFR/RET/EGFR, was found to target ACVR1 (K _d = 150 nmol/L) and reduce DIPG cell viability in vitro but has limited ability to cross the blood-brain barrier. In addition to mTOR, everolimus inhibited ABCG2 (BCRP) and ABCB1 (P-gp) transporters and was synergistic in DIPG cells when combined with vandetanib in vitro. This combination was well tolerated i

SUBMITTER: Carvalho DM 

PROVIDER: S-EPMC7612365 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature