A phase I trial of S-Adenosylmethionine (SAMe) for chemoprevention of colorectal adenomas

About This Grant

Project Summary/Abstract Colorectal cancer (CRC) is the third most commonly diagnosed cancer and third leading cause of cancer death in U.S. women and men. It is widely recognized that most CRCs develop from precursor lesions broadly categorized as adenomas. The stepwise progression from normal colonic epithelium to adenoma to carcinoma has been characterized by early mutations in the APC/WNT/β-catenin pathway, which has been implicated in approximately 80-90% of sporadic CRCs. However, a preventative treatment for sporadic CRC that targets this key molecular pathway has not been established. We have generated exciting preclinical data showing that S- Adenosylmethionine (SAMe), a nutritional supplement, reduces polyp formation and elicits anticancer activity in CRC preclinical models through inhibition of the WNT/β-catenin pathway via reduction of β-catenin levels, nuclear β-catenin accumulation, and WNT target gene expression. We propose a phase I single-arm, single- institution, dose-finding clinical trial to evaluate the safety and feasibility of oral SAMe as a chemopreventive strategy in subjects with resected, stage I-II CRC undergoing surveillance. Patients with localized CRC having undergone curative resection who are at increased risk of developing adenomas post-surgery represent a targetable population for chemoprevention. The primary endpoint of this phase I trial will be to determine the recommended phase II dose (RP2D) of SAMe for CRC chemoprevention. We will enroll n=18 subjects with resected, stage I-II CRC planned for postoperative surveillance and no adjuvant chemotherapy to this dose- finding study using 3 dosing levels of oral SAMe (1600 mg/day, 2000 mg/day, and 2400 mg/day). Prior to study intervention, stool will be collected and a flexible sigmoidoscopy will be performed for a baseline colon biopsy. The RP2D will be assessed by the occurrence of dose-limiting toxicities (DLTs) within the first 4 weeks of SAMe treatment by escalation with overdose control, an adaptive Bayesian design. Following the DLT assessment period, patients will continue oral daily SAMe leading up to the first postoperative surveillance colonoscopy performed within 1 year of surgery as per standard of care (SOC) for a post-treatment colon biopsy. Post- intervention stool will also be collected. Secondary endpoints include the rate of postoperative adenomas detected by 1-year postoperative surveillance colonoscopy, safety, change in MAT2A (enzyme involved in SAMe biosynthesis) and WNT/β-catenin pathway targets in pre- and post-intervention biopsies (by pre-SAMe flexible sigmoidoscopy and post-SAMe SOC colonoscopy), and change in gut microbiota and stool metabolites in pre- and post-intervention stool samples. Our study is innovative in that we have an agent that specifically targets a canonical molecular pathway in the colorectal adenoma-carcinoma sequence (i.e., WNT/β-catenin). Ultimately, our findings could support the advancement of a practice-changing strategy in sporadic CRC chemoprevention. SAMe is naturally occurring and available as a nutritional supplement, thereby reinforcing the attractiveness of SAMe’s chemopreventive potential given that it is exquisitely safe and readily available for clinical translation.