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

项目总结/摘要 桑福德·马科维茨博士因在遗传学领域的多项里程碑式发现而闻名， 胃肠道（GI）癌症。马科维茨有了开创性的发现， 信号传导是大多数人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）一种新的胃肠道肿瘤抑制因子和ii）一种关键的下调 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 结肠癌和食道癌，基于检测身体排泄物中异常甲基化的肿瘤DNA。 我们特别基于Markowitz团队的开创性工作，发现了15- PGDH在结肠癌中的应用在最近发表在《科学》、《科学转化医学》和《PNAS》上的研究中，我们 一个实验室改写了将PGE 2增加与结肠癌联系起来的经典途径，发现：i）15- PGDH，一种前列腺素降解酶，是：a）考克斯-2的有效体内拮抗剂，B）有效结肠癌 抑制基因，以及c）在85%的结肠癌中关闭。ii）此外，我们已经显示15-PGDH功能为 组织损伤后组织干细胞增殖的关键负调节因子。iii）我们已经确定了生殖系 15-PGDH及其途径伴侣PGT的遗传变异，与以下相关：a）增加的 结肠癌加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 减少了12倍v）我们已经显示具有低结肠15-PGDH赋予对结肠癌的抗性。 考克斯酶抑制剂塞来昔布和阿司匹林的结肠肿瘤预防作用，确定第一个耐药 这些常用的NSAID药物的机制。vi）我们开发了一种全新的化合物 它可以在结肠癌中重新诱导15-PGDH，并显示它们通过抑制一种新的和意想不到的 途径介导15-PGDH蛋白降解。我们的愿景是，15-PGDH现在提供主要的新 识别结肠癌高危个体的机会，制定结肠癌新策略 预防和开发结肠癌治疗的新方法。我们建议追求的目标是： i）鉴定15-PGDH途径调节结肠中干细胞样细胞的基本机制。 ii）鉴定结肠中15-PGDH水平自身调节的机制。㈢利用15-PGDH (plus PGE 2代谢中的伴侣基因），以开发强大的新测试，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PGE 2代谢中的伴侣基因）来开发新的 和强大的新测试，以更好地确定谁是敏感或耐药的非甾体抗炎药的结肠癌的个人 化学预防此外，我们建议开发15-PGDH作为结肠癌的治疗靶点 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阻断15-PGDH蛋白质周转的新型化合物。

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.