Georgios Karagkounis, Jennifer DeVecchio, BA, Sylvain Ferrandon, PhD, Matthew F Kalady, MD. Cleveland Clinic
Introduction: Neoadjuvant chemoradiation (CRT) for rectal cancer induces variable responses, and better response has been associated with improved oncologic outcomes. Our group has previously shown that administration of HMG-CoA reductase inhibitors, commonly known as statins, is associated with improved response to neoadjuvant CRT in rectal cancer patients. In addition, we have shown that colorectal cancer initiating cells (CR-CIC), known also as cancer stem cells, are important mediators of tumor resistance to cytotoxic therapy. The purpose of this study was to study the effects of simvastatin on patient-derived CR-CICs and explore its potential as a radiation-sensitizer in vitro.
Methods: Three patient-derived CR-CIC lines were used to test the effects of simvastatin alone, radiation alone, and combination therapy. Differentiated cells (non-CICs) derived from the same three cell lines were used as control. Outcome measures included ATP-based cell viability assays, and CR-CIC sphere formation assays, which define the CR-CIC phenotype and correlates directly with tumor formation in mice.
Results: CR-CICs were more resistant than non-CICs to both low-dose (2 Gy) and high-dose radiation (6 Gy) (decrease in viability 10-50% compared to 90-95% for non-CICs, p<0.001). However, all CR-CIC lines were more sensitive to treatment with simvastatin alone at both 1uM and 5uM concentrations compared to non-CICs (decrease in viability 60-98% compared to 0-15%, p<0.001). In addition, the combination of simvastatin and radiation was more effective than either therapy alone in inhibiting CR-CIC viability. Importantly, this also translated into effects on the sphere forming ability of CR-CICs: while radiation alone demonstrated limited inhibition, the addition of simvastatin significantly reduced the percentage of CR-CICs that formed spheres (further decrease 50-75%, p<0.01).
Conclusions: Treatment with simvastatin hinders CR-CIC viability and enhances radiation sensitivity in vitro. These findings suggest that simvastatin could be a potential adjunct therapy for rectal cancer patients. Mechanistic and in vivo studies are in progress, with the ultimate goal of paving the way for a clinical trial.
Presented at the SAGES 2017 Annual Meeting in Houston, TX.
Abstract ID: 79205
Program Number: S042
Presentation Session: Colorectal 1
Presentation Type: Podium