June 11, 1999

Grant paves way to probe aspirin as cancer preventer

Grant paves way to probe aspirin as cancer preventer

The National Cancer Institute has awarded a multi-disciplinary group of scientists in the Vanderbilt-Ingram Cancer Center a major grant to learn more precisely how aspirin and similar drugs may play a role in preventing colon cancer.

The "chemoprevention" program project grant will provide more than $1 million during the first year, with an additional $4 million in support recommended over the next four years. In addition to the amount of financial support it provides, the grant is significant because it is the first to the VICC to be specifically earmarked for cancer prevention research. It is also among the first awarded by the NCI to support this kind of basic cancer research into so-called chemoprevention, the design of drugs to prevent cancer rather than treat it.

"This program integrates a lot of different but related efforts in pathology, surgery, clinical pharmacology, biochemistry and medicine, and it brings a lot of people together," said Dr. Raymond N. DuBois, Mina Cobb Wallace Professor of Gastroenterology and Cancer Prevention and director of the division of Gastroenterology. "This program project funding mechanism by the NCI really puts more expertise into the project."

DuBois will serve as principal investigator and his research group will conduct one of four separate research projects supported in the program. DuBois and his colleagues will continue their work in cell lines and animal models to learn more about how non-steroidal anti-inflammatory drugs (NSAIDs) help prevent the development of colon cancer.

Over the past several years, nearly three dozen studies have been published in the scientific literature documenting a 40-50 percent reduced risk of developing colon cancer among people who regularly take aspirin or other NSAIDs. DuBois and his colleagues' work has focused on the mechanism for that preventive effect, and they have made the link to an enzyme called cyclooxygenase-2 (COX2), one of the primary targets for aspirin and NSAIDs. DuBois and his team have found that COX2 is elevated in colon cancer and have demonstrated in animals that colon tumors will shrink dramatically if treated with drugs that inhibit COX2 activity.

Other researchers in the chemoprevention program are looking at other pieces of the NSAIDS-COX2-colon cancer puzzle. Better understanding of the precise role of COX2 and related biochemical components in the development/prevention of colon cancer is hoped to ultimately lead to development of highly specific drugs to prevent colon cancer, the third leading cancer killer in men and women in the United States.

These scientists include:

— Dr. R. Daniel Beauchamp, John L. Sawyers Professor of Surgery, professor of Cell Biology and director of the division of Surgical Oncology.

Beauchamp and his colleagues are working to better understand regulators that increase levels of COX2 in colon cancer. Specifically, they are focusing on transforming growth factor beta (TGFb) and RAS. They have found that TGFb produces both good and bad signals in the development of cancer – some that suppress tumor growth and others that increase the production of COX2, among others. They also have found that TGFb and RAS have a synergistic effect on the development of colon cancer and that they appear to be collaborators in the increase of COX2 levels.

"If we can learn how this occurs, the hope is that we'll be able to intervene with drugs that would block the increase in COX2 and maybe other 'bad signals' of TGFb," Beauchamp said.

— Dr. Jason D. Morrow, associate professor of Medicine and Pharmacology; Dr. Robert J. Coffey Jr., Ingram Professor of Cancer Research and professor of Medicine and Cell Biology; and Dr. John A. Oates, Harvey Branscomb Distinguished Professor.

Their collaboration focuses on the role of a group of prostaglandins, cyclopentenones, in the growth of colon cancer cells. These prostaglandins are produced by COX2. The group uses mass spectrometry to characterize the chemistry of these prostaglandins and then links that data with information about their metabolism and biologic activity, Morrow said.

"This is a unique union that couldn't really happen anywhere except Vanderbilt," Morrow said. "Most centers don't have this capability. The other unique feature of this program is that it melds into one common theme a strong group of researchers that might not otherwise collaborate. For instance, before this, Dr. Coffey was interested in colon cancer but not prostaglandins. I was interested in prostaglandins, but not colon cancer."

— Lawrence J. Marnett, Ph.D., Mary Geddes Stahlman Professor of Cancer Research and associate director of research programs for the VICC.

Marnett and his colleagues are trying to better understand a byproduct of COX2, malondialdehyde (MDA), which is capable of damaging DNA.

"We're interested in the possibility that once colon cells undergo the conversion to producing too much COX2, the production of MDA in turn causes more DNA damage," Marnett said. The group uses a highly sensitive method to measure MDA-caused DNA damage in benign and malignant tissue samples and will study the impact of COX2 inhibitors on that process.

The NCI grant also supports a core facility to provide chemical analysis of prostaglandins, which will be directed by Morrow, and a tissue collection and analysis core facility, directed by Dr. Mary Kay Washington, assistant professor of Pathology.