Repurposing Vandetanib plus Everolimus for the Treatment of ACVR1 -Mutant Diffuse Intrinsic Pontine Glioma

  • Carvalho D
  • Richardson P
  • Olaciregui N
  • et al.
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Abstract

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.

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Carvalho, D. M., Richardson, P. J., Olaciregui, N., Stankunaite, R., Lavarino, C., Molinari, V., … Jones, C. (2021). Repurposing Vandetanib plus Everolimus for the Treatment of ACVR1 -Mutant Diffuse Intrinsic Pontine Glioma. Cancer Discovery. https://doi.org/10.1158/2159-8290.cd-20-1201

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