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https://dora.health.qld.gov.au/qldresearchjspui/handle/1/1895| Title: | ALK2 inhibitors display beneficial effects in preclinical models of ACVR1 mutant diffuse intrinsic pontine glioma | Authors: | Jones, Chris Carvalho, Diana Taylor, Kathryn R. Olaciregui, Nagore Gene Molinari, Valeria Clarke, Matthew Mackay, Alan Ruddle, Ruth Henley, Alan Valenti, Melanie Hayes, Angela Brandon, Alexis De Haven Eccles, Suzanne A. Raynaud, Florence Boudhar, Aicha Monje, Michelle Popov, Sergey Moore, Andrew Mora, Jaume Cruz, Ofelia Vinci, Mara Brennan, Paul E. Bullock, Alex N. Carcaboso, Angel Montero |
Issue Date: | 2019 | Source: | 2 , 2019, p. 156 | Pages: | 156 | Journal: | Communications biology | 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.eCollection. Cited Medium: Internet. NLM ISO Abbr: Commun Biol. PubMed Central ID: PMC6509210. Linked References: J Neurooncol. 2017 Apr;132(2):255-266. (PMID: 28110411); Nat Genet. 2014 May;46(5):444-450. (PMID: 24705251); Nat Med. 2017 Apr;23(4):493-500. (PMID: 28263307); Nature. 2006 Dec 7;444(7120):761-5. (PMID: 17151667); Nat Rev Mol Cell Biol. 2007 Dec;8(12):970-82. (PMID: 18000526); Nat Neurosci. 2017 Jan;20(1):10-15. (PMID: 27775720); Cancer Discov. 2013 May;3(5):512-9. (PMID: 23539269); Cancer Cell. 2017 May 8;31(5):635-652.e6. (PMID: 28434841); Nat Genet. 2012 Jan 29;44(3):251-3. 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Grant Information: United Kingdom WT_ Wellcome Trust; C13468/A14078 United Kingdom CRUK_ Cancer Research UK; 106169/ZZ14/Z United Kingdom WT_ Wellcome Trust Date of Electronic Publication: 2019 May 09. ; Original Imprints: Publication: London, United Kingdom : Nature Publishing Group UK, [2018]- | DOI: | 10.1038/s42003-019-0420-8 | Resources: | https://search.ebscohost.com/login.aspx?direct=true&AuthType=ip,athens&db=mdc&AN=31098401&site=ehost-live | Keywords: | Pyrazoles/pharmacokinetics;Pyridines/pharmacokinetics;Survival Analysis;Target validation*;Pyrimidines/pharmacokinetics;Xenograft Model Antitumor Assays;CNS cancer*;Paediatric cancer*;Activin Receptors, Type I/*geneticsAntineoplastic Agents/*pharmacology;Brain Stem Neoplasms/*drug therapy;Diffuse Intrinsic Pontine Glioma/*drug therapy;Protein Kinase Inhibitors/*pharmacology;Pyrazoles/*pharmacology;Pyridines/*pharmacology;Pyrimidines/*pharmacology;Activin Receptors, Type I/antagonists & inhibitors;Activin Receptors, Type I/metabolism;Administration, Oral;Animals;Antineoplastic Agents/pharmacokinetics;Apoptosis/drug effects;Apoptosis/genetics;Brain Stem Neoplasms/genetics;Brain Stem Neoplasms/mortality;Brain Stem Neoplasms/pathology;Cell Line, Tumor;Cell Proliferation;Child;Diffuse Intrinsic Pontine Glioma/genetics;Diffuse Intrinsic Pontine Glioma/mortality;Diffuse Intrinsic Pontine Glioma/pathology;Drug Administration Schedule;Drug Evaluation, Preclinical;Female;Gene Expression;High-Throughput Screening Assays;Humans;Mice;Mice, SCID;Mutation;Protein Kinase Inhibitors/pharmacokinetics | Type: | Article |
| Appears in Sites: | Children's Health Queensland Publications |
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