Model development and preclinical screening
In order to translate our increased understanding of the biology of paediatric high grade glioma and DIPG to the clinic, we need accurate preclinical models which faithfully recapitulate the disease subgroups we have defined. We are working to do this with collaborators worldwide, and currently have more than 60 patient-derived in vitro cultures, many of which have also been established as orthotopic xenografts in vivo.
Drug screening of these models have revealed multiple genetic dependencies for preclinical development, which are currently being validated and explored in more depth in the lab. We have specific projects aimed at developing genetically engineered models and testing a range of compounds directed against certain key childhood glioma driver genes.
We discovered somatic mutations in ACVR1 to be present in around 25% of DIPGs in 2014, and have generated a wealth of preclinical data demonstrating the efficacy of ACVR1 inhibitors in patient-derived DIPG models. In collaboration with Swen Hoelder, the ICR has also generated a novel series of such compounds for further development.
Additional projects are focussed on histone H3.3 G34R/V mutations, which we have previously shown to specifically upregulate the oncogene MYCN, and ATRX, which is involved with H3.3 deposition, and mutations in which appear to confirm a specific synthetic lethality to a DNA repair process we are exploring.