Abstract CN06-01: Phase IIa trial of sulindac in individuals at increased risk for melanoma

Abstract

Abstract Some epidemiological studies and several experimental publications suggest that regular use of non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of melanoma. However, specific information on the ability of NSAIDs to reach melanocytes in vivo and to modulate key biomarkers in pre-neoplastic lesions such as dysplastic nevi have not been evaluated to date. Methods: We conducted a randomized, double-blind, placebo controlled trial of sulindac in individuals at risk for melanoma to determine whether sulindac and related metabolites are bioavailable in the nevi and whether sulindac intervention has an effect on apoptosis and vascular endothelial growth factor (VEGF) expression in atypical nevi (AN). Fifty healthy subjects with ≥ 4 large (≥5 mm and < 15 mm) AN and one benign nevus (BN) were enrolled between 2/09 and 7/10. Subjects underwent clinical and dermoscopic evaluation of their melanocytic lesions with 2 AN randomized to be excised at baseline for biomarker evaluation and 2 AN to post-intervention evaluation. Subsequently, participants were randomized to receive sulindac (150 mg BID) or placebo for 8 weeks. Upon completion of the intervention the residual 2 AN and the BN were surgically removed. Results: The study intervention was well tolerated with some mild or moderate gastrointestinal adverse events that were possibly or probably related to the intervention. Sulindac, sulindac sulfone, sulindac sulfide concentrations were 0.31 ± 0.36, 1.56 ± 1.35, 2.25 ± 2.24 μg/ml, respectively, in post-intervention plasma samples from the sulindac group. Sulindac, sulindac sulfone, sulindac sulfide concentrations were 0.51 ± 1.05, 1.38 ± 2.86, 0.12 ± 0.12 μg/g tissue, respectively, in post-intervention nevi samples. Eight weeks of sulindac intervention did not result in significant changes in VEGF expression. Sulindac intervention increased the expression of a marker of apoptosis, cleaved caspase 3 (an increase of 3 ± 33 in the sulindac arm vs. a decrease of 25 ± 45 in the placebo arm, p = 0.0056) in dysplastic nevi. After adjusting for baseline expression, the significance of this finding is attenuated to a p-value of 0.1103 based on a linear regression model. Overall, these findings are consistent with the identification of high concentrations of sulindac sulfone, a pro-apoptotic metabolite in the nevi. Conclusion: The study showed that sulindac and sulindac metabolites can reach measurable levels in melanocytic nevi. Eight weeks of sulindac intervention induced the expression of a marker of apoptosis in dysplastic nevi but did not result in significant changes in VEGF expression. The study findings support the further evaluation of sulindac as a chemopreventive agent for melanoma. Citation Information: Cancer Prev Res 2011;4(10 Suppl):CN06-01.