Examining the therapeutic potential of the investigational agent, 15dPMJ2, in mismatch repair proficient colon cancer

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Ariel Myers (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Despite the success of immune checkpoint inhibitor (ICI) therapy in many cancers, colon cancer with low microsatellite instability (MSI-L), also known as proficient mismatch repair (pMMR), does not respond to these agents. This colon cancer subtype is characterized by low neoantigen production and immune cell infiltration, which results in suboptimal reactivity to ICI therapy. This highlights the need for therapeutics that increase the immunogenicity of pMMR colon cancers. Accumulating evidence suggests that the damage associated molecular pattern (DAMP) signaling pathway is a promising target for the development of these types of immunostimulatory therapeutics. DAMP signals, including the cell surface expression of calreticulin and the extracellular release of ATP, have been shown to increase tumor immunogenicity and stimulate an antitumor immune response. It is also becoming clear that inhibitory DAMPs (iDAMPs), which activate immunosuppressive cell types, also play a role in the ultimate outcome of DAMP activation. These iDAMPs also act on tumorigenic cells to promote proliferation and tumor progression. Thus, the present study sought to investigate the role of stimulatory and inhibitory DAMPs on the anti-tumor activity of the investigational agent, 15-deoxy-?12,14-Prostaglandin Ethanolamide J2 (15dPMJ2), in pMMR colon cancer. The results from our in vivo and in vitro experiments show that 15dPMJ2 was cytotoxic in murine CT26 cells, which are a model of pMMR colon cancer. 15dPMJ2 also increased ER stress and apoptosis, two processes needed for stimulatory DAMP expression. In addition, 15dPMJ2 increased cell surface expression of anti-tumor DAMPs: calreticulin and extracellular release of ATP. 15dPMJ2 also increased the expression of the iDAMP and proliferative signal, prostaglandin E2 (PGE2). However, PGE2 had no effect on the cytotoxic activity of 15dPMJ2. These results indicate the cytotoxicity of 15dPMJ2 against pMMR colon cancer was independent of the pro-proliferative effects of PGE2.

Additional Information

Publication

Dissertation

Language: English

Date: 2023

Subjects

Colon cancer;anti-cancer therapeutic;mismatch repair;prostamides;DAMPs;PGE2

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