ALK2 inhibitors display beneficial effects in preclinical models of ACVR1 mutant diffuse intrinsic pontine glioma

TLDR

Diffuse intrinsic pontine glioma is a lethal childhood brainstem tumour, with about 25 % of cases harbouring ACVR1 (ALK2) mutations, yet systematic evaluation of this drug target and screening of available inhibitors in patient‑derived models has been limited. The study investigates the dependence of DIPG cells on mutant ALK2 and tests the preclinical efficacy of two distinct ALK2 inhibitor chemotypes in vitro and in vivo. Both LDN‑193189 and LDN‑214117 are orally bioavailable, well‑tolerated, penetrate the brain, and treatment of orthotopic xenografts with either compound for 28 days significantly extended survival compared with vehicle controls.

Abstract

Abstract Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brainstem tumour, with a quarter of patients harbouring somatic mutations in ACVR1 , encoding the serine/threonine kinase ALK2. Despite being an amenable drug target, little has been done to-date to systematically evaluate the role of ACVR1 in DIPG, nor to screen currently available inhibitors in patient-derived tumour models. Here we show the dependence of DIPG cells on the mutant receptor, and the preclinical efficacy of two distinct chemotypes of ALK2 inhibitor in vitro and in vivo. We demonstrate the pyrazolo[1,5-a]pyrimidine LDN-193189 and the pyridine LDN-214117 to be orally bioavailable and well-tolerated, with good brain penetration. Treatment of immunodeprived mice bearing orthotopic xenografts of H3.3K27M, ACVR1 R206H mutant HSJD-DIPG-007 cells with 25 mg/kg LDN-193189 or LDN-214117 for 28 days extended survival compared with vehicle controls. Development of ALK2 inhibitors with improved potency, selectivity and advantageous pharmacokinetic properties may play an important role in therapy for DIPG patients.