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)

• 批准号: 9406781
• 负责人: SANFORD D. MARKOWITZ
• 金额: $ 95.1万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 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/9406781
• 关键词: Aspirin; Colon; Colon Carcinoma; Colonic Neoplasms; Development; Dinoprostone; Early Diagnosis; Enzyme Inhibitor Drugs; Enzymes; Excretory function; Genes; Genetic; Goals; Human; Individual; Injury; Laboratories; Malignant neoplasm of esophagus; Malignant neoplasm of gastrointestinal tract; Mediating; Metabolism; Methods; Molecular; Mutation; Non-Steroidal Anti-Inflammatory Agents; Oxidoreductase; PTGS2 gene; Pathway interactions; Pharmaceutical Preparations; Prevention; Prostaglandins; Proteins; Publishing; Resistance; Role; Science; Seminal; Signal Transduction; Stem cells; Stream; Testing; Tissues; Transforming Growth Factor beta; Translational Research; Tumor Suppressor Genes; Tumor Suppressor Proteins; Vision; Work; base; cancer chemoprevention; cancer risk; celecoxib; colon cancer prevention; colon cancer risk; colon cancer screening; colon cancer treatment; genetic variant; in vivo; mRNA Expression; novel; novel therapeutics; protein degradation; resistance mechanism; stem-like cell; therapeutic target; translational medicine; tumor DNA

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.

项目摘要/摘要 桑福德·马克维茨（Sanford Markowitz 胃肠道（GI）癌症。马科维茨（Markowitz 信号传导是大多数人类GI癌的发展的关键步骤。此外，马科维茨随后确定了15- 前列腺素脱氢酶（15-PGDH）AS：i）一种新型GI癌的肿瘤抑制和II）键向下 TGF-β诱导的流效应子。此外，马科维茨开创性发明了分子测试以提早检测 基于检测到体内外排出异常甲基化肿瘤DNA的结肠和食道癌。 我们特别基于Markowitz团队的开创性工作，发现了15-- 结肠癌中的PGDH。在最近发表的科学，科学转化医学和PNAS的研究中，我们的 实验室改写了连接PGE2与结肠癌增加的经典途径，发现：i）15-- PGD​​H，一种前列腺素降解酶是：a）Cox-2的体内拮抗剂的潜在潜在 抑制基因，c）在85％的结肠癌中关闭。 ii）此外，我们显示了15-PGDH的功能 组织损伤后组织干细胞增殖的关键负调节剂。 iii）我们已经确定了种系 与15-PGDH的遗传变异及其途径合作伙伴PGT有关：a） 结肠癌加上b）15-PGDH功能降低。 iv）我们已经在许多人结肠15-pgdh级别上显示 减少多达12倍。 v）我们已经显示出低结肠15-PGDH赋予对抗性的抵抗力 Cox酶抑制剂，塞来昔布和阿司匹林的结肠肿瘤预防作用，鉴定出第一种抗性 这些常用的NSAID药物的机制。 vi）我们已经开发了一类全新的化合物 可以在结肠癌中重新诱导15-PGDH，并通过抑制新颖而意外的 介导15-PGDH蛋白降解的途径。我们的愿景是15-PGDH现在提供了主要的新 识别高结肠癌风险的人的机会，为结肠癌制定新策略 预防，以及开发新方法进行结肠癌治疗。我们建议追求的目标是： i）确定15-PGDH途径调节结肠中的细胞的基本机制。 ii）确定在结肠中自身调节15-PGDH水平的机制。 iii）使用15-pgdh （加上PGE2代谢中的合作伙伴基因）以开发强大的新测试以更好地识别个人 结肠癌风险。 iv）类似地利用15-PGDH（加上其PGE2代谢中的伴侣基因）来发展新的 和强大的新测试，以更好地识别对结肠癌敏感或耐NSAID的人 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）制定上调15-PGDH mRNA的新策略 在结肠中的表达和vi）开发新药，以稳定并增加活性15-PGDH蛋白 结肠，基于一种新颖的化合物，我们发现阻断了15-PGDH蛋白的周转率。