Deep Functional Characterization of MiT/TFE Fusions in Translocation Renal Cell Carcinoma
Abstract
Objective and Rationale: There are over 60,000 new cases of kidney cancer each year in the United States and kidney cancer is one of the five most common cancers diagnosed among United States Veterans. There are many different subtypes of kidney cancer. About 70% of kidney cancer is of the so-called clear cell kidney cancer variety. The other 30% of kidney cancer is called non-clear cell kidney cancer, of which there are multiple different subtypes. Over the past several years, there have been many promising treatments tested and approved for clear cell kidney cancer, including various types of targeted therapies and immunotherapies. However, recent studies suggest that therapies approved for clear cell kidney cancer are less effective in patients with non-clear cell kidney cancer. This is because clear cell kidney cancer and non-clear cell kidney cancer have significant molecular differences, so treatments developed for clear cell kidney cancer cannot be readily applied to treat patients with non-clear cell kidney cancer. One specific subtype of non-clear cell kidney (renal) cancer is called translocation renal cell carcinoma. This type of cancer makes up about 1%-5% of all kidney cancers in adults and may make up over half of kidney cancers in children. Translocation renal cell carcinoma is rare, aggressive, and usually strikes younger, female patients. It responds very poorly to therapies typically used for clear-cell kidney cancer. There are currently no therapies that are specifically approved for translocation renal cell carcinoma, which is a major unmet need in kidney cancer research. Translocation renal cell carcinoma is so named because on the molecular level, it has a joining (translocation) between two genes. One of the genes in the translocation is a transcription factor (protein that binds DNA) in a family of genes named MiT/TFE. The other gene in the translocation can be any one of several possible partner genes. The protein created by the joining of the MiT/TFE gene and the partner gene is known as an MiT/TFE fusion. Previous studies, including our prior work, support the notion that the MiT/TFE fusion is the key mutation in translocation renal cell carcinoma, and hence the prime therapeutic target in this disease. Because translocation renal cell cancer is so rare, it has not been extensively studied. This proposal seeks to answer several fundamental questions about how MiT/TFE fusions cause translocation renal cell cancer. First, which exact regions of the MiT/TFE fusion protein allow it to cause cancer? Second, what other proteins and RNAs in the cell does the MiT/TFE fusion protein bind to, and what can this tell us about how MiT/TFE fusions promote translocation renal cell carcinoma? Third, are there any genes or pathways in a normal cell that can replace the activity of the MiT/TFE fusion? Answering these questions will allow for an enhanced biological understanding of translocation renal cell carcinoma and may nominate new drug targets in this disease. FY21 KCRP Areas of Emphasis: This project addresses the following FY21 areas of emphasis: basic biology research to understand cancer etiology/progression; biology of rare kidney cancers; novel therapeutic strategies for the treatment of kidney cancer. Applicability/Impact: This research is designed to improve the lives of patients with translocation renal cell carcinoma, a rare and aggressive kidney cancer type that has major molecular differences from clear cell kidney cancer. The types of studies that we propose here are necessary to gain a complete picture of the genes and pathways important for translocation kidney cancer. Our hope is that this proposal will nominate new drug targets for translocation renal cell carcinoma within the next 5 years. Ultimately, this will allow us to develop therapeutics that are specifically tailored to translocation renal cell carcinoma. Such drugs will likely
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211016
Entities
People
- Srinivas R Viswanathan
Organizations
- Dana–Farber Cancer Institute
- United States Army