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Guanylyl cyclase C (GUCY2C) is a tumor-suppressing receptor silenced by loss of expression of the luminocrine hormones guanylin and uroguanylin early in colorectal carcinogenesis. This observation suggests oral replacement with a GUCY2C agonist may be an effective targeted chemoprevention agent. Previous studies revealed that linaclotide, an oral GUCY2C agonist formulated for gastric release, did not persist to activate guanylyl cyclase signaling in the distal rectum. Dolcanatide is an investigational oral uroguanylin analog, substituted with select D amino acids, for enhanced stability and extended persistence to activate GUCY2C in small and large intestine. However, the ability of oral dolcanatide to induce a pharmacodynamic (PD) response by activating GUCY2C in epithelial cells of the colorectum in humans remains undefined. Here, we demonstrate that administration of oral dolcanatide 27 mg daily for 7 d to healthy volunteers did not activate GUCY2C, quantified as accumulation of its product cyclic GMP, in epithelial cells of the distal rectum. These data reveal that the enhanced stability of dolcanatide, with persistence along the rostral-caudal axis of the small and large intestine, is inadequate to regulate GUCY2C across the colorectum to prevent tumorigenesis. These results highlight the importance of developing a GUCY2C agonist for cancer prevention formulated for release and activity targeted to the colorectum.

Introduction Time-to-treatment-failure (TTF) is the interval from chemotherapy initiation to premature discontinuation. We evaluated TTF based on age. Methods Pooled analyses were conducted with first-line chemotherapy trials for advanced NSCLC (CALGB 9730, 30203, and 30801). Comparisons among patients who were 65 years and older and 70 years and older were performed for TTF (primary endpoint), reasons for early chemotherapy cessation, grade 3+ adverse events, and overall survival. Results Among 1006 patients, 460 (46%) were older than 65 years of age. One hundred forty-five older patients (32% of this age cohort) completed all six planned chemotherapy cycles as did 170 (32%) younger patients. Median TTF was 2.9 months (95% confidence interval: 2.7– 3.2) in older patients and 3 months (95% confidence interval: 2.9–3.5) in younger patients; adjustment for performance status and stratification by chemotherapy by trial yielded no statistically significant age-based difference in TTF. However, reasons for early chemotherapy cessation differed between age groups (multivariate p = 0.004). Older patients were less likely to discontinue from cancer progression (41% versus 55%) and more likely from toxicity or patient choice (16% and 15%, respectively) compared to younger patients (13% and 6%, respectively). Older patients were more likely to experience grade 3+ adverse events (86% versus 79%) with no statistically significant difference in survival. An age cutpoint of 70+ years showed no difference in TTF, a lower trend of early cessation due to cancer progression, and somewhat shorter older patient survival. Conclusions TTF was comparable between older and younger patients; but different, age-based, and potentially modifiable reasons account for it.