Approaches to the study of FKBP51 for development of a novel melanoma biomarker.

Very recently, we have identified that FKBP51 controls response of melanoma to DNA damaging agents. In particular, we found that FKBP51-silencing activated apoptosis in irradiated melanoma, both in vitro and in vivo. Increased levels of FKBP51 were found in melanoma skin samples, with maximal expression in metastasis. A clear FKBP51 expression was also documented in cancer stem/initiating cells, together with a radiosensitizing effect of protein knockdown in these cells. Aim of the present project is to generate molecular knowledge of FKBP51 in malignant melanoma biology and to transfer it in clinical setting in the areas of diagnosis, prognosis and therapy. The experimental plan includes: 1) mechanistic studies of the role of FKBP51 in the regulation of signaling pathways responsible for resistance to cell death, with particular regard to NF-??B and protein kinase C (PKC) signaling; 2) a proteomic study complemented with conventional immunohistochemistry to evaluate FKBP51 co-expression with oncoproteins, in a large number of primary melanoma specimens; 3) a pre-clinical study on murine model of metastatic melanoma, to evaluate the efficacy of FKBP51 siRNA treatment, in association with external beam radiation focused on metastatic organ.