Assessment of PI3 kinase as a druggable target in melanoma

Abstract

8521 Background: PI3 (phosphatidylinositol-3) kinase is central to a major intracellular signal transduction pathway that influences numerous cellular functions, including growth, differentiation and survival. Drugs that target PI3 kinase have demonstrated preclinical activity, and are undergoing further development. The PI3 kinase inhibitor, SF1126 is expected to enter clinical trials in 2007. The hallmarks for a valuable drug target include differential expression between normal and malignant cells and an association with disease progression. PI3 kinase expression has not been thoroughly evaluated in melanoma. We sought to determine the expression and prognostic value of PI3 kinase in a large cohort of primary and metastatic melanomas and to compare the expression with that of benign nevi. Methods: Tissue microarrays containing 548 melanomas and 540 benign nevi were employed to assess PI3 kinase expression. We used a novel method of in situ automated quantitative analysis (AQUA) of protein levels. We applied S100 conjugated to Cy3 to identify a melanoma tumor mask within a histospot, and measured PI3 kinase expression levels using Cy5 conjugated antibodies within the mask. Continuous AQUA scores were correlated with clinical and pathological variables. Results: PI3 kinase expression was higher in melanomas than in nevi by unpaired t-tests (p < 0.0001), and was significantly higher in metastatic than in primary specimens (p < 0.0001). High PI3 kinase scores were associated with Clark levels of IV-V (p = 0.0126), Breslow thickness > 2mm (p = 0.044) and absence of tumor infiltrating lymphocytes (p = 0.014). High PI3 kinase expression strongly correlated with decreased survival by Cox univariate analysis (p = 0.0024), but was not independent of disease stage. Conclusions: PI3 kinase expression is remarkably higher in malignant melanocytes than in benign nevi. Moreover, high PI3 kinase expression is associated with disease aggression, making PI3 kinase an attractive drug target for melanoma. This is the first large study assessing PI3 kinase levels in melanoma in a quantitative fashion. Assessment of the association between PI3 kinase levels and response to therapy is warranted. No significant financial relationships to disclose.