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Targeting 15-Prostaglandin Dehydrogenase (15-PGDH) in Cancer Risk, Prevention, and Treatment

针对癌症风险、预防和治疗中的 15-前列腺素脱氢酶 (15-PGDH)

基本信息

批准号：
10524057
负责人：
SANFORD D. MARKOWITZ
金额：
$ 93.2万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-29 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10524057
关键词：
Aspirin Colon Colon Carcinoma Colonic Neoplasms Development Dinoprostone Early Diagnosis Enzyme Inhibitor Drugs Enzymes Excretory function Genes Genetic Goals Human Individual Laboratories Malignant neoplasm of esophagus Malignant neoplasm of gastrointestinal tract Mediating Metabolism Methods Methylation Molecular Mutation Non-Steroidal Anti-Inflammatory Agents Oxidoreductase PTGS2 gene Pathway interactions Persons Pharmaceutical Preparations Prevention Proliferating Prostaglandins Proteins Publishing Resistance Role Science Seminal Signal Transduction Stream Testing Transforming Growth Factor beta Translational Research Tumor Suppressor Genes Tumor Suppressor Proteins Vision Work Writing antagonist base cancer chemoprevention cancer risk celecoxib colon cancer prevention colon cancer risk colon cancer screening colon cancer treatment genetic variant in vivo invention mRNA Expression novel novel therapeutics protein degradation resistance mechanism stem-like cell therapeutic target tissue injury tissue stem cells translational medicine tumor DNA

项目摘要

PROJECT SUMMARY/ABSTRACT Dr. Sanford Markowitz is recognized for making multiple landmark discoveries in the genetics of gastrointestinal (GI) cancers. Markowitz made the seminal discovery that mutations that inactivate TGF-β signaling are a key step in the development of most human GI cancers. Moreover, Markowitz then identified 15- Prostaglandin Dehydrogenase (15-PGDH) as: i) a novel tumor suppressor of GI cancers and ii) a key down stream effector induced by TGF-β. Moreover, Markowitz pioneered inventing molecular tests for early detection of colon and esophagus cancers, based on detecting aberrantly methylated tumor DNA in body excretions. We particularly base this proposal on the Markowitz team's groundbreaking work discovering the role of 15- PGDH in colon cancer. In recent studies published in Science, Science Translational Medicine, and PNAS, our laboratory has rewritten the classical pathway connecting increased PGE2 to colon cancer, discovering: i) 15- PGDH, a prostaglandin degrading enzyme is: a) a potent in vivo antagonist of COX-2, b) a potent colon cancer suppressor gene, and c) turned off in 85% of colon cancers. ii) Further, we have shown 15-PGDH functions as a key negative regulator of proliferation of tissue stem cells after tissue injury. iii) We have identified germline genetic variants of 15-PGDH, and its pathway partner PGT, that are associated with: a) an increased risk of colon cancer plus b) reduced function of 15-PGDH. iv) We have shown in many people colon 15-PGDH levels are reduced by as much as 12-fold. v) We have shown having low colon 15-PGDH confers resistance to the colon tumor prevention effects of COX enzyme inhibitors, celecoxib and aspirin, identifying the first resistance mechanism for these commonly used NSAID drugs. vi) We have developed a totally new class of compounds that can re-induce 15-PGDH in colon cancers, and shown they work via inhibiting a novel and unanticipated pathway mediating 15-PGDH protein degradation. Our vision is that 15-PGDH now provides major new opportunities for identifying individuals at high colon cancer risk, for developing new strategies for colon cancer prevention, and for developing new methods for colon cancer treatment. Goals that we propose to pursue are: i) To identify the fundamental mechanism by which the 15-PGDH pathway regulates stem like cells in the colon. ii) To identify the mechanism by which 15-PGDH level is itself regulated in the colon. iii) To utilize 15-PGDH (plus its partner genes in PGE2 metabolism) to develop powerful new tests to better identify individuals at high colon cancer risk. iv) To similarly utilize 15-PGDH (plus its partner genes in PGE2 metabolism) to develop new and powerful new tests to better identify individuals who are sensitive or resistant to NSAIDs for colon cancer chemoprevention. Furthermore, we propose to develop 15-PGDH as a therapeutic target for colon cancer prevention and for colon cancer treatment, by v) developing new strategies for up-regulating 15-PGDH mRNA expression in the colon, and vi) developing new drugs that stabilize and increase active 15-PGDH protein in the colon, and that are based on a novel compound we have discovered that blocks 15-PGDH protein turnover.

