SETD2 Deficiency is a Therapeutic Target to Upregulate Viral Mimicry in Treating Aggressive Clear Cell Renal Cell Carcinoma Patients
Abstract
Large-scale sequencing efforts of human cancers have identified recurrent mutations and deletions in genes that modulate the way cancer causing or suppressor genes are expressed. More specifically, the depletion of a modification to the protein that DNA wraps itself around, histone H3K36 tri-methylation (H3K36me3), is known to play an important role in diverse cancers. This cancer-causing modification is the result of an impaired expression of the gene, SETD2, most notably in clear cell renal cell carcinoma (ccRCC). The importance of SETD2 is that its loss in function results in changes of multiple genes leading to cancer ccRCC imitation and metastatic progression. The relative 5-year survival rate of localized ccRCC is 91%, however, survival rates drop to 11% once the ccRCC has metastasized (advanced ccRCC). Thus, there is an urgent need to develop novel treatments to target H3K36me3-compromised cancer cells, as these alterations may represent an attractive target for diagnostic and treatment purposes. We found longstanding agents that are known to de-methylate DNA, with strong safety records, are especially useful in addressing ccRCC cells with a loss in SETD2. Not only did such agents limit tumor growth in clinically relevant ccRCC preclinical models, it also strikingly improved the efficacy of immune-based therapy, the current standard for the care of ccRCC patients. In this proposal we will evaluate the use of DNA de-methylating agents in combination with immune therapy in kidney cancer models with genetic changes similar to human disease inclusive VHL and/or Setd2 loss. We hope to better understand how DNA de-methylating agents impact both tumor growth and the immune system, especially in the context of SETD2 loss, affecting about 20% of all ccRCC patients. We believe that the success of this project will lead to near-term clinical translation for those with aggressive kidney cancers having impaired H3K36me3 levels.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311069
Entities
People
- Gangning Liang
Organizations
- United States Army
- University of Southern California