Identification of Novel Therapeutic Strategies for Chromophobe RCC
Abstract
Chromophobe renal cell carcinoma (ChRCC) represents about 5% of all kidney cancers. It is very different from the more common clear cell type of kidney cancer (ccRCC). These differences include the appearance under the microscope, the genetic mutations that occur in the tumor cells, the part of the kidney from which ChRCC arise, and most importantly the response to therapy. In ccRCC, there has been stunning progress, with at least a dozen effective drugs approved by the U.S. Food and Drug Administration. In contrast, no treatments have been proven to have efficacy for metastatic ChRCC. In preliminary studies, we have discovered that ChRCC are hypersensitive to drugs, including a drug called IKE, that block the uptake of cysteine. Cysteine is a sulfur-containing amino acid that is taken into cells via a molecular transporter called xCT. Cysteine is used to make glutathione, the most abundant intracellular antioxidant. When ChRCC cells are treated with IKE, oxidative stress is induced, and they undergo a specific type of cell death termed ferroptosis. The fundamental hypothesis of this proposal is that ferroptosis inducing therapies can be used to specifically target and treat metastatic ChRCC. The project includes a high throughput screen of small molecules to identify drugs that synergize with IKE to induce cell death in ChRCC, and testing of these drugs in mouse models of ChRCC. Ultimately, our goal is to develop highly effective therapies for ChRCC. This would represent a breakthrough in chromophobe RCC research, which has lagged far behind clear cell RCC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310975
Entities
People
- Carmen Priolo
Organizations
- United States Army