Tamoxifen is a candidate first-in-class inhibitor of acid ceramidase that reduces amitotic division in polyploid giant cancer cells-Unrecognized players in tumorigenesis.

Polyploid giant cancer cells (PGCC) represent a poorly understood, small subpopulation of tumor cells that are increasingly being recognized for their critical role in therapy resistance, metastasis, and cancer recurrence. PGCC have the potential to generate progeny through primitive or cleavage-like division, which allows them to evade antimitotic insults. We recently demonstrated that the sphingolipid enzyme acid ceramidase (ASAH1) is required for this process. Since specific ASAH1 inhibitors are not clinically available, we investigated whether tamoxifen, which interferes with ASAH1 function via off-target effects, has a potential clinical benefit independent of estrogen signaling. Our results show that tamoxifen inhibits generation of PGCC offspring in prostate cancer, glioblastoma, and melanoma cells. Analysis of two state-level cancer registries revealed that tamoxifen improves survival outcomes for second, nonbreast cancers that develop in women with early stage breast cancer. Our results suggest that tamoxifen may have a clinical benefit in a variety of cancers that is independent of estrogen signaling and could be due to its inhibition of acid ceramidase. Thus the distinct application of tamoxifen as potentially a first-in-class therapeutic that inhibits the generation of PGCC offspring should be considered in future clinical trials.

Colorectal cancer prevention by a CLEAR principles-based colonoscopy protocol: an observational study.

BACKGROUND AND AIMS: Colorectal cancer (CRC) prevention by colonoscopy has been lower than expected. We studied CRC prevention outcomes of a colonoscopy protocol based on Clean the colon, Look Everywhere, and complete Abnormality Removal (CLEAR) principles. METHODS: This observational follow-up study studied patients provided screening colonoscopy at a free-standing private ambulatory surgery center in South Carolina by 80 endoscopists from October 2001 to December 2014, followed through December 2015. The colonoscopy protocol, optimized for polyp clearance, featured in-person bowel preparation instructions reinforced by phone, polyp search and removal throughout insertion and gradual withdrawal with circumferential tip movements, and a team approach using all personnel present to maximize polyp detection, patient safety, and clear-margin polypectomy including requesting repeat inspection or additional tissue removal. Outcome measures were postscreening lifetime CRC risk relative to Surveillance Epidemiology and End Results (SEER)-18 and interval cancer rate (postcolonoscopy CRCs among cancer-free patients at screening). RESULTS: Of 25,862 patients (mean age, 58.1 years; 52% black; 205,522 person-years of observation), 159 had CRC at screening and 67 patients developed interval CRC. The interval CRC rate was 3.34 per 10,000 person-years of observation, 5.79 and 2.24 among patients with and without adenomas, respectively. The rate was similar among older patients (mean age 68.5 years at screening) and with prolonged follow-up. Postscreening lifetime CRC risk was 1.6% (bootstrap 95% confidence interval, 1.3%-1.8%) versus 4.7% in SEER-18, 67% lower. Subgroups with mean screening ages of 50 and 68.5 years showed risk reductions of 80% and 72%, respectively. The adverse event rate was less than usually reported rates: perforation 2.6 per 10,000, bleeding with hospitalization 2.4 per 10,000, and no deaths. CONCLUSIONS: A colonoscopy protocol optimized for polyp clearance prevented 67% of CRC compared with a SEER-18 population given ongoing population screening.