Selective Metabolic Dependencies in Kidney Cancer with Mitochondrial Mutations
Abstract
Renal cell carcinoma is the most common kidney cancer, representing about 90% of cases. There are several subtypes of renal cell carcinoma that are important when deciding the type of treatment. Clear cell renal carcinoma is the most common among renal cell carcinoma (about 70%). The rest of the non-clear renal carcinomas are mainly formed by papillary renal cell carcinoma, the second most common class (15% of renal cell carcinoma); and chromophobe renal cell carcinoma, accounting for 5% of renal cell carcinoma. Treatment with drugs is mainly based on chemicals that block growth and angiogenesis. Immuno-targeted treatments include immune checkpoint inhibitors (PD-1, PD-L1, CTLA-4 inhibitors) and cytokines. The cause of papillary kidney cancer is unknown, but smoking, obesity, and genetic predisposition may contribute. Chromophobe kidney cancer can be part of a rare genetic disorder called Birt-Hogg-Dubbe syndrome, and the only treatment for patients is surgery. As differences clearly exist compared to renal cell carcinomas, these cancers should be clinically considered as different diseases. For example, low rate mutations exist compared to other kidney cancers, and important to this application, specific mutations of mitochondrial (powerhouse of the cell, generates energy and controls metabolism) energetic and metabolic genes are a key feature of these papillary and chromophobe kidney cancers. Specific mutations (generating defective proteins), particularly in proteins localized in the mitochondria, are significantly enriched in kidney tumors, especially chromophobe and papillary types, indicating that inactivation or blockage of these mitochondrial proteins might have an active role in kidney cancer. This high frequency of mitochondrial DNA mutations is mutually exclusive to other current mutated cancer genes in kidney tumors. These studies suggest that mitochondrial DNA mutations have been conserved for these kidney cancer subtypes and might provide specific ways to treat these tumors. In fact, other studies have found that mitochondrial mutations that occur in other diseases (mitochondrial diseases) have energetic and metabolic problems due to the inability to produce sufficient amount of anti-oxidant molecule called NADPH. These cells become very sensitive to metabolic blockage of other anti-oxidant and metabolic pathways called pentose phosphate pathway (PPP) and malic enzyme (ME1). Thus, the rationale of these studies is that mitochondrial DNA mutations occurring in chromophobe kidney cancer cells, similar to mitochondrial mutant cells in patients with mitochondrial diseases, provide specific vulnerabilities (and therefore ways to kill these malignant cells) to the blockage (through specific drugs) to PPP and ME anti-oxidant proteins. The objective of these experimental studies is to investigate whether these drugs that block PPP and ME1 target proteins in human chromophobe kidney cancer cells can be used to treat and kill a subset of kidney tumors. This research covers an important gap in kidney cancer as there is no current treatment for chromophobe kidney tumors. Thus, outcomes from these studies will determine whether kidney tumors with mitochondrial DNA mutations will be sensitive or vulnerable to PPP and ME1 blockage providing novel potential treatments to treat kidney cancer types. The innovation of these studies is based on the discovery of novel drug-targeted therapies for chromophobe kidney cancer, focusing on drugs that block PPP and ME1 enzymes. There is another innovation part that relates to the potential effects of these drugs in the immune antitumor activity or modulation of current immunotherapies. The expectation of these studies is that CRCC with mitochondrial DNA mutations, similar to human mitochondrial disease mutant cells, will be sensitive to PPP and ME1 chemical inhibitors providing novel potential therapies to treat selective kidney cancer types. The impact of thes
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110163
Entities
People
- Pere Puigserver i Burguera
Organizations
- Dana–Farber Cancer Institute
- United States Army