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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)

基本信息

批准号：
10524057
负责人：
SANFORD D. MARKOWITZ
金额：
$ 93.2万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10524057
关键词：
Aspirin Colon Colon Carcinoma Colonic Neoplasms Development Dinoprostone Early Diagnosis Enzyme Inhibitor Drugs Enzymes Excretory function Genes Genetic Goals Human Individual Laboratories Malignant neoplasm of esophagus Malignant neoplasm of gastrointestinal tract Mediating Metabolism Methods Methylation Molecular Mutation Non-Steroidal Anti-Inflammatory Agents Oxidoreductase PTGS2 gene Pathway interactions Persons Pharmaceutical Preparations Prevention Proliferating Prostaglandins Proteins Publishing Resistance Role Science Seminal Signal Transduction Stream Testing Transforming Growth Factor beta Translational Research Tumor Suppressor Genes Tumor Suppressor Proteins Vision Work Writing antagonist base cancer chemoprevention cancer risk celecoxib colon cancer prevention colon cancer risk colon cancer screening colon cancer treatment genetic variant in vivo invention mRNA Expression novel novel therapeutics protein degradation resistance mechanism stem-like cell therapeutic target tissue injury tissue stem cells translational medicine tumor DNA

项目摘要

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.

项目总结/文摘