Around one-third of people with oral squamous cell carcinoma don’t survive it, but US dental researchers have found deleting or inhibiting a protein in the tongue might stall tumour growth.
Researchers at Boston University’s Henry M. Goldman School of Dental Medicine have found that dialling back—or even genetically deleting—a protein that seems to spur the cancer’s growth might help limit a tumour’s development and spread.
Their findings—published in Molecular Cancer Research—make the protein, an enzyme called lysine-specific demethylase 1, a potential “druggable target”—something that doctors could aim chemo and immuno-oncology therapies at to take down a tumour.
“These findings have significant implications for new and potentially more effective therapies for oral cancer patients,” lead author Dr Manish Bais said.
In previous research, Dr Bais had found that lysine-specific demethylase 1 (LSD1)—an enzyme that typically plays a crucial role in normal cell and embryo development—goes out of control, or is “inappropriately upregulated”, in a range of cancers, including in the head and neck, as well as those in the brain, esophagus, liver, and lung.
“The expression of this enzyme goes up with each tumour stage,” Dr Bais said. “The worse the tumour, the higher the expression of this protein.”
In his lab, Dr Bais began testing what would happen to tumours in the tongue if LSD1 was blocked. To restrict the enzyme, the researchers either knocked it out—by manipulating genes so LSD1 is effectively switched off—or used a type of drug called a small molecule inhibitor, which enters a cell and impedes its normal function. Already in clinical trials for treating other cancers, small molecule inhibitors haven’t previously been tested against oral cancer. The team found that disrupting LSD1 curbed the tumour’s growth.
“The aggressiveness, or bad behaviour, of the tumour went down,” Dr Bais said. “We found that when we inhibit this protein, it promotes anti-tumour immunity—our body tries to fight by itself.”
But LSD1 isn’t the only troublemaker in the tumour: when it’s upregulated, it messes with a cell communication process—the Hippo signaling pathway-YAP—that normally helps control organ growth and tissue regeneration. YAP, LSD1, and a couple of other proteins then get stuck in a vicious cycle, each one pushing the other into increasingly aggressive and harmful moves.
“We need to break this cycle,” Dr Bais said.
To find a new way of doing that, the researchers coupled the effort to inhibit LSD1 by targeting YAP with a different inhibitor, a drug called verteporfin. The combination proved effective. Thew researchers also threw a third drug into the mix. Using the LSD1 inhibitor in combination with a common immunotherapy drug that helps white blood cells in the immune system kill cancer cells—an immune checkpoint inhibitor called anti-Programmed Death 1 ligand antibody—showed a favourable response.
“Our findings provide a basis for future clinical studies based on the inhibition of LSD1, either as monotherapy or in combination with other agents to treat oral cancer in humans,” Dr Bais said.