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

Area of Science:

• Oncology
• Pharmacology
• Artificial Intelligence in Medicine

Background:

• Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor with a poor prognosis.
• Somatic mutations in ACVR1 are present in approximately 25% of DIPG cases, yet no targeted therapies are currently licensed.
• ACVR1 signaling plays a critical role in the pathogenesis of ACVR1-mutant DIPG.

Observation:

• An AI platform screened approved compounds and identified vandetanib and everolimus as a potential therapeutic combination for ACVR1-mutant DIPG.
• Vandetanib targets ACVR1 and reduces DIPG cell viability but has limited blood-brain barrier penetration.
• Everolimus inhibits mTOR, ABCG2, and ABCB1 transporters, showing synergy with vandetanib in DIPG cells.

Findings:

• The combination of vandetanib and everolimus demonstrated synergistic effects in vitro, reducing DIPG cell viability.
• In vivo studies showed the combination was well-tolerated, significantly extending survival and reducing tumor burden in an ACVR1-mutant DIPG xenograft model.
• Preliminary clinical treatment of four patients with ACVR1-mutant DIPG with vandetanib plus an mTOR inhibitor informed dosing and toxicity.

Implications:

• This study validates a novel therapeutic strategy for ACVR1-mutant DIPG using a combination identified by artificial intelligence.
• The findings support the further clinical investigation of vandetanib and everolimus (or similar mTOR inhibitors) for children with this specific DIPG subtype.
• The successful application of AI in drug discovery for rare pediatric cancers highlights its potential to accelerate therapeutic development.