Abstract A66: Phase IIa placebo controlled trial of sulindac in individuals at increased risk for melanoma: Preliminary findings

Abstract

Abstract Some epidemiological studies and several experimental publications suggest that regular use of NSAIDs may reduce the risk of melanoma. Proposed mechanisms of action include: inhibition of MAP kinase activity and nuclear translocation, reduction in the concentration of prostaglandins associated with the inhibition of VEGF and bFGF production and HIF-1α stabilization, reduction of the activation state of the VEGF and Ftl-1 genes, and inhibition of PI-3 kinase/Akt signaling pathway. 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: A phase IIa placebo controlled clinical intervention trial was designed with the primary end point to determine whether oral sulindac and related metabolites were present in benign nevi (BN) after an 8 week course of oral sulindac; secondary end points were included to determine whether a short exposure to sulindac had an effect on apoptosis and VEGF expression in atypical nevi (AN), as well as measurement of sulindac and metabolite levels in plasma. Exploratory objectives will evaluate the feasibility of reverse phase protein microarray to identify intervention related changes in cell signaling proteins, focusing initially on the pAKT/mTOR pathway and COX expression. Fifty healthy subjects with ≥ 4 large (≥5 mm and < 15 mm) AN and one 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: To date, accrual has been completed and study intervention in all subjects is expected to be concluded in 09/10. The study intervention was well tolerated with some mild or moderate gastrointestinal adverse events that are possibly or probably related to the intervention. Sulindac, sulindac sulfide, sulindac sulfone concentrations were 0 — 1.4, 0 −9.07, and 0 — 6.1 µg/ml, respectively, in 41 post-intervention plasma samples analyzed to date. Sulindac, sulindac sulfide, sulindac sulfone concentrations were 0 — 5.2, 0 — 0.25, and 0 — 14.27 µg/g, respectively, in 40 postintervention BN samples. Conclusion: Current results suggest that NSAIDs, in particular sulindac and the active sulindac metabolites, can reach measurable levels in the skin, and specifically in melanocytic nevi, further supporting the need to assess the effect of this group of drugs as chemopreventive agents for melanoma. Supported by N01CN35158 from the National Cancer Institute, Division of Cancer Prevention. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A66.