Synthetic Triterpenoids Show Promise in Preventing Colitis-Associated Colon Cancer in Preclinical Study
Researchers from Case Western Reserve and Dartmouth have shown that a class of small antioxidant molecules carries promise for suppressing colon cancer associated with colitis. These preclinical findings, published in the Journal of Clinical Investigation, offer hope that physicians ultimately will be able to dramatically reduce the number of patients with this inflammatory bowel disease (IBD) who go on to develop colon cancer.
The molecules, known as synthetic triterpenoids, appear to achieve their positive effect in two ways. First, they impede inflammation, which often contributes to the development of colon cancer. Second, they increase 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a gene product that at high levels is known to protect against colon cancer. The oral administration of synthetic triterpenoids showed such success in mice that the researchers believe that clinical trials could demonstrate their efficacy in chemoprevention.
Inflammation and Colon Cancer
“Patients with inflammatory bowel disease have a 10-fold greater risk of colon cancer, placing it among the top three high-risk conditions for colorectal cancer,” said senior author and hematologist/oncologist John Letterio, MD, Professor of Pediatrics, Case Western Reserve University School of Medicine, and Director of the Angie Fowler Adolescent and Young Adult Cancer Institute, University Hospitals Rainbow Babies & Children’s Hospital. “Common epithelial cancers develop over a period of years, even decades, in populations at high risk due to genetic predisposition, so chemoprevention strategies could delay, or even halt, onset of clinically evident colon cancer,” he added.
“We have been intrigued by recent findings that inflammatory cytokines, such as TNF-alpha, hinder the expression of 15-PGDH,” Dr. Letterio said. “We found that triterpenoids could reverse the inflammatory process by allowing 15-PGDH expression to resume. Triterpenoids also impede expression of the cyclooxygenase-2 (COX-2), an enzyme known to fuel inflammation. Between reversing the effects of TNF-alpha and of COX-2, this class of small molecules might suppress colitis-associated colon cancer.”
Study Details
In mice genetically engineered to be prone to inflammation-driven intestinal neoplasia, orally administered triterpenoids increased the survival of the mice. Triterpenoid molecules also suppressed intestinal epithelial neoplasia by decreasing production of inflammatory mediators and increasing expression of colon cancer–suppressing 15-PGDH.
Investigators also found that triterpenoids administered to normal mice prevented their development of inflammation and colon cancer, despite their exposure to carcinogens known to cause these two conditions. In addition, they discovered that triterpenoids trigger epithelial cells’ responses to TGF-beta, a signaling pathway known to activate 15-PGDH.
“Two observations are particularly significant in this study,” Dr. Letterio said. “First, our studies in mice demonstrate a cancer chemoprevention effect with triterpenoids. Second, our data also show that the production of 15-PGDH in mice depended on the presence of an intact TGF-beta signaling pathway. This pathway ensures that internal conditions remain relatively constant in intestinal mucosa, both in the regulation of epithelial cell differentiation and development of inducible regulatory T cells to fend off cancer.”
Next Steps
The research team next will focus on assessing the effect of triterpenoids for models of IBD and colon cancer that are not related to colitis. Investigators also plan to explore whether natural triterpenoids with similar properties to synthetic triterpenoids might offer a comparable benefit.
“The argument is strong for pursuing human trials in cancer chemoprevention with triterpenoids,” Dr. Letterio said. “There are many questions about safety, efficacy, intermittent vs continuous administration, and synthetic vs natural triterpenoid. Carefully designed clinical trials and a collaborative approach between industry and academics will be needed to address these questions.”
“Colon cancer is among the most feared consequences of long-term ulcerative colitis,” commented study author Sanford Markowitz, MD, PhD, of Case Western Reserve School of Medicine. “Even with intense surveillance of the colon by colonoscopy and random biopsies, development of cancer is not always caught in time. The finding that synthetic triterpenoids can prevent colon cancer in the mouse model is the first true advance in this field and opens up a novel opportunity for developing new drugs for use in human patients.”
Dr. Letterio is the corresponding author for the Journal of Clinical Investigation article.
The study was supported by grants from the National Institutes of Health.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
