Could blocking or deleting a protein help prevent common oral cancers?

27 April 2022
4 min read
Published:

Boston University dental researchers have found deleting or inhibiting a protein in the tongue might stall tumour growth in patients with oral squamous cell carcinoma – the most common form of head and neck cancer.

Patients who are lucky enough to see a dentist early enough have a shot at being able to prevent the lesions from turning cancerous—or can at least make sure treatment starts when it’s most effective. But for those who aren’t that lucky, the outlook can be bleak: the five-year survival rate of oral squamous cell carcinoma (OSCC) is around 66 percent.

According to a news release by Eureka Alert, “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. They say their findings 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. The study was published in February in Molecular Cancer Research.”

Given that 20 per cent of UK adults are not visiting dentists regularly (less than every two years), according to Denplan's 2022 Oral Health Consumer Survey, “the discovery could be a future lifesaver for those who miss out on preventative care”, according to the media outlet.

“These findings have significant implications for new and potentially more effective therapies for oral cancer patients,” says Manish V. Bais, a lead author on the study and SDM assistant professor of translational dental medicine. “This study is an important step toward the development of novel ground-breaking therapies to treat oral cancer.”

Maria Kukuruzinska, SDM’s associate dean for research and a co-author on the study, says it was rare in the past for dental schools to be diving into the science behind head and neck cancers, with most of the research happening in cancer centres. But that’s changing and “dental schools have an advantage over traditional cancer centres when it comes to investigating the science behind the development of OSCC,” she says, “because we can get access to premalignant lesions, where cancer centres basically just see patients who are presenting with fully developed disease.”

Helping the body fight back
Once OSCC takes hold, says Bais, there’s little chance of eliminating it completely. Clinicians can try chemotherapy and radiotherapy, even cutting out a tumour. “But there is no cure – you can shrink the tumour, but not eliminate it,” Bais says.

The news release explains that in previous research, “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, oesophagus, liver, and lung.”

“The expression of this enzyme goes up with each tumour stage. The worse the tumour, the higher the expression of this protein,” continues Bais.

Eureka Alert shares, “In his lab, 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. Bais found that disrupting LSD1 curbed the tumour’s growth.” “The aggressiveness, or bad behaviour, of the tumour went down,” he says. “We found that when we inhibit this protein, it promotes anti-tumour immunity – our body tries to fight by itself.”

According to the news report, “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. Bais says 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,” says Bais.

The media outlet shared, “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. Originally developed to help treat serious eye conditions like macular degeneration, verteporfin is being tested by other researchers as a potential cancer treatment, including in ovarian cancer. The combination proved effective, according to Bais. He also threw a third drug into the mix. Bais says using the LSD1 inhibitor in combination with a common immunotherapy drug that helps white blood cells in the immune system kill cancer cells ‘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,” he says. The work was recently boosted with a new $2.6 million National Institute of Dental and Craniofacial Research grant. “Although our studies are preclinical, restricted to mice and some human tissue, we want to expand to look at human clinical trial samples.”

Human success?
According to Kukuruzinska, Bais’ focus on the biology of oral cancer may also help make the development of other future treatments more efficient.

“People get very excited when you have a drug that may show some positive preliminary results, but very frequently, these studies move forward to humans, cost billions of dollars, and then eventually fail,” says Kukuruzinska, who’s also director of SDM’s predoctoral research program and a professor of translational dental medicine. “If you really understand what pathways, what cell processes are impacted by these inhibitors, then it allows you to predict in advance whether something is going to be successful in human patients.”