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

> **NIH NIH F30** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $46,069

## Abstract

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.

## Key facts

- **NIH application ID:** 9979802
- **Project number:** 5F30CA232397-03
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Garrett Joseph Brinkley
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $46,069
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979802

## Citation

> US National Institutes of Health, RePORTER application 9979802, Role of Oncometabolite L-2 Hydroxyglutarate in Reprogramming Renal Cell Carcinoma Metabolism (5F30CA232397-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9979802. Licensed CC0.

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