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

> **NIH NIH R35** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $951,000

## Abstract

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 strategi...

## Key facts

- **NIH application ID:** 9830032
- **Project number:** 5R35CA197442-04
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** SANFORD D. MARKOWITZ
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $951,000
- **Award type:** 5
- **Project period:** 2016-12-29 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830032

## Citation

> US National Institutes of Health, RePORTER application 9830032, Targeting 15-Prostaglandin Dehydrogenase (15-PGDH) in Cancer Risk, Prevention, and Treatment (5R35CA197442-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9830032. Licensed CC0.

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