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, ACVR1R206H 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.
Highlights
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
Whilst H3.3 K27M mutations are present in other midline regions such as the thalamus, spine and cerebellum, ACVR1 mutations are associated with H3.1K27M substitutions, and appear restricted to DIPG13
We identified 50/212 (23.6%) cases with ACVR1 mutation, and found no differences in age at diagnosis between R206H (n = 10, median = 5.35 years), R258G (n = 7, median = 5.2 years), G328E/V/W (n = 28, median = 5.5 years) and G356D (n = 5, 4.8 years) variants (p = 0.6957, ANOVA), though together, mutant cases were significantly younger than ACVR1 wild-type DIPG (5.25 vs 7.0 years, p < 0.0001, t-test) (Fig. 1a)
Summary
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. ACVR1 encodes the receptor serine/threonine kinase ALK2, and in models of FOP, it has recently been reported that the characteristic mutations confer an aberrant sensitivity to the ligand activin A, produced as part of the inflammatory response, rather than the canonical BMPs21. This results in increased pathway activation and cell signalling via a canonical phosphorylated SMAD1/5/8-SMAD4 pathway to drive expression of target genes including ID1/2/3, SNAIL and HEY122. Continued improvements in selectivity have been reported in a newer series based instead on a pyridine scaffold, the prototype of which is K0228825
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