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

基本信息

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
项目类别：
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

项目摘要

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）是美国最常诊断出的癌症。美国每年诊断出约 100 万新的 NMSC 病例，据报道，普通人群中的发病率逐年增加。 NMSC 的形成主要是由于反复暴露于太阳紫外线 B (UVB) 造成的。巨噬细胞迁移抑制因子（MIF）是一种多效性细胞因子，由多种细胞产生，包括活化的巨噬细胞和中性粒细胞。这两种细胞类型都会导致 UVB 光诱导的皮肤炎症，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、血管生成的促进剂、p53 的抑制剂，最近被重新发现可充当趋化因子。越来越多的证据表明，MIF 是慢性炎症和癌症发展之间的重要联系。我们实验室使用 MIF-/- BALB/c 小鼠进行的研究以及其他研究人员使用 MIF 转基因小鼠进行的研究发现，MIF 在紫外线照射后诱导真皮炎症和 NMSC 的后续发育中发挥着关键作用。在最近的初步研究中，我们发现鳞状细胞癌（SCC）患者的肿瘤以及无毛SKH-1小鼠在紫外线照射后形成的肿瘤中MIF mRNA水平显着增加。这些发现表明，MIF 参与了急性 UVB 诱导的皮肤炎症以及慢性 UVB 诱导的 NMSC 发育的发病机制。本申请的目的是测试以下假设：MIF 是使用新型口服生物可利用的 MIF 拮抗剂化学预防和/或治疗 UVB 诱导的 NMSC 的潜在药物靶点。目标 1 将确定 MIF 的阻断是否可以预防无毛 SKH-1 小鼠中急性 UVB 诱导的皮肤炎症和随后的肿瘤发展。目标 2 将研究 MIF 是否是治疗紫外线暴露 SKH-1 小鼠已形成肿瘤的治疗靶点。由于 MIF/免疫学/病理学 (Satoskar)、皮肤癌 (Oberyszyn) 和 MIF 拮抗剂 (Sieecki) 方面的互补专业知识，我们的团队特别准备检验这一假设并进行这些研究。这些研究完成后，我们将确定MIF是否是预防和治疗NMSC的靶点，以及小分子MIF拮抗剂是否可以成为新型抗癌药物。这些数据将为RO1后期应用开发更好、更安全的MIF拮抗剂作为预防和治疗皮肤癌的新药奠定基础。公共健康相关性：该项目的目标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靶点，并测试新型 MIF 抑制剂作为潜在抗癌药物的功效。 NMSC。