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

描述(申请人提供)：非黑色素瘤皮肤癌(NMSC)是美国最常见的确诊癌症。在美国，每年约有一百万新确诊的NMSC病例，普通人群中的报告发病率每年都在增加。NMSC的发展主要是由于反复暴露于来自太阳的紫外线B(UVB)所致。巨噬细胞移动抑制因子(MIF)是一种由多种细胞产生的多向刺激细胞因子，包括活化的巨噬细胞和中性粒细胞。这两种类型的细胞都与紫外线引起的皮肤炎症有关，并与非黑色素瘤皮肤癌(NMSC)的发生有关。MIF是促炎细胞因子的诱导者，是血管生成的促进者，是P53的抑制者，最近被重新发现具有趋化因子的作用。越来越多的证据表明，MIF在慢性炎症和癌症发展之间起着重要的联系作用。我们实验室使用MIF-/-BALB/c小鼠和其他研究人员使用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随后的NMSC发展中发挥关键作用。在最近的初步研究中，我们发现在鳞状细胞癌(SCC)患者的肿瘤中，以及紫外线照射后在无毛SKH-1小鼠中发展起来的肿瘤中，MIF mRNA水平显著增加。这些结果表明，MIF参与了UVB诱导的急性皮肤炎症和慢性UVB诱导的NMSC的发生发展。本申请的目的是通过使用一种新的口服生物可用MIF拮抗剂来验证MIF是化学预防和/或治疗UVB诱导的NMSC的潜在药物靶点的假设。目的1将确定阻断MIF是否能阻止UVB诱导的急性皮肤炎症和随后的无毛SKH-1小鼠肿瘤的发展。目的2将研究MIF是否是治疗紫外线照射的SKH-1小鼠已建立的肿瘤的治疗靶点。由于在MIF/免疫学/病理学(Satoskar)、皮肤癌(Oberyszyn)和MIF拮抗剂(Sielecki)方面的互补专业知识，我们的团队能够独一无二地测试这一假设并进行这些研究。在这些研究完成后，我们将确定MIF是否是预防和治疗NMSC的靶点，以及小分子MIF拮抗剂是否可能成为新型抗癌药物。这些数据将为后来的RO1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。 公共卫生相关性：本项目的目标是确定巨噬细胞移动抑制因子(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NMSC潜在抗癌药物的疗效。

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.