Colon cancer cells

Researchers lead team in discovering possible approach to slow growth of certain colon cancers

The body’s most common amino acid just may provide a path to slow the growth of certain colon cancers.

Researchers at the Case Western Reserve School of Medicine led an international team in demonstrating that depriving certain kinds of colorectal cancer cells of glutamine suppresses the ability of such tumors to develop and expand.

In a study published online in Nature Communications, the scientists demonstrated that colorectal cancer cells containing a genetic mutation, called PIK3CA, are susceptible to an intervention targeting glutamine.

“In layman’s terms, we discovered that colon cancers with PIK3CA oncogenic mutations are addicted to glutamine, a particular nutrient for cancer cells. We also demonstrated that these cancers can be starved to death by depriving glutamine with drugs,” said Zhenghe John Wang, professor of genetics and genome sciences, co-leader of the GI Cancer Genetics Program at the Case Comprehensive Cancer Center and a key leader of the study. “We also demonstrated that these cancers can be starved to death by depriving glutamine with drugs.”

The National Cancer Institute (NCI) reports that colorectal cancer is the fourth most common cancer in the U.S., responsible for about 8 percent of all new cancer cases and 8.3 percent of cancer-related deaths. In 2016, the NCI estimates, more than 49,000 people will die from colon cancer and more than 134,000 will be diagnosed with the disease.

Studies indicate the PIK3CA mutation is present in between 10 and 25 percent of colorectal cancers, and also is found in several other forms of disease, among them breast, liver and ovarian cancer.

The team of scholars, which included several from Case Western Reserve as well as scientists from Johns Hopkins University, Israel and China, focused squarely on colorectal cancer.

They approached the work in two phases. First, they wanted to understand how colorectal cells processed glutamine, an amino acid that can assist with digestion, immunity and muscle growth. The researchers found that colorectal cells with the PIK3CA mutation broke down significantly more glutamine than cells without the mutation—which meant that cells with PIK3CA present needed significantly more of the amino acid that the others.

With that knowledge in hand, the researchers proceeded to explore how to lower the amount of glutamine available to those cancer cells. They applied a specific compound, aminooxyacetic acid, known for its ability to inhibit activity and processes of several enzymes. After experiencing success in laboratory tests, they repeated the process in mouse models—and again the approach suppressed tumor growth in the cells with the PIK3CA mutation. Colorectal cells without the mutation did not experience the same effects.

“This study provides the basis for a colon cancer treatment clinical trial that will be started in the summer at the University Hospitals Seidman Cancer Center,” according to Neal Meropol, the Dr. Lester E. Coleman, Jr. Professor of Cancer Research and Therapeutics at the School of Medicine and chief of Division of Hematology and Oncology at UH Case Medical Center.

This clinical trial will be led by Jennifer Eads, Neal Meropol and Alok Khorana.

The study, titled “Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer” and published online June 20 in Nature Communications, was an international collaboration between researchers at Case Western Reserve University, Johns Hopkins University, and Hathaway Brown School (United States); The Weizmann Institute of Science (Israel); and Wannan Medical College, Third Military Medical University, and Suzhou Health College (China). Financial support was provided by National Institutes of Health grants R01CA196643, R21CA160060, R21CA181859, R01CA127590, P50CA150964 and P30 CA043703 (to Z.W.) and R37-DK060596 and R01-DK053307 (to M.H.).