Protein analysis uncovers new targets for improving immuno-oncology in colon cancer

Over the past decade, oncology research has ushered in tremendous advances in the understanding of genes that can mutate and cause cancer. But what, exactly, is going awry with those genes that leads to this destructive disease process? A new analysis focusing on 8,000 proteins involved in colon cancer could provide some answers to that question—and new targets for treating the disease.

Researchers led by Pacific Northwest National Laboratory (PNNL) analyzed genes and proteins in tissue samples from colon cancer patients, comparing diseased tissue to samples from adjacent healthy tissue. They zeroed in on proteins that are regulated by kinases, which regulate the location and duration of protein activation in the body. Their findings could improve the development of immuno-oncology treatments for colon cancer, they reported in the journal Cell.

“Our data revealed a surprising relationship between enzymes of metabolism and immune cells in some colon tumors, which presents a new opportunity to improve immunotherapies,” said co-author Daniel Liebler, professor of biochemistry at Vanderbilt University, in a statement. The research team included Vanderbilt, Baylor University and the National Cancer Institute.

Specifically, the team discovered that the process by which cells create energy, called glycolysis, is impaired in tumors that are microsatellite instability (MSI) high. These tumors have a genetic defect that interferes with the ability of cancer cells to repair their DNA, making them resistant to standard treatments. Merck’s immune-checkpoint inhibitor Keytruda is FDA approved to treat MSI-high tumors wherever they occur in the body, but Liebler suggests that another way to attack these tumors might be to block their ability to produce energy.

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Another surprising finding from the PNNL-led study was that the protein retinoblastoma may promote colon cancer. Retinoblastoma has long been considered a cancer suppressor, but the researchers discovered that in colon cancer, the protein prevents programmed cell death. The researchers suggested that future therapies should be aimed at inhibiting CDK, a protein that activates retinoblastoma.

There are CDK inhibitors on the market to treat breast cancer, and some have been tried in colorectal cancer, too, including Eli Lilly’s Verzenio. But Verzenio missed the mark in a phase 3 lung cancer trial, casting doubt on the drug’s potential in other indications. Pfizer is cosponsoring a combination trial of its CDK inhibitor, Ibrance, in colon cancer.

The researchers from PNNL, Vanderbilt and their colleagues hope their new study will uncover other promising targets for treating colon cancer.

“Colon cancer-associated proteins … identified from our tumor versus [healthy tissue] comparisons had very little overlap with known cancer genes,” they wrote in the study, “providing a novel information layer to our understanding of colon cancer.” The findings have been stored in publicly available data repositories, they added, and they believe the insights reveal “new therapeutic opportunities for targeting signaling proteins, metabolic enzymes, and tumor antigens in colon cancer treatment.”