Hg-67preclinical Efficacy of Alk2 Inhibitors in Acvr1 Mutant Dipg
Year: 2016
Type: article
Abstract: We recently reported somatic mutations in ACVR1, encoding the serine/threonine kinase ALK2 receptor, in diffuse intrinsic pontine glioma (DIPG) and have explored its utility as a novel drug target in these incurable childhood brainstem tumours. 50/206(24%) DIPG patients harboured ACVR1 mutations, with the extended survival times (p = 0.0041) and H3.1K27M associations (p = 0.046) of this genotype restricted to G328E/V/W substitutions; the common germline variant in fibrodysplasia ossificans progressiva (FOP), R206H, instead frequently co-segregated with H3.3K27M and a shorter overall survival. This mutation is reported to confer abnormal responsiveness to activin A in FOP, a phenomenon recapitulated in vitro in both R206H and G328V primary patient-derived DIPG models assessed by Western blot for p-Smad1/5/8 and ID1/2. Unlike classical BMP ligands, the spatiotemporal expression of activin A in neurodevelopment correlates with the suggested origins of DIPG. Screening mutant and wild-type DIPG cultures with a range of quinazolinone- and pyrazolo[1,5-a]pyrimidine-based ALK2 inhibitors, both published and newly-derived in-house, demonstrated differential effects on cell viability down to sub-micromolar concentrations, recapitulating genetic knockdown with shRNA, and corresponding to sustained time- and concentration-dependent reduction in signaling. Preclinical studies showed LDN-193189 and LDN-214117 to be orally bioavailable and tolerated, with penetration of the CNS at potentially active concentrations. Treatment of mice bearing orthotopic xenografts of H3.3K27M, ACVR1 R206H mutant HSJD-DIPG-007 cells with 25mg/kg LDN-193189 for 28 days significantly extended animal survival compared to vehicle control (p = 0.0053). Continued development of novel ALK2 inhibitors with increased potency, selectivity and pharmacokinetic properties may play an important role in future trials of DIPG patients.
Source: Neuro-Oncology
Authors: Diana Carvalho, Kathryn Taylor, Nagore G. Olaciregui, Melanie Valenti, Ruth Ruddle, Alan Henley, Angela Hayes, Alexis De Haven Brandon, Albert Hallsworth, Alan Mackay, Valeria Molinari, Maria Vinci, Sergey Popov, Aicha Boudhar, Paul Brennan, Andrew Moore, Liam Hudson, Swen Hoelder, Alex Bullock, Florence Raynaud, Sue Eccles, Angel M. Carcaboso, Chris Jones
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2441469502