Thursday, May 2, 2024
5/2/2024
Project Summary Only the microsatellite instability high (MSI-H) human colorectal cancer, which accounts for 10-15% of all human colorectal cancer cases, responds to PD-(L)1 blockade immunotherapy. The vast majority (85-90%) of human colorectal cancer is the microsatellite stable (MSS) subtype that does not respond to PD-(L)1 blockade immunotherapy. PD-(L)1 blockade immunotherapy works through blocking PD-1 function to activate cytotoxic T lymphocytes (CTLs). The activated CTLs then target tumor cells to activate the death pathways to induce tumor cell death. Therefore, two factors are essential for the efficacy of PD-(L)1 blockade immunotherapy: CTLs must be activated and the target tumor cells must be sensitive to cell death induction. Human colorectal tumor cells, especially the metastatic colorectal tumor cells, are highly resistant to cell death induction. Literature and our published data indicate that, although MSI-H human colorectal cancer has high level of tumor-infiltrating CTLs, CTLs are also present in the MSS human colorectal carcinoma. Our published data further determined that tumor-infiltrating CTLs are functionally impaired in human colorectal carcinoma. SUV39H1 is a histone 3 lysine 9 (H3K9) site-specific histone methyltransferase that catalyzes H3K9me3. Literature and our preliminary studies determined that the SUV39H1-H3K9me3 epigenetic axis represses both the death receptor FAS expression in human metastatic colon tumor cells and Gzmb expression in colon tumor-infiltrating CTLs. To target SUV39H1-H3K9me3 axis, we have developed a small molecule SUV39H1- selective inhibitor (termed F5446). We determined that F5446 is effective in: 1) decreasing H3K9me3 deposition at the FAS promoter in metastatic human colon tumor cells to increase tumor cell sensitivity to FasL-induced cell death; and 2) decreasing H3K9me3 deposition at the Gzmb promoter to increase Gzmb expression in tumor-infiltrating CTLs to suppress colon tumor growth in immune competent mice. To achieve tumor-selective delivery for improved safety and efficacy, we have now developed the expansile nanoparticle encapsulated F5446 (termed eNP-F5446). Our hypothesis is that eNP-F5446 is an effective and safe agent for overcoming colorectal cancer resistance to PD-1 blockade immunotherapy. Three specific aims will be pursue to achieve our objectives: 1) determine the tumor/cell/subcellular localization, trafficking, and biodistribution of eNP-F5446 in the syngeneic mouse colon tumor liver metastasis and human colon cancer xenograft liver metastasis models; 2) conduct pharmacokinetics and toxicology studies of eNP-F5446 in tumor-free and colon tumor-bearing mice; 3) determine the efficacy of eNP-F5446 in overcoming human metastatic colorectal cancer resistance to PD-1 blockade immunotherapy in vivo.
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