Metabolomics for therapeutic discovery: how do Isocitrate Dehydrogenase (IDH1) mutations impact on cellular metabolism?

The metabolic consequences of genetic and proteomic changes are widely implicated in cancer but remain poorly understood. D-2-hydroxyglutarate (D-2-HG) is the earliest known tumour-forming small-molecule reporter in glioma/glioblastoma, breast cancer, sarcoma and leukemia. The in vivo source of D-2-HG is a mutant form of the cytosolic enzyme isocitrate dehydrogenase (IDH, isoforms 1 and 2). However, it is unclear whether the IDH mutation, and subsequent D-2-HG production, is a consequence of the tumourigenic phenotype, or is directly driving the formation of tumours. Understanding the association of IDH mutations with changes in metabolism is important for understanding disease aetiology and development of early-intervention chemotherapy.

We will investigate the impact of IDH mutations and elevated levels of 2-HG on metabolism in IDH mutant cells using a mouse model and patient-derived tissues including bio-fluids using a novel metabolomics platform combined with stable isotope tracers to elucidate metabolic flux and pathway analysis. We will determine a robust molecular phenotype elucidating mutant-specific changes to metabolic pathways.
The aims of future work will be to use knowledge of aberrant metabolism to develop and test therapeutic interventions targeting IDH mutant-specific biochemistry.