Researchers make discovery in colon cancer prevention

A new study finds that individuals who have low expression of the “Celebrex gene,” 15-PGDH, are actually resistant to Celebrex treatment when used to prevent colon cancer.

The study, published in this week's issue of the Proceedings of the National Academy of Sciences (PNAS), is by Sanford Markowitz, M.D., Ph.D., the Markowitz-Ingalls Professor of Cancer Genetics at the Case Western Reserve University School of Medicine and an oncologist at the Ireland Cancer Center of University Hospitals Case Medical Center and his colleagues.

“These findings have two important practical implications,” said Markowitz, who is also an investigator in the Howard Hughes Medical Institute. “First, they suggest that measurement of 15-PGDH may identify which individuals are most likely to benefit from treatment with Celecoxib as a colon tumor preventative. Second, they suggest that identifying drugs that could increase 15-PGDH expression in the colon could be a potent new strategy for preventing development of tumors in the colon.”

In the Adenoma Prevention with Celecoxib (APC) trial, a clinical trial conducted by Monica Bertagnolli, M.D. at the Harvard Brigham and Women's Hospital and designed to test Celecoxib for the prevention of sporadic colorectal adenomas, the researchers showed that Celecoxib (brand name Celebrex, a Cox-2 inhibitor that relieves pain and inflammation without harming the digestive tract) treatment of individuals who had previously developed colon adenomas cut the rate of developing new adenomas by one-third, and cut the rate of developing new large adenomas by two-thirds. Some individuals however proved resistant to Celecoxib treatment and developed new colon tumors even while on the drug. Colon adenomatous polyps are benign tumors that are the immediate precursors of colon cancers.

Previous studies by Markowitz published in PNAS (December 2004 and July 2006) discovered that the gene 15-PGDH is expressed by the normal colon and acts similarly to Celecoxib in preventing colon tumors by inhibiting the COX-2 pathway.

The current study leads the researchers to ask, 'could protection from colon tumors by Celecoxib actually require the joint action of both the drug and the 15-PGDH gene?'

To answer the question the investigators examined mice that genetically lacked the gene 15-PGDH. In these mice, Celecoxib proved unable to prevent the development of colon tumors, suggesting that both the drug and the gene are needed to protect the colon from tumor development.

The investigators then examined colon biopsies from human patients who had participated in the APC trial of Celecoxib. They found that among these individuals colon 15-PGDH levels varied by 12-fold from lowest to highest. Most importantly, they found that the patients who were resistant to Celecoxib and had developed new colon tumors were all individuals who had low levels of colonic 15-PGDH. Thus in both mice and humans, Celecoxib works to prevent colon tumors only if levels of colonic 15-PGDH are high, while low levels of 15-PGDH leads to Celecoxib resistance.

Markowitz and Bertagnolli point out that these findings should be further confirmed in additional studies with larger numbers of patients. They also agree that it will be important to determine if differences in 15- PGDH levels also account for differences between different individuals in the effectiveness of Celecoxib and similar type drugs, when used for treating pain or inflammation.

Lead authors on the paper are Min Yan, Ph.D., Seung-Jae Myung, M.D., and Stephen Fink, Ph.D., of the department of medicine at the Case Western Reserve University School of Medicine and the Ireland Cancer Center at University Hospitals. Also involved were researchers from the University of Texas M.D. Anderson Cancer Center and the University of Kentucky.

Colon cancer, the second leading cause of cancer deaths in the U.S., accounts for 50,000 deaths annually.

About Case Western Reserve University School of Medicine

Founded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and is among the nation's top medical schools for research funding from the National Institutes of Health. The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching. The School's innovative and pioneering Western Reserve2 curriculum interweaves four themes–research and scholarship, clinical mastery, leadership, and civic professionalism–to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century. Eleven Nobel Laureates have been affiliated with the school.

Annually, the School of Medicine trains more than 770 M.D. and M.D./Ph.D. students and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News and World Report “Guide to Graduate Education.”

The School of Medicine's primary affiliate is University Hospitals Case Medical Center and is additionally affiliated with MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic, with which it established the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2002. http://casemed.case.edu.

About University Hospitals

With 150 locations throughout Northeast Ohio, University Hospitals serves the needs of patients through an integrated network of hospitals, outpatient centers and primary care physicians. At the core of our Health System is University Hospitals Case Medical Center. The primary affiliate of Case Western Reserve University School of Medicine, University Hospitals Case Medical Center is home to some of the most prestigious clinical and research centers of excellence in the nation and the world, including cancer, pediatrics, women's health, orthopedics and spine, radiology and radiation oncology, neurosurgery and neuroscience, cardiology and cardiovascular surgery, organ transplantation and human genetics. Its main campus includes the internationally celebrated Rainbow Babies & Children's Hospital, ranked among the top hospitals in the nation; MacDonald Women's Hospital, Ohio's only hospital for women; and Ireland Cancer Center, part of the NIH-designated Case Comprehensive Cancer Center.