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For most people, occasional inflammation is an annoying but fleeting fact of life.
A bee sting may cause pain, redness, swelling and perhaps even temporary loss of function at the sting site, but the symptoms usually disappear in a matter of hours or days. That’s the body’s inflammatory response at work, which is part of the healing process.
However, for reasons not entirely understood, some people develop prolonged inflammation. Rather than being beneficial, chronic inflammation has a destructive effect on tissues and can lead to inflammation-related diseases, such as cancer.
“People affected with inflammatory bowel disease are at higher risk to develop colon cancer,” said Emmanuelle J. Meuillet, PhD, a member of the Arizona Cancer Center’s Cancer Biology and Genetics Program and BIO5 Institute.
Dr. Meuillet aims to understand the role of inflammation in colon carcinogenesis and to develop a novel targeted therapy to treat it. A five-year, $1,784,878 grant from the National Cancer Institute will fund her research.
“During the process of inflammation, there are many inflammatory molecules that are produced, and one of them that seems to play a detrimental role in many different types of cancers is called prostaglandin E2, or PGE2,” Dr. Meuillet said. “If it’s out of balance too much, it can induce tumor growth, among many other things. The last enzyme that is responsible for the synthesis of this molecule is microsomal Prostaglandin E Synthase, or mPGES-1, and that’s the one we are focusing on.”
A drug that inhibits mPGES-1 activity could reduce production of PGE2, which is overexpressed in many cancers and inflammatory diseases, and slow – or even reverse – tumor growth, said Dr. Meuillet, who is also assistant professor of nutritional sciences in the UA College of Agriculture and Life Sciences and molecular and cellular biology in the UA College of Sciences. The benefit of developing a drug that targets a specific protein is that targeted therapies usually have fewer side effects for patients than traditional treatments.
The discovery of mPGES-1 a few years ago was important because a previous attempt to control the inflammatory response had negative outcomes. A popular drug known as Vioxx worked to reduce inflammation by inhibiting COX-2, which also plays a role in PGE2 synthesis. However, after the drug hit the market, it was discovered that the products of COX-2 were also involved in cardiovascular function, and the drug had to be recalled due to harmful secondary effects.
Meuillet’s target, mPGES-1, is downstream from COX-2 in the pathway, so the belief is that it won’t cause those secondary effects. However, she isn’t taking any chances. The first step in the grant is to use colon cancer cell lines and inflammatory colon cancer animal models to find clear evidence that mPGES-1 plays a role in colon carcinogenesis and will be a good drug target for the treatment of colon cancer.
“What we’re trying to do is understand the role of mPGES-1 in the process of inflammation in the colon,” she said. “It’s overexpressed in cancer, but its mechanical function, its regulation and its interplay with the stroma and the tumor is not at all known. That’s why this grant is so important, because it involves developing inhibitors to this but making sure also that inhibiting it is not going to be a disaster clinically.”
Dr. Meuillet is optimistic because in an earlier study she conducted, thanks in part to two small Arizona Cancer Center pilot research grants, mPGES-1 appeared to be a good drug target and a particular molecule showed promise as an mPGES-1 inhibitor.
“With the preliminary data we have, we have a lead compound that’s not toxic, that shows very good anti-tumor activity and even regression after the treatment,” she said.
Dr. Meuillet will work with several collaborators in a multidisciplinary effort to perform her translational research. She will work with Daniel W. Rosenberg, PhD, professor of medicine and co-director of the Colon Cancer Prevention Program at University of Connecticut, to investigate the role of mPGES-1 in normal and colon cancer animal models. At the University of Arizona, Dr. Meuillet has enlisted the help of a team of pharmacologists and chemists, and will work with Christopher Hulme, PhD, professor of organic and medicinal chemistry in the Department of Pharmacology and Toxicology, and Vijay Gokhale, PhD, assistant research scientist in the Department of Pharmacology and Toxicology, to identify additional novel compounds that can bind to mPGES-1 and inhibit its activity and to synthesize those compounds.
Finally, Dr. Meuillet’s laboratory will conduct all in vitro and in vivo testing of these compounds in human colon cancer cells and mouse models of colon carcinogenesis. These novel compounds will be used to better understand the role of the enzyme in the early stage of colon carcinogenesis.
Though this grant funds research focused on colon cancer treatment, the findings may have widespread applications. Because the targeted therapy would inhibit a cellular process, it could potentially reduce inflammation for patients with other inflammation-associated cancers, such as inflammatory breast cancer, pancreatitis (which leads to pancreatic cancer) and chronic obstructive pulmonary disease (which leads to lung cancer), as well as gingivitis, rheumatoid arthritis and atherosclerosis.
“It’s not only important for colon cancer,” said Dr. Meuillet. “It’s very important in any inflammation-derived cancer and any disease that starts with an inflammation process. These are all areas that need attention.”
Making slight adjustments to her method would also allow her to investigate potential preventative applications. She’s writing additional grants now to look into ways to prevent inflammatory bowel disease from ever developing into colon cancer and she is working on another gastrointestinal cancer – pancreatic cancer – for which patient outcome remains bleak.
“Dr. Meuillet’s innovative research has the potential to greatly influence future treatment and prevention of cancer,” said David S. Alberts, MD, director of the Arizona Cancer Center.
Dr. Meuillet is excited and nervous about being on the verge of such a potentially powerful discovery. If mPGES-1 is indeed a good drug target, and if the new target therapy works as expected, many patients with many conditions could benefit from her work.
“The impact is huge,” Dr. Meuillet said. “The possibilities are endless.”