Malignant melanoma, a deadly skin cancer, is the result of the unregulated proliferation of melanocytes. Therapeutic approaches targeting specific proliferation pathways may be useful for the treatment of melanocytic tumors. We have shown that in human skin, cytokine stimulation of melanocytes with cell factor (SCF) cause melanocyte proliferation, while inhibition of the SCF receptor, KIT, results in melanocyte loss. This is the only cytokine pathway that has been shown to have the pharmacologic capacity to control melanocyte homeostasis within human skin; however, it is not clear how pharmacologic manipulation of this pathway will affect benign and malignant melanocytic neoplasias. Our objective is to determine the extent to which the KIT pathway controls growth and maintenance of melanocytes in benign and malignant tumor types in vivo, and to develop an in vitro system suitable for the study of KIT pathway in melanocytes and melanoma cell lines. We developed a xenografting technique that allow us to engraft human skin, nevi, and early melanoma tissues on immunodeficient mice. The xenografts can be maintained long term and allow for pharmacologic manipulation of human skin without potential risks to the patient. We have demonstrated that SCF drives melanocytic proliferation in the human skin grafts and that the changes reflect those seen at the SCF injection site in patients who have received recombinant SCF in phase one trails. Further, we have demonstrated that inhibition of KIT with K44.2, a specific inhibitory antibody, results in melanocyte loss. We intend to utilize the pharmacologic treatment of human xenografted tissue to determine the role of the SCF/KIT pathway on the growth and maintenance of benign and malignant melanocytic tumors. Potential mechanisms by which this pathway elicits its effects will be studied with a focus on proliferation, apoptosis, and differentiation status. In order to study the mechanism by which KIT-inhibition results in melanocyte loss and the mechanisms of KIT resistance, which may be present in advanced melanomas, a KIT- sensitive culture system will be developed by growth factor, substrate attachment, cell co-culture, and media modifications. This culture system will allow us to evaluate the direct effect of KIT inhibition on individual melanocytes and melanoma cells and to potentially determine whether it is possible to reactivate SCF/KIT pathway dependence in resistant tumor lines. The proposed experiments will define to what extent manipulation of the KIT pathway will be useful for the therapeutic treatment of proliferative melanocytic disease processes.
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