The Foundation has approved its first UK research grant of £90,000 to Dr Chris Jones at The Institute of Cancer Research to study the role of ACVR1/ALK2 mutations in DIPG.
Diffuse intrinsic pontine glioma (DIPG) have a universally dismal prognosis (median 9-12 months), with neither chemotherapeutic nor targeted agents showing any substantial survival benefit in clinical trials in children with these tumours.
Dr Jones and his team recently identified recurrent activating mutations in the ACVR1/ALK2 gene, which encodes a type I activin receptor serine/threonine kinase, in nearly 20% of DIPG samples [Taylor et al., submitted; Buczkowicz et al., submitted]. Strikingly, these somatic mutations (R206H, Q207E, R258G, G328E/V/W, G356D) have not been reported previously in cancer, but are identical to those found in the germline of patients with the congenital childhood developmental disorder fibrodysplasia ossificans progressiva (FOP), and have been shown to constitutively activate the BMP/TGF-b signalling pathway. ACVR1/ALK2 mutations represent novel targets for therapeutic intervention in this otherwise incurable disease, and we aim to exploit these findings to investigate the role of ACVR1/ALK2 mutations and activation in DIPG. Specifically, Dr Jones and his team will evaluate the therapeutic potential of targeting the mutant receptor through genetic and pharmacological inhibition, both in vitro and in vivo, and to better understand the mechanism by which these mutations promote gliomagenesis by generating genetically engineered mouse models of the disease. This data has the potential to be rapidly translated to the clinical setting given the poor clinical outcome of these patients and the lack of currently open trials in the UK.