During my postdoctoral research at the UCL Cancer Institute (2014-2018), I established a novel brain tumor modeling approach that delivers transposons into endogenous neural stem cells during fetal brain development. I used this to create the first molecularly and histologically faithful model of H3K27M-driven pediatric glioma. This model enables exploration of biological mechanisms and therapeutic opportunities for a type of cancer in which human material is scarce. More generally, this work demonstrated for the first time that a mutation in a core chromatin component can drive brain tumors by stalling the normal development of discrete fetal progenitors and has implications for other brain tumor types in which epigenetic deregulation occurs.

I then set up my own lab at Cambridge in 2019, where my team has developed 16 additional pediatric glioma models driven by various combinations of histone mutations and partner alterations that together recapitulate the genetic diversity of this heterogeneous disease entity. We have used these models to identify tumor subtype-specific biology and opportunities for targeted therapy. Cell lines derived from these models are also uniquely capable of engrafting in immunocompetent, syngeneic recipients, making them the most suitable models for evaluating tumor microenvironment (TME) interactions and immunotherapy approaches. Additionally, in collaboration with other groups, we have extensively profiled the composition of the TME in pediatric glioma patient samples and compared this information to data from our mouse models. We found that the models share a high degree of correspondence with human tumors. We also evaluated a novel combination therapy designed to increase the efficacy of checkpoint blockade. This significantly improved survival by substantially increasing infiltration of immune cells, demonstrating that the microenvironment can be therapeutically reprogrammed in these famously immunologically cold tumors.

My group at the Ludwig Institute for Cancer Research Oxford Branch explores: 1) precision therapy opportunities (including CAR-T cells); 2) the role of the TME and infiltrating immune cells; and 3) the biology of resistance using in vivo genetic barcoding and CRISPR screening. The modelling approach will also be expanded to encompass additional brain tumor entities.