ALK2 inhibitors display beneficial effects in preclinical models of ACVR1 mutant diffuse intrinsic pontine glioma.
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Date
2019-05-09Author
Carvalho, D
Taylor, KR
Olaciregui, NG
Molinari, V
Clarke, M
Mackay, A
Ruddle, R
Henley, A
Valenti, M
Hayes, A
Brandon, ADH
Eccles, SA
Raynaud, F
Boudhar, A
Monje, M
Popov, S
Moore, AS
Mora, J
Cruz, O
Vinci, M
Brennan, PE
Bullock, AN
Carcaboso, AM
Jones, C
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Cell Line, Tumor
Animals
Humans
Mice
Mice, SCID
Brain Stem Neoplasms
Pyrazoles
Pyridines
Pyrimidines
Activin Receptors, Type I
Antineoplastic Agents
Protein Kinase Inhibitors
Administration, Oral
Drug Administration Schedule
Survival Analysis
Drug Evaluation, Preclinical
Xenograft Model Antitumor Assays
Apoptosis
Cell Proliferation
Gene Expression
Mutation
Child
Female
High-Throughput Screening Assays
Diffuse Intrinsic Pontine Glioma
Research team
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Glioma Team
Language
eng
Date accepted
2019-04-08
License start date
2019-01
Citation
Communications biology, 2019, 2 pp. 156 - ?
Publisher
NATURE PUBLISHING GROUP