Chemopreventition and treatment of non-melanoma skin cancer by targeting MIF

通过靶向 MIF 化学预防和治疗非黑色素瘤皮肤癌

• 批准号: 8230915
• 负责人: Abhay R Satoskar
• 金额: $ 7.63万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230915
• 关键词: Acute; Angiogenesis Promoter; Animal Model; Antineoplastic Agents; Attenuated; Autoimmune Process; B-Lymphocytes; Basal cell carcinoma; Basophils; Biological; Biological Availability; Blood flow; Cells; Chemoprevention; Chronic; DNA Damage; Data; Delayed Hypersensitivity; Dendritic Cells; Dermal; Dermis; Development; Drug Delivery Systems; Edema; Epithelial Cells; Erythema; Esters; Exposure to; Foundations; Gene Expression; General Population; Goals; Half-Life; Human; Immigration; Immune; Immunology; In Vitro; Inbred BALB C Mice; Inbred HRS Mice; Incidence; Inflammation; Inflammatory; Inflammatory Response; Laboratories; Light; Link; Malignant Neoplasms; Mediator of activation protein; Messenger RNA; Migration Inhibitory Factor; Mus; Mutation; Neutrophil Infiltration; Oral; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Phenols; Play; Prevention; Production; Quinones; Reporting; Research Personnel; Role; Safety; Science; Skin; Skin Cancer; Skin Carcinoma; Skin Neoplasms; Squamous cell carcinoma; T-Lymphocyte; Testing; The Sun; Toxic effect; Toxicology; Transcript; Transgenic Mice; Tumor Suppressor Genes; UV Radiation Exposure; UV induced; Ultraviolet Rays; United States; Vascular Permeabilities; cancer diagnosis; cell type; chemokine; cytokine; efficacy testing; eosinophil; in vivo; inhibitor/antagonist; interest; macrophage; mast cell; monocyte; mouse model; neutrophil; novel; phenylpyruvate tautomerase; pre-clinical; prevent; small molecule; therapeutic target; tumor; tumor progression; ultraviolet

DESCRIPTION (provided by applicant): Non-melanoma skin cancer (NMSC) is the most frequently diagnosed cancer in the United States. Each year approximately one million new cases of NMSC are diagnosed in the United States with reported incidences increasing annually among the general population. Development of NMSC is primarily caused by repeated exposure to ultraviolet B (UVB) light from sun. Macrophage migration inhibitory factor (MIF) is a pleiotropi cytokine which is produced by variety of cells, including activated macrophages and neutrophils. Both of these cell types contribute to dermal inflammation induced by UVB light and have been implicated in the development of non-melanoma skin cancer (NMSC). MIF is an inducer of pro-inflammatory cytokines, a promoter of angiogenesis, a suppressor of p53 and has recently been re-discovered to act as a chemokine. Mounting evidence suggests that MIF serves as an important link between chronic inflammation and the development of cancer. Studies from our laboratory using MIF-/- BALB/c mice and by other investigators using MIF transgenic mice have found that MIF plays a critical role in induction of dermal inflammation and subsequent development of NMSC after UV light exposure. In recent preliminary studies, we have found that MIF mRNA levels are significantly increased in tumors of patients with squamous cell carcinoma (SCC) as well as in tumors that develop in hairless SKH-1 mice after UV exposure. These findings indicate that MIF is involved in the pathogenesis of acute UVB-induced skin inflammation as well as chronic UVB-induced NMSC development. The goals of this application are to test the hypotheses that MIF is a potential drug target in the chemoprevention and/or treatment of UVB-induced NMSC using a novel orally bio-available MIF antagonist. Aim 1 will determine whether blockade of MIF prevents acute UVB-induced dermal inflammation and subsequent tumor development in hairless SKH-1mice. Aim 2 will investigate whether MIF is a therapeutic target in treatment of established tumors in UV-exposed SKH-1 mice. Our team is uniquely poised to test this hypothesis and perform these studies due to complementary expertise in MIF/immunology/pathology (Satoskar), skin cancer (Oberyszyn) and MIF antagonists (Sielecki). Upon completion of these studies we will have determined whether MIF is a target in the prevention and treatment of NMSC, and whether small molecule MIF antagonists could be novel anti-cancer drugs. These data will lay the foundation for a latter RO1 application to develop better and safer MIF antagonists as novel drugs for prevention and treatment of skin cancer. PUBLIC HEALTH RELEVANCE: The goal of this project is to determine whether macrophage migration inhibitory factor (MIF) is a novel target in prevention and treatment of non melanoma skin cancer and to test the efficacy of novel MIF inhibitor as a potential anti-cancer drug for NMSC.

描述（由申请人提供）：非黑色素瘤皮肤癌（NMSC）是美国最常见的癌症。在美国，每年大约有100万例新的NMSC病例被诊断出，据报道，一般人群中每年的发病率增加。 NMSC的发展主要是由于反复暴露于Sun中的紫外线B（UVB）光。巨噬细胞迁移抑制因子（MIF）是多种细胞因子，由多种细胞（包括活化的巨噬细胞和中性粒细胞）产生。这两种细胞类型都会导致UVB光引起的皮肤炎症，并与非黑色素瘤皮肤癌（NMSC）的发展有关。 MIF是促炎细胞因子的诱导剂，促炎细胞因子是血管生成的启动子，p53的抑制剂，最近已重新发现作为趋化因子。越来越多的证据表明，MIF是慢性炎症与癌症发展之间的重要联系。使用MIF - / - BALB/C小鼠和其他研究人员使用MIF转基因小鼠的研究发现，MIF在紫外线暴露后的真皮炎症以及随后的NMSC发展中起着至关重要的作用。在最近的初步研究中，我们发现，鳞状细胞癌（SCC）的肿瘤以及紫外线暴露后无毛SKH-1小鼠的肿瘤中MIF mRNA水平显着增加。这些发现表明，MIF参与急性UVB诱导的皮肤炎症以及慢性UVB诱导的NMSC发育的发病机理。该应用的目标是测试MIF是使用一种新型口服生物可用的MIF拮抗剂的化学预防和/或处理UVB诱导的NMSC的潜在药物靶标的假设。 AIM 1将确定MIF的阻滞是否阻止了无毛SKH-1小米的急性UVB诱导的皮肤炎症和随后的肿瘤发育。 AIM 2将研究MIF是否是治疗紫外线暴露的SKH-1小鼠中已建立肿瘤的治疗靶点。由于MIF/免疫学/病理学（Satoskar），皮肤癌（Oberyszyn）和MIF拮抗剂（Sielecki）（Sielecki）的补充专业知识，我们的团队唯一准备检验这一假设并进行这些研究。完成这些研究后，我们将确定MIF是否是NMSC预防和治疗的目标，以及小分子MIF拮抗剂是否可以成为新型的抗癌药物。这些数据将为后一种RO1应用奠定基础，以发展更好，更安全的MIF拮抗剂，作为预防和治疗皮肤癌的新型药物。 公共卫生相关性：该项目的目的是确定巨噬细胞迁移抑制因子（MIF）是否是预防和治疗非黑色素瘤皮肤癌的新目标，并测试新型MIF抑制剂作为NMSC的潜在抗癌药物的功效。