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

Somatic mutations in <i>ACVR1</i> 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 <i>ACVR1</i>-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 (<i>K</i> _d = 150 nmol/L) and reduce DIPG cell viability <i>in vitro</i> 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 <i>in vitro</i>. This combination was well tolerated <i>in vivo</i> and significantly extended survival and reduced tumor burden in an orthotopic <i>ACVR1</i>-mutant patient-derived DIPG xenograft model. Four patients with <i>ACVR1</i>-mutant DIPG were treated with vandetanib plus an mTOR inhibitor, informing the dosing and toxicity profile of this combination for future clinical studies. SIGNIFICANCE: Twenty-five percent of patients with the incurable brainstem tumor DIPG harbor somatic activating mutations in <i>ACVR1</i>, but there are no approved drugs targeting the receptor. Using artificial intelligence, we identify and validate, both experimentally and clinically, the novel combination of vandetanib and everolimus in these children based on both signaling and pharmacokinetic synergies.<i>This article is highlighted in the In This Issue feature, p. 275</i>.