Role of Oncometabolite L-2 Hydroxyglutarate in Reprogramming Renal Cell Carcinoma Metabolism

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Renal cell carcinoma (RCC) is among the ten most common neoplasias for both men and women in the United States. Tragically, 25% to 30% of RCC patients present with metastatic disease, with 5-year survival rate of only 5%. There are currently very few therapeutic options for locally advanced or metastatic RCC. Metabolite studies by our lab identified high levels of the putative oncometabolite L-2 Hydroxyglutarate (L-2HG) in kidney cancer. Build up of L-2HG in RCC is due to reduced expression of the enzyme L-2HG dehydrogenase (L2HGDH). L2HGDH frequently undergoes copy loss in RCC. This enzyme normally functions to revert L-2HG back into alpha-ketoglutarate (αKG), a Kreb cycle intermediate. Our lab has demonstrated that restoration of L2HGDH in renal cancer cells suppresses tumor phenotypes. Oncometabolites, metabolites that build up in cancer cells, such as L-2HG, can affect gene transcription by competitively inhibiting αKG-dependent enzymes that modify DNA and histone methylation. Due to their high abundance in cancer cells, oncometabolites present a viable option for the development of personalized treatment strategies in RCC as well as other cancer types. Preliminary studies from our laboratory demonstrate that L-2HG can suppress the expression of genes involved in amino acid biosynthesis and that this loss alters nutrient requirements in high L-2HG RCC cells. Based on these preliminary data, we hypothesize that loss of these enzymes demonstrates a targetable metabolic liability in RCC. In aim 1, we will dissect the molecular underpinnings by which L-2HG can suppress amino acid biosynthesis. In aim 2, we will assess the potential to target these findings therapeutically. Through our studies, we hope to identify novel, metabolism-based approaches for patients with cancers that are oncometabolite driven.