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.
The goal of this Diversity supplement is to support the career development of Andres Sanin, a talented young scientist and future physician who has been working in the Henske laboratory for the past six months. His project will involve a high throughput small molecule screen to identify compounds that selectively inhibit the proliferation of chromophobe kidney cancer-derived cells. He has already worked on the ?hits? from a similar project and has developed technical and knowledge skills that will allow him to succeed in the proposed project. The impact of this project for patients will be the identification of novel potential therapies for chromophobe kidney cancer. The impact for Andres will be to provide scientific training that will support his future career as a physician investigator.
| Priolo, Carmen; Khabibullin, Damir; Reznik, Ed et al. (2018) Impairment of gamma-glutamyl transferase 1 activity in the metabolic pathogenesis of chromophobe renal cell carcinoma. Proc Natl Acad Sci U S A 115:E6274-E6282 |
