Program Official

Principal Investigator

Sanford D.
Awardee Organization

Case Western Reserve University
United States

Fiscal Year
Activity Code
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

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

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 15Prostaglandin 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 15PGDH 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) 15PGDH, 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.


  • Nayak L, Molinaro AM, Peters K, Clarke JL, Jordan JT, de Groot J, Nghiemphu L, Kaley T, Colman H, McCluskey C, Gaffey S, Smith TR, Cote DJ, Severgnini M, Yearley JH, Zhao Q, Blumenschein WM, Duda DG, Muzikansky A, Jain RK, Wen PY, Reardon DA. Randomized Phase II and Biomarker Study of Pembrolizumab plus Bevacizumab versus Pembrolizumab Alone for Patients with Recurrent Glioblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2021 Feb 15;27(4):1048-1057. Epub 2020 Nov 16. PMID: 33199490
  • Forrest ME, Saiakhova A, Beard L, Buchner DA, Scacheri PC, LaFramboise T, Markowitz S, Khalil AM. Colon Cancer-Upregulated Long Non-Coding RNA lincDUSP Regulates Cell Cycle Genes and Potentiates Resistance to Apoptosis. Scientific reports. 2018 May 9;8(1):7324. PMID: 29743621
  • Moinova HR, LaFramboise T, Lutterbaugh JD, Chandar AK, Dumot J, Faulx A, Brock W, De la Cruz Cabrera O, Guda K, Barnholtz-Sloan JS, Iyer PG, Canto MI, Wang JS, Shaheen NJ, Thota PN, Willis JE, Chak A, Markowitz SD. Identifying DNA methylation biomarkers for non-endoscopic detection of Barrett's esophagus. Science translational medicine. 2018 Jan 17;10. (424). PMID: 29343623
  • Hu B, Toda K, Wang X, Antczak MI, Smith J, Geboers S, Nishikawa G, Li H, Dawson D, Fink S, Desai AB, Williams NS, Markowitz SD, Ready JM. Orally Bioavailable Quinoxaline Inhibitors of 15-Prostaglandin Dehydrogenase (15-PGDH) Promote Tissue Repair and Regeneration. Journal of medicinal chemistry. 2022 Nov 24;65(22):15327-15343. Epub 2022 Nov 2. PMID: 36322935
  • Cohen AJ, Saiakhova A, Corradin O, Luppino JM, Lovrenert K, Bartels CF, Morrow JJ, Mack SC, Dhillon G, Beard L, Myeroff L, Kalady MF, Willis J, Bradner JE, Keri RA, Berger NA, Pruett-Miller SM, Markowitz SD, Scacheri PC. Hotspots of aberrant enhancer activity punctuate the colorectal cancer epigenome. Nature communications. 2017 Feb 7;8:14400. PMID: 28169291
  • Hao Y, He B, Wu L, Li Y, Wang C, Wang T, Sun L, Zhang Y, Zhan Y, Zhao Y, Markowitz S, Veigl M, Conlon RA, Wang Z. Nuclear translocation of p85β promotes tumorigenesis of PIK3CA helical domain mutant cancer. Nature communications. 2022 Apr 13;13(1):1974. PMID: 35418124
  • Markowitz SD. Cancer bypasses the lymph nodes. Science (New York, N.Y.). 2017 Jul 7;357(6346):35-36. PMID: 28684492
  • Dogan AB, Rohner NA, Smith JNP, Kilgore JA, Williams NS, Markowitz SD, von Recum HA, Desai AB. Polymer Microparticles Prolong Delivery of the 15-PGDH Inhibitor SW033291. Pharmaceutics. 2021 Dec 30;14. (1). PMID: 35056981
  • Antczak MI, Zhang Y, Wang C, Doran J, Naidoo J, Voruganti S, Williams NS, Markowitz SD, Ready JM. Inhibitors of 15-Prostaglandin Dehydrogenase To Potentiate Tissue Repair. Journal of medicinal chemistry. 2017 May 11;60(9):3979-4001. Epub 2017 Apr 25. PMID: 28398755
  • Rathore M, Zhang W, Wright M, Bhattacharya R, Fan F, Vaziri-Gohar A, Winter J, Wang Z, Markowitz SD, Willis J, Ellis LM, Wang R. Liver Endothelium Promotes HER3-Mediated Cell Survival in Colorectal Cancer with Wild-Type and Mutant KRAS. Molecular cancer research : MCR. 2022 Jun 3;20(6):996-1008. PMID: 35276002
  • Cooper GS, Markowitz SD, Chen Z, Tuck M, Willis JE, Berger BM, Brenner DE, Li L. Evaluation of Patients with an Apparent False Positive Stool DNA Test: The Role of Repeat Stool DNA Testing. Digestive diseases and sciences. 2018 Jun;63(6):1449-1453. Epub 2018 Mar 7. PMID: 29516325
  • Ho WJ, Smith JNP, Park YS, Hadiono M, Christo K, Jogasuria A, Zhang Y, Broncano AV, Kasturi L, Dawson DM, Gerson SL, Markowitz SD, Desai AB. 15-PGDH regulates hematopoietic and gastrointestinal fitness during aging. PloS one. 2022 May 19;17(5):e0268787. doi: 10.1371/journal.pone.0268787. eCollection 2022. PMID: 35587945
