CUTANEOUS ONCOLOGY

这是MD Anderson癌症中心医学教授兼皮肤科主任Madeleine Duvic的中期职业发展奖申请。它将支持皮肤肿瘤学的一个新项目，并使她能够指导该领域的新助理教授、研究员、住院医生和医学生。申请者在进行以患者为中心的临床研究方面有着出色的记录，并在开发皮肤T细胞淋巴瘤(CTCL)治疗新疗法方面处于领先地位。我们坚定不移地致力于在职业发展的各个层面进行以患者为导向的研究和指导。该奖项将使申请者从目前一半的临床职责中解放出来，使她能够将60%以上的时间用于面向患者的翻译维甲酸研究和指导活动。临床研究课程、肿瘤学研究员研讨会系列和机构会议将进一步促进申请者和学生的职业发展。两个利用维甲酸治疗癌症的转化研究项目被提出。1]一种新的II类肿瘤抑制基因--他扎罗汀诱导基因3(TIG-3)的缺失将在非黑色素瘤皮肤癌的发生和发展中进行研究。与配对的正常皮肤相比，侵袭性皮肤癌和非侵袭性皮肤癌以及基底和鳞癌中TIG-3显著降低的发现将通过更大的样本集、cDNA测序和杂合性丢失研究来检验。侵袭性肿瘤患者口服Acutane辅助治疗可能与TIG-3表达上调有关。2]塔格列汀是一种实验性的RXR选择性维甲酸，塔格列汀的分子标记的开发将在CTCL的外用和口服治疗中进行评估。塔格列汀可能通过改变细胞因子，促进淋巴细胞渗出细胞的凋亡，恢复表皮RAR和RXR受体的表达。治疗前后患者的皮肤损伤将用免疫组织化学和原位杂交法研究视黄醇受体、细胞因子和Fas/Fas配体。将利用基因组展示来探索维甲酸治疗后大细胞进展和基因表达的遗传基础，并将加强分子生物学方面的培训。了解皮肤癌和CTCL的生物学以及新型治疗药物的作用机制，应该会导致开发出更好、毒性更低的癌症治疗方法。接受皮肤癌适当检测、预防和治疗方面的高级培训的年轻医生和学生将是一种资源，可能会改善未来患者的预后。

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.