Somatic mutations in ACVR1 are found in a quarter of children with diffuse intrinsic pontine glioma (DIPG), however, 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 (Kd=150nM) and reduce DIPG cell viability in vitro but has limited ability to cross the blood brain barrier. In addition to mTOR, everolimus inhibits ABCG2 (BCRP) and ABCB1 (P-gp) transporters and was synergistic in DIPG cells when combined with vandetanib in vitro. This combination is well-tolerated in vivo, and significantly extended survival and reduced tumor burden in an orthotopic ACVR1-mutant patient-derived DIPG xenograft model. Four patients with ACVR1-mutant DIPG were treated with vandetanib plus mTOR inhibitor, informing the dosing and toxicity profile of this combination for future clinical studies 1).

Carvalho DM, Richardson PJ, Olaciregui N, Stankunaite R, Lavarino C, Molinari V, Corley EA, Smith DP, Ruddle R, Donovan A, Pal A, Raynaud FI, Temelso S, Mackay A, Overington JP, Phelan A, Sheppard D, Mackinnon A, Zebian B, Al-Sarraj S, Merve A, Pryce J, Grill J, Hubank M, Cruz O, Morales La Madrid A, Mueller S, Carcaboso AM, Carceller F, Jones C. Repurposing vandetanib plus everolimus for the treatment of ACVR1-mutant diffuse intrinsic pontine glioma. Cancer Discov. 2021 Sep 22:candisc.1201.2020. doi: 10.1158/2159-8290.CD-20-1201. Epub ahead of print. PMID: 34551970.
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  • Last modified: 2021/09/23 16:49
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