ATF4 in ccRCC: A New Therapeutic Approach
Abstract
Clear cell renal cell carcinoma is the most common type of kidney cancer in adults. Even with the newest immunotherapy approaches, metastatic clear cell renal cell carcinoma is a very dangerous disease. Although scientists have been studying clear cell renal cell carcinoma for many years and have made much progress in terms of the treatment of this type of cancer, there is still much more to be learned about how this cancer begins to grow in the body. We recently found that a protein in normal cells, ATF4, that controls aspects of cell metabolism and cell proliferation, is aberrantly and highly activated in human clear cell renal cell carcinoma. This ATF4 protein has not been studied before in clear cell renal cell carcinoma, and we propose to do this in this Idea Award application. We want to understand what this ATF4 protein does to potentially make the tumor cells much more aggressive and dangerous. We will do this by using human kidney cancer cell lines, kidney cancer organoids taken directly from human kidney cancer patients and studied in cell culture, and by using a unique mouse model in which we can study the initiation and early development of clear cell renal cell carcinoma, the TRACK model. Our rationale for studying this ATF4 protein is that it may be possible to block the activation of this ATF4 protein with a compound called ISRIB. This compound, ISRIB, could eventually be used in the treatment of clear cell renal cell carcinoma, although we are proposing initial experiments here since this is a new area of research in the field of kidney cancer. The FY21 KCRP Focus Area that we propose to work on is to increase understanding of the biology of kidney cancer. We will focus on clear cell renal cell carcinoma. While this project involves much early basic research, we should be able to achieve a clinically relevant outcome within the three years of this project by determining if inhibiting the ATF4 signaling pathway in cell lines and in the TRACK mouse model is likely to be effective. We work with many clinicians who treat kidney cancer patients here at Weill Cornell Medicine, and if inhibition of ATF4 in our studies is effective in our kidney cancer models, these clinicians, such as our long-term collaborator, Dr. David Nanus, will work to translate our findings into new therapies for patients. As many Service Members, their families, Veterans, and the American public develop kidney cancer, new treatments for this cancer are worth fighting for and are desperately needed.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210873
Entities
People
- Lorraine Gudas
Organizations
- United States Army
- Weill Cornell Medicine