Abstract IA019: Clinical trials of GUCY2C (GCC) agonists for colorectal cancer prevention

Abstract

Abstract Guanylyl cyclase C (GUCY2C), expressed on intestinal epithelial cells, is the receptor for heat-stable enterotoxins (STs) produced by diarrheagenic bacteria. Fluid secretion reflects ST activation of GUCY2C, which produces cyclic (c)GMP activating ion channels. Beyond toxins, GUCY2C binds uroguanylin in small intestine and guanylin in colorectum, which also stimulate secretion. This mechanism is the basis for the oral agonists linaclotide (ST analog) and plecanatide (uroguanylin analog) to treat constipation. Guanylin is the most commonly lost gene product, while GUCY2C expression is retained, in colorectal tumors. Eliminating GUCY2C promotes tumor formation, while oral GUCY2C agonists or transgenic guanylin reduce intestinal tumors, in mice. These data support a hypothesis in which loss of guanylin silencing GUCY2C is a key step in intestinal transformation which can be prevented by oral GUCY2C agonists. However, GUCY2C agonists are formulated for duodenal activity, without bioavailability in the colorectum. Here, we explored whether this pharmacokinetic (PK) barrier could be abrogated with high doses (HD) of linaclotide. Indeed, HD linaclotide induced a cGMP response in mucosal biopsies obtained by colonoscopy following oral polyethylene glycol (PEG) preparation. This cGMP response was validated by VASP phosphorylation and suppression of crypt proliferation. Similarly, HD linaclotide induced cGMP in colon biopsies obtained by sigmoidoscopy following oral PEG. However, HD linaclotide failed to induce cGMP in colon biopsies obtained by sigmoidoscopy i n the absence of oral PEG . Thus, oral PEG abrogated the PK barrier, delivering linaclotide to the colorectum. Unfortunately, dolcanatide, a proteolysis-resistant analog of plecanatide, also failed to overcome the colorectal PK barrier, although it produced duodenal secretion and diarrhea. Thus, guanylin loss silencing GUCY2C appears to be a key step in intestinal transformation. Preclinical models suggest that oral GUCY2C agonists stimulate GUCY2C signaling, opposing tumorigenesis. However, translation of these observations appears to be constrained by a PK barrier, reflecting agonists formulated for duodenal activity, without colorectal bioavailability. Exploiting GUCY2C for chemoprevention awaits agonists formulated for the colorectum. We are exploring the ability of GUCY2C agonists to activate cGMP in duodenum (within the PK barrier), as a prelude to trials in patients with FAP at risk for duodenal tumors. Citation Format: Scott A. Waldman. Clinical trials of GUCY2C (GCC) agonists for colorectal cancer prevention [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA019.