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

以 15-PGDH 为靶点进行结肠癌的预后、预测、治疗和预防

• 批准号: 8555227
• 负责人: SANFORD D. MARKOWITZ
• 金额: $ 41.97万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-14 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8555227
• 关键词: 18q; Adult; African American; American; Antineoplastic Agents; Biological Assay; Cancer Etiology; Cancer Prognosis; Caucasians; Caucasoid Race; Cell Line; Cells; Cessation of life; Chemicals; Chemopreventive Agent; Clinical; Colon; Colon Carcinoma; Colonic Adenoma; Colonic Neoplasms; Colonoscopy; Detection; Development; Diagnostic Neoplasm Staging; Dinoprostone; Disease; Drug resistance; Epithelial Cells; Ethnic Origin; Gender; Gene Expression; Genes; Genetic; Growth; Human; Individual; Intestinal Neoplasms; Knock-out; Lead; Libraries; Loss of Heterozygosity; Luciferases; MADH2 gene; MADH4 gene; Measurement; Mediating; Modeling; Mus; Neoplasms; Non-Malignant; Non-Steroidal Anti-Inflammatory Agents; Nuclear; Nude Mice; Oncogenes; Outcome; Oxidoreductase; PTGS2 gene; Participant; Pathway interactions; Pharmaceutical Preparations; Pilot Projects; Premalignant; Prevention; Preventive; Principal Investigator; Prognostic Marker; Prostaglandins; Publications; Recording of previous events; Recurrence; Relapse; Reporter; Research; Resistance; Risk; Screening procedure; Signal Pathway; Testing; Transfection; Transgenes; Translating; Translational Research; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor stage; United States National Academy of Sciences; Xenograft procedure; adenoma; base; cancer cell; cancer prevention; cancer risk; candidate marker; celecoxib; cohort; colon cancer cell line; cyclooxygenase 1; design; high risk; high throughput screening; human subject; in vivo; knockout gene; novel; prevent; prognostic; response; small molecule; tumor

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.

这项提议的主要研究者发现了一种新的有效的结肠癌抑制剂 由结肠癌抑制基因15-前列腺素脱氢酶（15-PGDH）介导的途径。15- PGDH控制着生物活性野牡丹素降解的限速步骤。因此，它是 在代谢上能够拮抗考克斯-2致癌基因的前列腺素生成活性， 在大多数结肠癌和结肠癌前病变中显著上调 腺瘤P.l.s显示：i）正常结肠细胞高度表达15-PGDH，但 在90%的结肠癌中，15-PGDH的表达显著丧失; ii）通过基因治疗恢复15-PGDH的表达， 转染阻断结肠癌异种移植物生长; iii）鼠15-PGDH的基因敲除促进 小鼠结肠肿瘤的发展; iv）并且结肠15-PGDH的低水平赋予对小鼠结肠肿瘤的抗性。 塞来昔布在小鼠模型和人类受试者初步研究中的结肠肿瘤预防作用。关键 该项目的转化研究目标是：i）确定结肠15-PGDH的水平 表达是个体发生结肠瘤形成风险的预后标志; il）确定15- PGDH表达是结肠癌预后的一个标志物;具体地说， 10%继续表达15-PGDH的结肠癌代表了侵袭性较低或更具侵袭性。 iii）确定结肠15-PGDH的低水平是否定义了疾病的侵袭性形式; 对塞来昔布的化学预防作用有抵抗力的个体;特别是延长飞行员 一项综合性研究比较了结肠15-PGDH水平与 结果在超过450个人在高风险的结肠肿瘤谁是研究腺瘤 预防与塞来昔布人体试验;和iv）确定和表征小分子，可以重新诱导 15-PGDH在结肠癌细胞中的表达，并且可以增加15-PGDH在正常结肠中的表达;这将是 通过对超过200，000个小的化合物库进行高通量筛选来完成 在基于敏感细胞的15-PGDH报告基因测定中，