Colorectal cancer treated with cholesterol inhibitor in UIC study 

Researchers at the University of Illinois Chicago successfully treated a common type of colorectal cancer tumor with a cholesterol inhibitor drug, demonstrating a promising treatment for the disease in animal experiments.  

The study, published in Nature Chemical Biology, found that cells that have a mutation in the APC gene, which is common in colorectal cancer, have elevated levels of cholesterol on the inside of their membranes. By inhibiting this cholesterol’s activity, the researchers were able to block it from activating cellular pathways that lead to the formation of tumors. 

“We are finally able to control cholesterol-induced cancer progression using the molecule that can block the cellular function of cholesterol, which has never been done before,” said Wonhwa Cho, Distinguished Professor of Chemistry at UIC and senior author of the paper. 

Colorectal cancer is the second most common cause of cancer death in the United States, and diagnoses in patients under 55 are increasing. Yet effective treatment for later stages of the disease remains elusive.  

An estimated 80% of colorectal cancer tumors contain mutation in the APC gene, which in healthy cells helps regulate cell growth and proliferation. The excess cholesterol in cancerous cells with the APC mutation causes improper activity in a process known as Wnt signaling, leading to tumor formation.  

Wnt signaling is involved in many types of cancers, and efforts to combat colorectal and other cancer tumors have often focused on inhibiting it. But Wnt signaling is an important process in healthy cells; it maintains stem cells and regenerates tissue in high-turnover areas like the intestines. That means Wnt-inhibiting drugs have been poorly tolerated in clinical trials. 

“The pharmaceutical industry was very interested in making Wnt-signaling inhibitors for colorectal cancer and other related cancers, but they basically gave up their effort in the past decade largely because of this toxicity problem,” said Cho, who is also a member of the University of Illinois Cancer Center. 

“Many people, including us, believe that we have to find a different approach,” he said. “Our focus has been to understand the cellular function of cholesterol-induced tumorigenesis and to specifically block the process.” 

In their study, Cho and his colleagues pinpointed the location of the excess cellular cholesterol and developed a small-molecule inhibitor that blocks its tumor-promoting functions. They tested it in mice and found that treatment with the inhibitor significantly decreased tumors. 

By precisely inhibiting cellular cholesterol, Cho and his colleagues avoided the problems other studies have faced that inhibit Wnt signaling in all cells.  

“The strength of our new inhibitor is that it only targets colorectal cancer cells with APC mutation, not normal cells. And because of that, our inhibitor shows no detectable toxicity,” Cho said. “That is a potential breakthrough.” 

The team is preparing the molecule for clinical use and developing a version of the drug that can be taken orally. They’ve filed a U.S. patent application for the compound and are in the process of licensing it to biotech companies interested in further developing it. 

In addition to Cho, UIC authors on the paper include Ashutosh Sharma, Julian Zalejski, Simona Kavrakova, Jiachen Sun, Koralege C. Pathmasiri, Ahmed Aloulou, Kyli Berkley, Charles F. Delisle, Young Wang, Pawanthi Buweneka, Dominick Pierre-Jacques, Sayandeb Mukherjee, Daesung Lee and Stephanie M. Cologna.