Targeting 15-PGDH in Colon Cancer Prognosis, Prediction, Treatment and Prevention

这项建议的主要研究人员发现了一种新的有效的结肠癌抑制剂 结肠癌抑制基因15-前列腺素脱氢酶(15-PGDH)介导的途径。15- 前列腺素脱氢酶控制着生物活性前列腺素降解的限速步骤。因此，它是 代谢性地对抗COX-2癌基因的前列腺素生成活性，这是 在大多数结肠癌和癌前病变中显著上调 腺瘤。P.L.的研究表明：i)正常的结肠细胞高表达15-PGDH，但 在90%的结肠癌中显著丢失表达；ii)通过基因恢复15-PGDH的表达 转基因阻断结肠癌异种移植瘤生长；iii)小鼠15-PGDH基因敲除促进 小鼠结肠肿瘤的发生；iv)和低水平的结肠15-PGDH使人对 塞来昔布对小鼠模型和人类受试者的结肠癌预防作用。钥匙 本项目目前的翻译研究目标是：i)确定结肠组织中15-PGDH的水平 表达是个体患结肠肿瘤风险的预后标志；IL)以确定15- PGDH的表达是结肠癌预后的标志；具体地说，为了确定是否 10%持续表达15-PGDH的结肠癌表现为侵袭性较弱或较强 侵袭性形式的疾病；iii)确定结肠15-PGDH水平低是否定义了一组 对塞来昔布的化学预防作用具有抵抗力的个人；具体地说，是为了延长试点 一项综合研究显示了这种影响的分析，比较了结肠15-PGDH水平和 对450多名结肠癌高危人群进行腺瘤研究的结果 塞来昔布预防人体试验；以及iv)识别和表征可诱导 15-PGDH在结肠癌细胞中的表达，并能增加15-PGDH在正常结肠中的表达；这可能是 通过对超过200,000个小的化合物库进行高通量筛选来完成 敏感细胞中的分子以15-PGDH为基础的报告分析。

The Principal Investigators of this proposal are discovers of a novel and potent colon cancer suppressor pathway mediated by the colon cancer suppressor gene 15-Prostaglandin Dehydrogenase (15-PGDH). 15- PGDH controls the rate limiting step in the degradation of bioactive prostaglandins. As such, it is metabolically poised to antagonize the prostaglandin generating activity of the COX-2 oncogene, which is well characterized as being markedly up-regulated in most colon cancers and precancerous colon adenomas. The P.l.s have shown: i) that 15-PGDH is highly expressed by normal colonocytes, but that expression is dramatically lost in 90% of colon cancers; ii) that restoring 15-PGDH expression by gene transfection blocks colon cancer xenograft growth; iii) that gene knockout of murine 15-PGDH promotes development of murine colon tumors; iv) and that low levels of colonic 15-PGDH confers resistance to the colon tumor preventive effects of Celecoxib in murine models and in a pilot study of human subjects. Key translational research objectives of this project are now: i) to determine if levels of colonic 15-PGDH expression are a prognostic marker of individual's risk of developing colonic neoplasia; il) to determine if 15- PGDH expression Is a prognostic marker of colon cancer outcome; specifically, to determine whether the 10% of colon cancers that continue to express 15-PGDH represent either a less aggressive or a more aggressive form of the disease; iii) to determine If low levels of colonic 15-PGDH defines a cohort of individuals who are resistant to the chemopreventive effects of Celecoxib; specifically to extend a pilot analysis demonstrating this effect to a comprehensive study comparing colonic 15-PGDH levels versus outcome in over 450 individuals at high risk for colon neoplasia who were studied in the Adenoma Prevention with Celecoxib human trial; and iv) to identify and characterize small molecules that can reinduce 15-PGDH in colon cancer cells and can increase 15-PGDH expression in normal colon; this to be done by performing a high throughput screen of a chemical compound library of over 200,000 small molecules in a sensitive cell based 15-PGDH reporter assay.