University of Illinois researchers have 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 APCgene, which is common in colorectal cancer, have elevated levels of cholesterol on the inside of their membranes. By inhibiting 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 University of Illinois Chicago and senior author of the paper.
Collaborators from the School of Molecular & Cellular Biology at Illinois included Associate Professor of Molecular and Integrative Physiology Erik Nelson and Emad Tajkhorshid, J. Woodland Hastings Endowed Chair in Biochemistry. Nelson and Tajkhorshid are also members of the Cancer Center at Illinois.
“We have been aware of clinical associations between cholesterol and different cancers for a while, but we do not understand how cholesterol is driving cancer. This study shows that cholesterol accumulating on the inside of a cell membrane can directly activate signaling molecules known to drive cancer progression,” Nelson said.
Colorectal cancer is the second most common cause of cancer death in the United States. Unlike some cancers, the incidence of colorectal cancer in patients under 55 is increasing. Yet effective treatment for later stages of the disease remains elusive.
An estimated 80 percent of colorectal cancer tumors contain a 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 and growth.
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,” Cho said.
“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.
Tajkhorshid and team used computer modeling to discover exactly how cholesterol interacted with proteins in the Wnt pathway, and then predicted where to block these interactions – a critical first step towards drug development. Nelson and team were able to take the putative drug candidates developed by Cho and test them in animal models bearing colorectal tumors.
“Several years ago we recognized that in order to figure out how cholesterol was influencing cancer and how we might be able to intervene therapeutically, we were going to have to assemble a team with expertise from molecules to humans,” Nelson said.
For this study, Emad Tajkhorshid provided expertise at the molecular scale. Wonhwa Cho led the study and provided biochemical and chemical expertise. Stephanie Cologna a chemistry professor at UIC, was able to use techniques to quantify cholesterol and the new molecules. Nelson assisted in testing new molecules in animal tumor models.
“We believe that this is the first in what will be several collaborative breakthroughs,” Nelson said.
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.
“Our goal is to develop several approaches to treating cancer. That way, patients and their care teams can select the treatment that works best for them and their tumors. We hope that this new molecule and others in development will add to the library we can choose from," Nelson said.
In addition to Nelson and Tajkhorshid, University of Illinois Urbana-Champaign authors on the paper include Shruti Vijay Bendra, Hale Siir Hasdemir, Defne Gorgun Ozgulbas, Ruicheng Shi, Erin Weisser, and Bo Wang.
