2. Academic Validation
  3. ALK2 inhibitors display beneficial effects in preclinical models of ACVR1 mutant diffuse intrinsic pontine glioma

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

  • Commun Biol. 2019 May 9;2:156. doi: 10.1038/s42003-019-0420-8.
Diana Carvalho # 1 2,  Kathryn R Taylor # 1 2 3,  Nagore Gene Olaciregui 4,  Valeria Molinari 1 2,  Matthew Clarke 1 2,  Alan Mackay 1 2,  Ruth Ruddle 2,  Alan Henley 2,  Melanie Valenti 2,  Angela Hayes 2,  Alexis De Haven Brandon 2,  Suzanne A Eccles 2,  Florence Raynaud 2,  Aicha Boudhar 5 6,  Michelle Monje 3,  Sergey Popov 1 2 7,  Andrew S Moore 8 9,  Jaume Mora 4,  Ofelia Cruz 4,  Mara Vinci 1 2 10,  Paul E Brennan 5 6,  Alex N Bullock 5,  Angel Montero Carcaboso 4,  Chris Jones 1 2
Affiliations

Affiliations

  • 1 1Divisions of Molecular Pathology, The Institute of Cancer Research, London, SM2 5NG UK.
  • 2 2Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG UK.
  • 3 3Stanford University School of Medicine, Stanford, 94305 CA USA.
  • 4 Institut de Recerca Sant Joan de Deu, Barcelona, 08950 Esplugues de Llobregat Spain.
  • 5 5Structural Genomics Consortium, University of Oxford, Oxford, OX3 7DQ UK.
  • 6 6Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford, OX3 7FZ UK.
  • 7 7Department of Cellular Pathology, University Hospital of Wales, Cardiff, CF14 4XW UK.
  • 8 8Diamantina Institute and Child Health Research Centre, The University of Queensland, Brisbane, QLD 4101 Australia.
  • 9 Oncology Service, Queensland Children's Hospital, Brisbane, QLD 4029 Australia.
  • 10 10Bambino Gesù Children's Hospital, Rome, 00165 Roma RM Italy.
  • # Contributed equally.
PMID: 31098401 DOI: 10.1038/s42003-019-0420-8
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.

Keywords

CNS cancer; Paediatric cancer; Target validation.

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