Manav Pathania

During my postdoctoral research at the UCL Cancer Institute (2014-2018), I established a novel brain tumour modelling approach that delivers transposons into endogenous neural stem cells during foetal brain development. I used this to create the first molecularly and histologically faithful model of H3K27M-driven paediatric 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 tumours by stalling the normal development of discrete foetal progenitors and has implications for other brain tumour types in which epigenetic deregulation occurs.

I then set up my own lab at Cambridge in 2019, where my team developed 16 additional paediatric 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 tumour 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 tumour–microenvironment (TME) interactions and immunotherapy approaches. Additionally, in collaboration with other groups, we have extensively profiled the composition of the TME in paediatric 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 tumours. We also evaluated a novel combination therapy designed to increase the efficacy of checkpoint blockade. This significantly improved survival by substantially increasing lymphoid infiltration, demonstrating that the microenvironment can be therapeutically reprogrammed in these famously immunologically cold tumours.

From 2026 onwards, my group at the Ludwig Institute for Cancer Research Oxford Branch will explore: 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 tumour entities.