The melanoma inhibitory activity (MIA) protein is an early indicator for therapeutic response in preclinical melanoma models

5464 Melanoma inhibitory activity (MIA) is a 12-kDa protein secreted by melanoma tumor cells that is thought to play a role in detachment of cells from surrounding matrix. Studies have shown that increasing serum levels of MIA are associated with clinical disease progression, and MIA has been proposed as a potential prognostic marker for melanoma. In this report, we investigated the use of MIA as a possible biomarker for drug activity in preclinical melanoma models. MIA was secreted by melanoma cell lines and was detectable in the plasma of tumor bearing mice. MIA levels reflected tumor burden in several human melanoma xenograft models, including A375M, CHL-1 and two human tumor isolates (MEXF 276 and MEXF 1341). MIA levels were undetectable (≤ 3 ng/ml) in naive animals and ranged from 6 to 155 ng/ml in tumor-bearing mice. Treatment of mice with compounds, such as RAF265 (formerly known as CHIR-265), TKI258 (formerly known as CHIR-258) or sorafenib, that induced either tumor growth inhibition or regression of these xenografts was associated with a decrease in circulating MIA levels consistent with response. MIA levels dropped below the limit of detection following treatment with RAF265 that induced tumor regression. We also demonstrated that the decrease in MIA levels preceded tumor response, indicating that MIA is an early marker of drug activity in these preclinical models. We propose that MIA could be used in a similar manner in clinical trials and may be useful as an early indicator of drug activity, particularly in trials of targeted agents that are cytostatic rather than cytotoxic.