In this project, Drs. Sudarshan and Absher will combine next generation sequencing with a functional screen to identify targets of a putative oncometabolite recently identified in kidney cancer.
Metabolism is an established hallmark of malignancy. As such, we embarked on a metabolomics approach to profile the small molecules present in kidney cancer. Our analysis identified elevations of a molecule referred as L-2-hydroxyglutarate (L-2HG). L-2HG is party of a growing list of “oncometabolites”- small molecules with transforming properties. A unifying theme amongst oncometabolites is the ability to inhibit enzymes involved in DNA modifications. Such inhibition could silence genes whose expression normally suppresses tumor development and progression. This collaborative project will identify regions of the genome impacted by this metabolite and the corresponding effects on gene expression. Candidate genes will then be screened for effects on tumorigenesis using animal models of renal tumor progression. The goal is to identify novel pathways affected by this small molecule as a means to develop personalized approaches for individuals affected by this malignancy.