Three Major NIH Grants for Defeating Colorectal Cancer

July 30, 2018—(BRONX, NY)—Among cancers affecting both men and women in the United States, colorectal cancer ranks second only to cancer of the lung and bronchus as the leading cause of cancer-related death. Each year more than 140,000 Americans develop colorectal cancer, and more than 50,000 die from it.

Winfried Edelmann, Ph.D. and Leonard Augenlicht, Ph.D.Some cases of colorectal cancer result from an inherited genetic susceptibility. But for well over 80 percent of people who develop the disease, studies involving human populations and animals show that diet strongly influences whether colorectal cancer will occur and whether it will progress. Intestinal tissue comes into direct contact with numerous dietary components over many years.

The National Institutes of Health has awarded Leonard Augenlicht, Ph.D., professor of medicine and of cell biology at Albert Einstein College of Medicine and director of the Albert Einstein Cancer Center’s Biology of Colon Cancer Program, three new grants totaling $7.1 million to further study how diet influences colon cancer.

Researchers know that intestinal stem cells—vital for maintaining intestinal tissue—can undergo malignant transformation leading to colon cancer. In previous studies, Dr. Augenlicht showed that feeding mice a Western-style diet that includes higher-fat and lower fiber profoundly alters the differentiation of intestinal stem cells and  their energy metabolism. He has hypothesized that these and other diet-induced changes he has observed in intestinal stem cells can turn specific stem cells into cancer stem cells.

With two five-year NIH grants of $2.5 million and $1.5 million (1RO1CA229216-01 and 1RO1CA214625-01A1), Dr. Augenlicht will study how feeding mice the higher-risk Western-style diet (as well as specific nutrients), influences the function of different kinds of stem cells in intestinal tissue. This research may identify markers for detecting elevated cancer risk and the underlying mechanisms that lead to tumor development, and it may also influence how nutrients are tested for their ability to either cause or prevent colorectal cancer.

The third grant, for $3.1 million over five years (1RO1CA222358-01A1), will allow co-principal investigators Augenlicht and Winfried Edelmann, Ph.D., along with co-investigator Matthew Gamble, Ph.D., to study colorectal cancer associated with Lynch syndrome (also called hereditary nonpolyposis colorectal cancer). Dr. Edelmann is a professor of cell biology and of genetics and the Joseph and Gertrud Buchler Chair in Transgenic Medicine, and Dr. Gamble is an associate professor of molecular pharmacology and cell biology.

Lynch syndrome occurs because people inherit mutations in one of their two copies of MSH2 or other genes in the mismatch DNA repair pathway—a crucially important pathway for repairing DNA replication errors. People with Lynch syndrome (about 150,000 Americans are affected) have up to an 80 percent risk of developing colorectal cancer during their lifetimes.

Dr. Edelmann has developed a new mouse genetic model of Lynch Syndrome that mimics the genetic and dietary influences of the human disease. The MSH2 gene was inactivated in cells lining the intestine, and another gene, TgfβRll, was engineered to be targeted for defective DNA repair. Drs. Edelmann and Augenlicht found that feeding the animals a Western-style higher risk diet strongly influences tumors to develop in the colon, just as in humans.

With the new grant, Drs. Augenlicht, Edelmann and Gamble will study genetic and dietary interactions in this Lynch syndrome mouse model. The researchers will investigate how those interactions affect signaling and regulatory pathways in intestinal stem cells, which are known to initiate colorectal cancer by transforming into cancer stem cells. They will also look for aberrant stem-cell signaling pathways that cause normal intestinal tissue to progress to invasive tumors that can metastasize, and they will look for ways to reverse those pathways involved in cancer initiation or progression. Findings from this research could lead to advances in detecting, preventing and treating Lynch syndrome in particular and colorectal cancer in general.

Posted on: Monday, July 30, 2018