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

项目摘要/摘要 桑福德·马科维茨博士因在遗传学上取得多项里程碑式的发现而受到认可 胃肠道(GI)癌。马科维茨发现了使转化生长因子-β失活的突变 信号转导是大多数人类胃肠道癌症发展过程中的关键步骤。此外，马科维茨随后确定了15- 前列腺素脱氢酶(15-PGDH)：一种新的胃肠道肿瘤抑制因子和一种关键基因 转化生长因子-β诱导的溪流效应。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，基于检测到体内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- 前列腺素脱氢酶与结肠癌的关系。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，我们的 实验室重写了PGE2升高与结肠癌之间的经典途径，发现：i)15- 前列腺素降解酶是：a)体内COX-2的强大拮抗剂，b)强大的结肠癌 C)在85%的结肠癌中处于关闭状态。Ii)此外，我们已经显示了15-PGDH的功能如下 组织损伤后组织干细胞增殖的关键负性调节因子。三)我们已经确定了生殖系 15-前列腺素脱氢酶及其途径伙伴前列腺素T的遗传变异与：a)增加的风险 结肠癌加b)15-前列腺素脱氢酶功能降低。IV)我们在许多人的结肠中显示了15-PGDH的水平 减少了多达12倍。V)我们已经证明，具有低位结肠15-PGDH可以增强对 环氧合酶抑制剂塞来昔布和阿司匹林对结肠癌的预防作用 这些常用的非甾体抗炎药的作用机制。六)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-前列腺素脱氢酶，并表明它们通过抑制一种新的和意想不到的 15-前列腺素脱氢酶蛋白降解的途径。我们的愿景是15-PGDH现在提供了主要的新的 识别结肠癌高危人群的机会，开发结肠癌新策略的机会 预防，并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-前列腺素脱氢酶途径调控结肠干细胞的基本机制。 Ii)确定15-前列腺素脱氢酶在结肠中自身水平的调节机制。三)利用15-前列腺素脱氢酶 (加上它在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 结肠癌风险。四)同样地利用15-前列腺素脱氢酶(加上其在前列腺素E_2代谢中的伙伴基因)开发新的 以及强大的新测试，以更好地识别对非类固醇抗炎药敏感或耐药的结肠癌患者 化学预防。此外，我们建议开发15-pgdh作为结肠癌的治疗靶点。 结肠癌的预防和治疗，通过v)开发上调15-PGDHmRNA的新策略 在结肠中的表达，以及vi)开发稳定和增加结肠中活性的15-PGDH蛋白的新药 这是基于我们已经发现的一种新的化合物，可以阻断15-PGDH蛋白的周转。

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.