  • Smith JNP, Otegbeye F, Jogasuria AP, Christo KF, Antczak MI, Ready JM, Gerson SL, Markowitz SD, Desai AB. Inhibition of 15-PGDH Protects Mice from Immune-Mediated Bone Marrow Failure. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020 Aug;26(8):1552-1556. Epub 2020 May 15. PMID: 32422251
  • Jin X, Demere Z, Nair K, Ali A, Ferraro GB, Natoli T, Deik A, Petronio L, Tang AA, Zhu C, Wang L, Rosenberg D, Mangena V, Roth J, Chung K, Jain RK, Clish CB, Vander Heiden MG, Golub TR. A metastasis map of human cancer cell lines. Nature. 2020 Dec;588(7837):331-336. Epub 2020 Dec 9. PMID: 33299191
  • Kim BW, Kim HJ, Kim SH, Baik HJ, Kang MS, Kim DH, Markowitz SD, Kang SW, Bae KB. 15-Hydroxyprostaglandin dehydrogenase inhibitor prevents contrast-induced acute kidney injury. Renal failure. 2021 Dec;43(1):168-179. PMID: 33459127
  • Kishore AH, Liang H, Kanchwala M, Xing C, Ganesh T, Akgul Y, Posner B, Ready JM, Markowitz SD, Word RA. Prostaglandin dehydrogenase is a target for successful induction of cervical ripening. Proceedings of the National Academy of Sciences of the United States of America. 2017 Aug 1;114(31):E6427-E6436. Epub 2017 Jul 17. PMID: 28716915
  • Smith JNP, Witkin MD, Jogasuria AP, Christo KF, Raffay TM, Markowitz SD, Desai AB. Therapeutic targeting of 15-PGDH in murine pulmonary fibrosis. Scientific reports. 2020 Jul 15;10(1):11657. PMID: 32669620
  • Yu M, Moinova HR, Willbanks A, Cannon VK, Wang T, Carter K, Kaz A, Reddi D, Inadomi J, Luebeck G, Iyer PG, Canto MI, Wang JS, Shaheen NJ, Thota PN, Willis JE, LaFramboise T, Chak A, Markowitz SD, Grady WM. Novel DNA Methylation Biomarker Panel for Detection of Esophageal Adenocarcinoma and High-Grade Dysplasia. Clinical cancer research : an official journal of the American Association for Cancer Research. 2022 Sep 1;28(17):3761-3769. PMID: 35705525
  • Kim HJ, Kim SH, Kim M, Baik H, Park SJ, Kang MS, Kim DH, Kim BW, Markowitz SD, Bae KB. Inhibition of 15-PGDH prevents ischemic renal injury by the PGE2/EP4 signaling pathway mediating vasodilation, increased renal blood flow, and increased adenosine/A2A receptors. American journal of physiology. Renal physiology. 2020 Dec 1;319(6):F1054-F1066. Epub 2020 Nov 2. PMID: 33135478
  • Cooper GS, Markowitz SD, Chen Z, Tuck M, Willis JE, Berger BM, Brenner DE, Li L. Performance of multitarget stool DNA testing in African American patients. Cancer. 2018 Oct 1;124(19):3876-3880. Epub 2018 Sep 7. PMID: 30193399
  • Smith JN, Dawson DM, Christo KF, Jogasuria AP, Cameron MJ, Antczak MI, Ready JM, Gerson SL, Markowitz SD, Desai AB. 15-PGDH inhibition activates the splenic niche to promote hematopoietic regeneration. JCI insight. 2021 Mar 22;6. (6). PMID: 33600377
  • Wang J, Cho NL, Zauber AG, Hsu M, Dawson D, Srivastava A, Mitchell-Richards KA, Markowitz SD, Bertagnolli MM. Chemopreventive Efficacy of the Cyclooxygenase-2 (Cox-2) Inhibitor, Celecoxib, Is Predicted by Adenoma Expression of Cox-2 and 15-PGDH. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2018 Jul;27(7):728-736. Epub 2018 May 16. PMID: 29769213
  • Douville C, Moinova HR, Thota PN, Shaheen NJ, Iyer PG, Canto MI, Wang JS, Dumot JA, Faulx A, Kinzler KW, Papadopoulos N, Vogelstein B, Markowitz SD, Bettegowda C, Willis JE, Chak A. Massively Parallel Sequencing of Esophageal Brushings Enables an Aneuploidy-Based Classification of Patients With Barrett's Esophagus. Gastroenterology. 2021 May;160(6):2043-2054.e2. Epub 2021 Jan 22. PMID: 33493502
  • Morris SM, Davison J, Carter KT, O'Leary RM, Trobridge P, Knoblaugh SE, Myeroff LL, Markowitz SD, Brett BT, Scheetz TE, Dupuy AJ, Starr TK, Grady WM. Transposon mutagenesis identifies candidate genes that cooperate with loss of transforming growth factor-beta signaling in mouse intestinal neoplasms. International journal of cancer. 2017 Feb 15;140(4):853-863. Epub 2016 Nov 7. PMID: 27790711
  • Huang W, Li H, Kiselar J, Fink SP, Regmi S, Day A, Yuan Y, Chance M, Ready JM, Markowitz SD, Taylor DJ. Small molecule inhibitors of 15-PGDH exploit a physiologic induced-fit closing system. Nature communications. 2023 Feb 11;14(1):784. PMID: 36774348
  • Desai A, Zhang Y, Park Y, Dawson DM, Larusch GA, Kasturi L, Wald D, Ready JM, Gerson SL, Markowitz SD. A second-generation 15-PGDH inhibitor promotes bone marrow transplant recovery independently of age, transplant dose and granulocyte colony-stimulating factor support. Haematologica. 2018 Jun;103(6):1054-1064. Epub 2018 Feb 22. PMID: 29472361