Title: Chromatin proteins as drug targets for glioblastoma
Funder: The Brain Tumour Charity

Abstract: Glioblastomas (GBMs) have defects in the molecular machinery that controls whether genes are maintained in an ‘on’ or ‘off’ state. Of particular interest are families of proteins termed ‘chromatin regulators’, as there is intense effort to develop new anticancer drugs targeting these proteins. To date, however, it is unclear which of the ~1000 chromatin proteins should be prioritised for GBM drug development. In fact, our understanding of how these chromatin regulators interact with known ‘cancer pathways’ and their control of cell specialisation (termed differentiation) remains limited. Our aims are: 1) to increase knowledge of basic mechanisms; 2) identify which of the existing drugs are a priority for further development; 3) perform unbiased chemical and genetic screens to define the most important genes/pathways. GBM tumour cells can be grown in the laboratory (using stem cell culture conditions defined by us and others), enabling assessment of drug responses and tumour-specific vulnerabilities. We build on our exciting discovery that GBM cells may have vulnerabilities to inhibition of Trithorax group proteins (a particular class of chromatin regulator). In parallel, we will exploit the very latest powerful ‘genome editing’ tools to comprehensively define the most promising therapeutic targets. This will include systematic and sophisticated genetic follow up studies, to generate valuable engineered cellular models that are critical for rapid drug development and mechanistic understanding that is needed for effective clinical trials. Our team approach – bringing together scientists from Toronto, Edinburgh and Copenhagen – and collaborative links to the Structural Genomics Consortium (Oxford and Toronto), means we have complementary expertise in: GBM stem cells, genome editing, chromatin biology/biochemistry, drug development and drug screening. Our groups will meet regularly to compare and contrast results. This comprehensive collaborative approach will save considerable time and effort, and move drugs as quickly as possible into clinical trials

Lay abstract: Glioblastomas (GBMs) have defects in the molecular machinery that controls whether genes are maintained in an ‘on’ or ‘off’ state. Of particular interest are families of proteins termed ‘chromatin regulators’, as there is intense effort to develop new anticancer drugs targeting these proteins. To date, however, it is unclear which of the ~1000 chromatin proteins should be prioritised for GBM drug development. In fact, our understanding of how these chromatin regulators interact with known ‘cancer pathways’ and their control of cell specialisation (termed differentiation) remains limited. Our aims are: 1) to increase knowledge of basic mechanisms; 2) identify which of the existing drugs are a priority for further development; 3) perform unbiased chemical and genetic screens to define the most important genes/pathways. GBM tumour cells can be grown in the laboratory (using stem cell culture conditions defined by us and others), enabling assessment of drug responses and tumour-specific vulnerabilities. We build on our exciting discovery that GBM cells may have vulnerabilities to inhibition of Trithorax group proteins (a particular class of chromatin regulator). In parallel, we will exploit the very latest powerful ‘genome editing’ tools to comprehensively define the most promising therapeutic targets. This will include systematic and sophisticated genetic follow up studies, to generate valuable engineered cellular models that are critical for rapid drug development and mechanistic understanding that is needed for effective clinical trials. Our team approach – bringing together scientists from Toronto, Edinburgh and Copenhagen – and collaborative links to the Structural Genomics Consortium (Oxford and Toronto), means we have complementary expertise in: GBM stem cells, genome editing, chromatin biology/biochemistry, drug development and drug screening. Our groups will meet regularly to compare and contrast results. This comprehensive collaborative approach will save considerable time and effort, and move drugs as quickly as possible into clinical trials

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS