In this study, we isolated and characterized TCRs recognizing the intestinal epithelial cell receptor and colorectal cancer Ag GUCY2C to establish a model to study self-antigen-specific tolerance mechanisms.
Here, the cancer vaccine Ad5-GUCY2C-PADRE was evaluated in a first-in-man phase I clinical study of patients with early-stage colorectal cancer to assess its safety and immunological efficacy.
Moreover, retained expression by tumors arising from TAs has established GUCY2C as a diagnostic and therapeutic target to prevent and treat metastatic CRC.
Taken together, the results demonstrate that targeting cGMP with either PDE5 inhibitors or GCC agonists alters epithelial homeostasis in a manner that reduces neoplasia, and suggests that this could be a viable chemoprevention strategy for patients at high risk of developing colorectal cancer.<i></i>.
It has been suggested that GC-C acts as an intestinal tumor suppressor with the potential to prevent the initiation and progression of colorectal cancer.
Because of these wide-ranging roles, dysregulation of the GUCY2C-cGMP signaling axis has been implicated in the pathogenesis of bowel transit disorders, inflammatory bowel disease, and colorectal cancer.
Thus, chronic colonization with <i>ETEC</i> producing ST could contribute to endemic cancer resistance in developing countries, reinforcing a novel paradigm of colorectal cancer chemoprevention with oral GUCY2C-targeted agents.
The intestinally restricted receptor guanylyl cyclase C (GUCY2C) is a target that has been investigated for the treatment of colorectal cancer and numerous animal, and clinical studies have demonstrated both efficacy and safety.
Together, TCR avidity enhancement may be leveraged by prime-boost immunization to improve GUCY2C-targeted colorectal cancer immunotherapeutic efficacy and patient outcomes without concomitant autoimmune toxicity.
Immune responses following Ad5-GUCY2C-PADRE administration were characterized by PADRE-specific CD4<sup>+</sup> T-cell and GUCY2C-specific B-cell and CD8<sup>+</sup> T-cell responses, producing antitumor immunity targeting GUCY2C-expressing colorectal cancer metastases in the lungs, without acute or chronic autoimmune or other toxicities.
In that context, GUCY2C ligand replacement therapy has been proposed as a strategy to prevent colorectal cancer, a translational opportunity that is underscored by the recent regulatory approval of the oral GUCY2C ligand linaclotide (Linzess™, Forest Laboratories and Ironwood Pharmaceuticals, Inc.).
In humans and mice, initiation of colorectal cancer is universally associated with loss of guanylin and uroguanylin, the endogenous ligands for the tumor suppressor guanylyl cyclase C (GUCY2C), disrupting a network of homeostatic mechanisms along the crypt-surface axis.
Moreover, the coincident regulation of energy balance and tumor suppression by a single hormone receptor system suggests that the GUCY2C axis might contribute to the established relationship between obesity and colorectal cancer.
This review describes the evolution of the tumor suppressor GUCY2C as a prognostic and predictive molecular biomarker that quantifies occult tumor burden in regional lymph nodes for staging patients with colorectal cancer.
The aim was to explore the utility for staging and prognostic impact of carcinoembryonic antigen (CEA), cytokeratin 20 (CK20), guanylyl cyclase C (GCC), CUB (complement protein subcomponents C1r/C1s, urchin embryonic growth factor, and bone morphogenic protein 1) containing domain protein 1 (CDCP1) and mucin 2 (MUC2) mRNA levels in mesenteric lymph nodes of colorectal cancer (CRC) patients.
The results of the present study suggest that peripheral blood GCC expressions along with CEA and CA19-9 can be used to determine the early respose to chemotherapy in patients with metastatic CRC.
Thus, a family of GUCY2C-targeted immunotherapeutics may bridge the gap in effective treatments for the 500,000 patients worldwide who die annually from colorectal cancer.
The roles of CDX2 and GCC in suppressing intestinal tumorigenesis, universal disruption in their signaling through silencing of hormones driving GCC, and the uniform overexpression of GCC by tumors underscore the potential value of oral replacement with GCC ligands as targeted prevention and therapy for colorectal cancer.
Though activation of GC-C by its ligands elevates intracellular cyclic GMP (cGMP) levels and inhibits cell proliferation, its persistent expression in colorectal carcinomas and occult metastases makes it a marker for malignancy.
Expression of GUCY2C in histologically negative lymph nodes appears to be independently associated with time to recurrence and disease-free survival in patients with pN0 colorectal cancer.
The correlative therapeutic hypothesis suggests that colorectal cancer is a disease of hormone insufficiency that can be prevented or treated by oral supplementation with GCC ligands.