Repurposing Vandetanib plus Everolimus for the Treatment ofACVR1-Mutant Diffuse Intrinsic Pontine Glioma

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 bloodbrain-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. STATEMENT OF SIGNIFICANCE25% patients with the incurable brainstem tumour DIPG harbour somatic activating mutations in ACVR1, however there are no approved drugs targeting the receptor. Using Artificial Intelligence, we identify and validate the novel combination of vandetanib and everolimus in these children based upon both signalling and pharmacokinetic synergies, experimentally and clinically.Research.

Receptor tyrosine kinase (RTK) targeting in pediatric high-grade glioma and diffuse midline glioma: Pre-clinical models and precision medicine

“…On the therapeutic side, one direction for RTK-altered pediatric gliomas is co-treatment of multiple TKIs, or one TKI with a synergistic drug to avoid or delay the development of drug resistance ( 100 ). As discussed, our group showed that the combination of PDGFRA inhibitor dasatinib with mTOR inhibitor everolimus significantly improved the survival of pediatric high-grade glioma than either treatment alone ( 41 ).…”

“…Vandetanib was later investigated in combination with dasatinib in another phase I trial, with median OS of 15 months ( 99 ). In addition, vandetanib and everolimus showed promising preclinical results and initial clinical case studies ( 100 ). Pazopanib targets several TKIs (among them VEGFR, KIT, PDGFR, and FGFR) to inhibit tumor angiogenesis; it was investigated in a phase II adult glioblastoma trial and did not prolong survival ( 101 ).…”

Gaps and Opportunities of Artificial Intelligence Applications for Pediatric Oncology in European Research: A Systematic Review of Reviews and a Bibliometric Analysis

“…The development of new treatments and drug repurposing is also an important issue ( 48 ). Interesting studies with initial evidence in this respect have recently been published ( 49 ). More tolerable and safe treatments would significantly improve the quality of life in this population.…”

Case Report: Reversible Hyperglycemia Following Rapamycin Treatment for Atypical Choroid Plexus Papilloma in an Infant

“…To reduce the blood supply to the tumor and tumor volume, the patient took 2.6 mg/m 2 /day rapamycin orally (divided into two equal doses) at the initial recommended dose of complicated vascular anomalies, but the trough concentration of plasma rapamycin was under 10–15 ng/ml after 7 days of rapamycin treatment. According to some reports, the recommended dose for children with brain tumors is 3–5 mg/m 2 /day ( 25 – 27 ), and the maximum dose for recurrent and refractory solid tumors reaches 150 mg/m 2 /day (once a week) without serious rapamycin-induced adverse effects ( 28 ). Furthermore, because of low oral bioavailability (15%–20%) ( 29 ) and poor blood–brain barrier penetration ( 30 – 32 ) [the ratio of the cerebrospinal fluid rapamycin concentration to the plasma rapamycin concentration was 0.0057 ( 33 )], the patient with aCPP finally received 7.8 mg/m 2 /day (divided into two equal doses), and the trough concentration of plasma rapamycin reached 14.8 ng/ml.…”