This is a mid-career development award application for Madeleine Duvic, Professor of Medicine and Chief of Dermatology at the MD Anderson Cancer Center. It would support a new program in Cutaneous Oncology and enable her to mentor new Assistant Professors, fellows, residents, and medical students in the field. The applicant has an outstanding track record in conducting patient oriented clinical research and is a leader in developing new therapies for the treatment of Cutaneous T Cell Lymphomas (CTCL). There is an unwavering commitment to the conduct of patient oriented research and mentoring at all levels of career development. The award would free the applicant from half of her current clinical duties, allowing her to spend greater than 60 percent of her time on patient oriented translational retinoid research and mentoring activities. A Clinical Research curriculum, an oncology fellows seminar series, and institutional conferences will enhance further career development of the applicant and students. Two translational research projects are proposed using retinoids for cancer. 1] The loss of a novel class II tumor suppressor, Tazarotene Induced Gene 3 (TIG-3), will be investigated in the development and progression of non-melanoma skin cancers. The finding that TIG-3 is significantly decreased in aggressive versus non-aggressive skin cancer and in basal and squamous carcinomas, compared to paired normal skin will be examined in a larger set of samples and by sequencing cDNAs and by loss of heterozygosity studies. Oral Accutane adjuvant therapy for patients with aggressive tumors may be related to upregulation of TIG-3. 2] Development of molecular markers for Targretin, an experimental RXR selective retinoid, Targretin, will be assessed in the topical and oral treatment of CTCL. Targretin may restore expression of RAR and RXR receptors in epidermis, by altering cytokines and fostering apoptosis of the lymphocytic infiltrates. Patient's skin lesions before and after therapy will be studied using immunohistochemistry and in situ hybridization for retinoid receptors, cytokines, and fas/fas ligand. Genetic basis of large cell progression and gene expression following retinoid therapy will be explored using genomic display and will enhance the training in molecular biology. Understanding the biology of skin cancer and CTCL and the mechanism of novel therapeutic agents should result in the development of better and less toxic therapies for cancer. Young physicians and students who receive advanced training in the proper detection, prevention, and treatment of skin cancers will be a resource and may improve outcomes for patients of the future.
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