Therapeutic Vulnerability of SETD2-Mutant RCC
Abstract
Clear cell renal cell carcinoma is the most common form of renal cell carcinoma, accounting for ~70% of all kidney cancer, and is particularly lethal once it has metastasized, or spread outside the kidney. Multiple factors increase the risk of kidney cancer in military Veterans, as kidney cancer more frequently affects males, smokers and workers with exposure to toxic chemicals. Additionally, kidney cancer is typically diagnosed later in life, with the average person being diagnosed at age 64. The age of the Veteran population is increasing, which suggests the risk of kidney cancer in this population will also increase. Currently, treatments for kidney cancer involve surgery and therapies that block blood vessel development or activate the immune system to fight the tumor growth. However, not all patients respond to these therapies, indicating that we need new strategies to slow or kill tumor growth. We believe that by investigating the processes by which tumors grow, we will identify new vulnerabilities of the tumors that can be targeted to improve patient treatment. Tumors grow in size because individual tumor cells are constantly dividing, i.e., one cell divides into two, two divide into four, etc. When normal cells divide, certain genes function to make sure this growth happens properly, so that the genetic material called DNA gets accurately duplicated and passed to each new cell. Failure to properly transmit the correct amount of DNA to new cells can result in the new cells having too much or little DNA and is the most common occurrence that correlates cancer. The fact that cells are constantly dividing and re-arranging their DNA creates tumor heterogeneity, where different regions of an individual s tumor are different. This heterogeneity promotes resistance or relapse to current therapies. Our group has identified two inhibitors, currently in clinical trials in other tumor types, that can inhibit specific renal cell carcinoma cells that are the most prone to tumor heterogeneity. The central mission of our proposal is to determine why these drugs kill heterogeneous renal cell carcinoma cells and whether this drug can function to kill tumors in human patient samples. We aim to use our knowledge, expertise, and access to patient samples to address three key questions: (1) How do these inhibitors kill kidney cancer cells? (2) Do these drugs kill kidney cancer cells using mouse models? and (3) Do these drugs work in human patient samples by killing tumor cells and/or activating the immune system? Ultimately, our goal is to ascertain how effective these drugs can be in killing human tumor cells, either as single agents or combined with current first-line therapies. Using a multidisciplinary and collaborative approach, this proposal will address the Areas of Emphasis by (a) identifying Mechanisms of Resistance and Response that occur downstream of Chromatin and Gene Regulation, and (b) investigate how drugs targeting cancer cells can activate the Immune System in the Microenvironment to kill kidney cancer. We anticipate that, at the conclusion of this award, we will have identified the efficacy of our drugs for kidney cancer and potential combination therapies, and determined which populations of patients with renal cell carcinoma it benefits most, which we anticipate could be all patients with clear cell renal cell carcinoma. This new therapeutic option may present a clear benefit for Service Members, Veterans, and the American population who do not respond to currently available treatments.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110786
Entities
People
- Frank Mason
Organizations
- United States Army
- Vanderbilt University