项目概要/摘要桑福德·马科维茨 (Sanford Markowitz) 博士因在遗传学方面做出多项里程碑式的发现而受到认可胃肠道（GI）癌症。马科维茨做出了开创性的发现，使 TGF-β 失活的突变信号传导是大多数人类胃肠道癌症发展的关键步骤。此外，马科维茨随后确定了 15- 前列腺素脱氢酶 (15-PGDH) 作为：i) 胃肠道癌症的新型肿瘤抑制剂，ii) 关键抑制剂 TGF-β诱导的流效应子。此外，马科维茨率先发明了用于早期检测的分子测试基于检测身体排泄物中异常甲基化的肿瘤 DNA 来诊断结肠癌和食道癌。我们特别以 Markowitz 团队的开创性工作为基础，发现了 15- PGDH 在结肠癌中的作用。在最近发表在《科学》、《科学转化医学》和《美国国家科学院院刊》上的研究中，我们实验室重写了将 PGE2 增加与结肠癌联系起来的经典途径，发现： i) 15- PGDH 是一种前列腺素降解酶：a) COX-2 的有效体内拮抗剂，b) 有效的结肠癌抑制基因，c) 在 85% 的结肠癌中关闭。 ii) 此外，我们还展示了 15-PGDH 的功能：组织损伤后组织干细胞增殖的关键负调节因子。 iii) 我们已经鉴定出种系 15-PGDH 及其途径伙伴 PGT 的遗传变异与以下因素相关：a) 风险增加结肠癌加上 b) 15-PGDH 功能降低。 iv) 我们已经在许多人的结肠中显示了 15-PGDH 水平减少多达 12 倍。 v) 我们已经证明，结肠 15-PGDH 水平较低会赋予对 COX酶抑制剂、塞来昔布和阿司匹林的结肠肿瘤预防作用，确定第一耐药性这些常用的 NSAID 药物的作用机制。 vi) 我们开发了一种全新的化合物可以在结肠癌中重新诱导 15-PGDH，并表明它们通过抑制一种新的、意料之外的物质发挥作用介导 15-PGDH 蛋白降解的途径。我们的愿景是 15-PGDH 现在提供重要的新功能识别结肠癌高风险个体、制定结肠癌新策略的机会预防，以及开发结肠癌治疗的新方法。我们建议追求的目标是： i) 确定 15-PGDH 通路调节结肠干细胞样细胞的基本机制。 ii) 确定结肠中 15-PGDH 水平自身调节的机制。 iii) 利用15-PGDH （加上 PGE2 代谢中的伙伴基因）开发强大的新测试，以更好地识别处于高水平的个体结肠癌风险。 iv) 类似地利用 15-PGDH（加上其在 PGE2 代谢中的伙伴基因）来开发新的和强大的新测试可以更好地识别对结肠癌非甾体抗炎药敏感或耐药的个体化学预防。此外，我们建议开发15-PGDH作为结肠癌的治疗靶点预防和结肠癌治疗，通过 v) 开发上调 15-PGDH mRNA 的新策略 vi) 开发稳定和增加结肠中活性 15-PGDH 蛋白的新药结肠，并且基于我们发现的一种新化合物，该化合物可以阻止 15-PGDH 蛋白质周转。