Chemopreventive treatment of familial melanoma

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DESCRIPTION (provided by applicant): Several tumor types are associated with specific gene mutations. At-risk individuals can opt to have the targeted organs removed in an effort to reduce the incidence of associated cancer types. Elective surgery is not available to familial melanoma patients, where cells prone to undergo malignant transformation are dispersed throughout the basal layer of the epidermis. Here we propose to selectively eliminate melanocytes from the skin to prevent tumorigenesis in familial melanoma patients. Melanocytes and their malignant derivatives uniquely express tyrosinase, the rate-limiting enzyme responsible for melanogenesis. Several compounds have been described that cause depigmentation of the skin through competitive inhibition of the tyrosinase enzyme. These same compounds are cytotoxic to melanocytic cells when converted into toxic orthoquinones by tyrosinase. Cell death thus results selectively in melanocytes and melanoma cells. Whereas such prodrugs can themselves be toxic upon systemic use, bleaching phenols have been approved for topical use in skin depigmenting creams for patients with progressive vitiligo. These compounds selectively deplete melanocytes from the epidermis. The cytotoxic activity of bleaching phenols further contributes to generating a source of melanocyte specific differentiation antigens that are processed by skin infiltrating dendritic cells which leads, in turn, to an autoimmune response to melanocytes and progressive loss of skin pigmentation. Vitiligo is commonly considered an undesirable autoimmune condition, yet the development of progressive depigmentation is a positive prognostic sign for melanoma patients. Here we hypothesize that topical application of well characterized depigmenting agents can be used to treat melanoma by a 2-tierd approach, through eliciting anti-tumor immune responses to the tumor and through depletion of melanoma precursor cells. This approach is thus of particular importance for patients that carry mutations in p16/Arf or CDK4 genes contributing to familial melanoma, where the presence of melanocytes is a constant concern for the development of future tumors. We propose to test our hypothesis according to the following specific aims: 1] To generate mice that spontaneously develop melanoma tumors and express pigmented epidermal melanocytes by cross breeding albino Ink4A/Arf -/- Tyr-RAS tg mice x black k14-SCF tg mice. 2] To assess skin depigmentation in SCF transgenic mice in response to monobenzyl ether of hydroquinone (MBEH), approved for depigmentation in vitiligo and in response to 4-tertiary butyl phenol (4-TBP), a known causative agent in occupational vitiligo. 3] To quantify melanoma tumor growth and measure immunologic parameters (cytokine secretion by ELISA and ELISPOT) in mice treated with bleaching agents and IL-2.