# The Metabolic Pathogenesis of Chromophobe Renal Cell Carcinoma

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $375,563

## Abstract

Abstract
This project is focused on metabolic reprogramming in chromophobe renal cell carcinoma (ChRCC). ChRCC
accounts for 5% of all sporadic renal cancers and can also occur in genetic syndromes including Birt-Hogg-
Dube' (BHD) and Tuberous Sclerosis Complex (TSC), both autosomal dominant disorders. There are currently
no specific therapies for metastatic ChRCC, and life expectancy is estimated to be less favorable than for
metastatic clear cell RCC, highlighting the potential clinical impact of this project
Using metabolomic profiling of ChRCC compared with matched normal kidney, we have uncovered a striking
decrease in intermediates of the gamma-glutamyl cycle, known as the glutathione salvage pathway.
Consistent with this distinctive metabolic phenotype, we found that Gamma-glutamyl transferase 1 (GGT1), the
key enzyme of this pathway, is expressed at >100-fold lower levels in ChRCC vs. normal kidney. Low GGT1
activity is predicted to result in lower utilization of exogenous glutathione, enhanced de novo glutathione
synthesis, and increased oxidative stress. These and other data lead to our central hypothesis: metabolic
reprogramming triggered by impairment of the glutathione salvage pathway is critical in the pathogenesis of
ChRCC. A key translational corollary of this hypothesis is that ChRCC will be selectively sensitive to agents
that inhibit glutathione biosynthesis and/or induce further oxidative stress.
Aim 1. To determine the role of impairment of the glutathione salvage pathway in the pathogenesis and
 therapy of ChRCC.
Aim 2. To determine the therapeutic impact of targeting glutathione biosynthetic pathways in ChRCC in vitro
 and in vivo.
Aim 3. To identify molecular and metabolic determinants of the metastatic potential of ChRCC.
If our hypotheses are correct, it will lead to a completely new pathogenic model for ChRCC, and to the
identification of candidate therapeutic targets. Our long-term goal is to identify paradigm-shifting targeted
therapeutic opportunities for patients with recurrent or metastatic ChRCC, for whom there are currently no
proven therapeutic options.

## Key facts

- **NIH application ID:** 9836809
- **Project number:** 5R01CA216922-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Elizabeth P Henske
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $375,563
- **Award type:** 5
- **Project period:** 2018-01-15 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9836809

## Citation

> US National Institutes of Health, RePORTER application 9836809, The Metabolic Pathogenesis of Chromophobe Renal Cell Carcinoma (5R01CA216922-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9836809. Licensed CC0.

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