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-? 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-?. 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.
Dr. Sanford Markowitz's laboratory is recognized for making multiple landmark discoveries in the genetics of GI cancers. This proposal is particularly based on our groundbreaking work discovering 15-PGDH, a prostaglandin degrading enzyme, is a potent colon cancer suppressor gene. Our vision is that 15-PGDH 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.
|Cooper, Gregory S; Markowitz, Sanford D; Chen, Zhengyi et al. (2018) Evaluation of Patients with an Apparent False Positive Stool DNA Test: The Role of Repeat Stool DNA Testing. Dig Dis Sci 63:1449-1453|
|Desai, Amar; Zhang, Yongyou; Park, Youngsoo et al. (2018) A second-generation 15-PGDH inhibitor promotes bone marrow transplant recovery independently of age, transplant dose and granulocyte colony-stimulating factor support. Haematologica 103:1054-1064|
|Moinova, Helen R; LaFramboise, Thomas; Lutterbaugh, James D et al. (2018) Identifying DNA methylation biomarkers for non-endoscopic detection of Barrett's esophagus. Sci Transl Med 10:|
|Cooper, Gregory S; Markowitz, Sanford D; Chen, Zhengyi et al. (2018) Performance of multitarget stool DNA testing in African American patients. Cancer 124:3876-3880|
|Wang, Jiping; Cho, Nancy L; Zauber, Ann G et al. (2018) Chemopreventive Efficacy of the Cyclooxygenase-2 (Cox-2) Inhibitor, Celecoxib, Is Predicted by Adenoma Expression of Cox-2 and 15-PGDH. Cancer Epidemiol Biomarkers Prev 27:728-736|
|Forrest, Megan E; Saiakhova, Alina; Beard, Lydia et al. (2018) Colon Cancer-Upregulated Long Non-Coding RNA lincDUSP Regulates Cell Cycle Genes and Potentiates Resistance to Apoptosis. Sci Rep 8:7324|
|Drew, David A; Chin, Samantha M; Gilpin, Katherine K et al. (2017) ASPirin Intervention for the REDuction of colorectal cancer risk (ASPIRED): a study protocol for a randomized controlled trial. Trials 18:50|
|Morris, Shelli M; Davison, Jerry; Carter, Kelly T et al. (2017) Transposon mutagenesis identifies candidate genes that cooperate with loss of transforming growth factor-beta signaling in mouse intestinal neoplasms. Int J Cancer 140:853-863|
|Antczak, Monika I; Zhang, Yongyou; Wang, Changguang et al. (2017) Inhibitors of 15-Prostaglandin Dehydrogenase To Potentiate Tissue Repair. J Med Chem 60:3979-4001|
|Kishore, Annavarapu Hari; Liang, Hanquan; Kanchwala, Mohammed et al. (2017) Prostaglandin dehydrogenase is a target for successful induction of cervical ripening. Proc Natl Acad Sci U S A 114:E6427-E6436|
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