Using WEE1 Inhibitor to Convert Immune Cold into Immune Hot for Aggressive Clear Cell Renal Cell Carcinoma with SETD2 Deficiency
Abstract
Large-scale sequencing efforts of human cancers have identified recurrent mutations and deletions in a variety of chromatin regulatory proteins that modulate DNA methylation, histone modifications, and nucleosome positioning. ,Decreased or depleted levels of histone H3K36 tri-methylation (H3K36me3) have been shown to play an important role in diverse forms of cancer due to somatic mutations in or down-regulation of SETD2 (H3K36 trimethylase), most notably in clear cell renal cell carcinoma (ccRCC). Altered chromatin modelers related to impaired H3K36me3 occupancy are linked to renal cancer aggressiveness. 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. Previous studies suggest that cancer cells displaying loss or depletion of H3K36 methylation show increased sensitivity to WEE1 inhibitor. In addition, the WEE1 inhibitor also can stimulate an immune response, meaning, the body s own immune system can be directed to kill the ccRCC by this approach and may further provide a specific synergistic therapeutic effect by a combination therapy with WEE1 inhibitor and immune checkpoint inhibitor. This proposal describes the use of the WEE1 inhibitor, alone or in combination immune checkpoint inhibitor, in preclinical models to improve treatment efficacy. Specifically, we will examine whether the defects of impaired H3K36 methylation are potential mechanisms for WEE1 inhibitor sensitivity and identify potential therapeutic target genes using in vitro approaches in Aim 1. In Aim 2, we will evaluate the antitumor and epigenetic changes caused by combination treatments of the WEE1 inhibitor and immune checkpoint inhibitor in preclinical kidney cancer models with genetic changes similar to human disease inclusive of Setd2 loss. We anticipate these preclinical models will allow us to evaluate and better understand the antitumor effects of the WEE1 inhibitor and immune checkpoint inhibitor on kidney cancer cells with altered chromatin modelers and subsequent impaired H3K36 methylation, as well as to challenge the current standard of care in developing personalized and precision treatments that impact survival times, especially aggressive kidney cancers. We believe that the success of this project will immediately lead to clinical trials for aggressive kidney cancers with impaired H3K36me3 levels using a precision medicine-based approach.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310160
Entities
People
- Gangning Liang
Organizations
- United States Army
- University of Southern California