Restoring moisture to the mouth

When someone survives cancer, at first, some of the side effects of treatment might not seem so bad, and the relief of having lived can make the little annoyances seem unimportant. However, as the years progress and surgery scars fade, some reminders of treatment become increasingly detrimental to quality of life. For many of the approximately 340,000 people who have survived head and neck cancer—about 200,000 in all—that reminder is a chronic dry mouth.

In 2016, it is estimated that there will be 48,330 new cases of oral cavity and pharynx cancer in the United States. The 5-year survival rate for this kind of cancer is about 64 percent, and that figure has been on the rise since 2001. Of course, an increasing survival rate is good news. The bad news? Many survivors of this type of cancer struggle with dry mouth syndrome for the rest of their lives as a result of radiation treatment.

Fei Liu, PhD, an associate professor at the Texas A&M College of Medicine, studies what goes wrong with the salivary gland during radiation therapy and what can be done to improve the lives of those affected. “The salivary gland is very sensitive to this damage,” he said. “We can relieve some of the symptoms, but the condition still has a major impact on quality of life. Cancer survivors have to carry water with them everywhere just to be able to speak, and they’re often woken in the middle of the night due to lack of moisture in their mouths, affecting their sleep.”

Liu and his team are taking a three-pronged approach to solve the problem of dry mouth syndrome after cancer treatment. First, he’s shown that activating a particular signaling pathway can improve salivary gland function if it is done soon enough after the radiation treatment. The body can recover from obstructive damages to the salivary gland by activating this pathway, called Hedgehog, which regulates adult stem cells to repair tissues after injury. However, it seems that radiation damages the cells and their microenvironment (the stem cell niche) too much for the activation to happen naturally, which is where Liu’s work comes in.

Thus far, Liu’s seen success in small animal models. “If we treat the problem shortly after radiation with a non-invasive local gene therapy to activate the Hedgehog pathway briefly in salivary glands, we can restore their function to about 40 to 60 percent of what is considered normal in a healthy individual,” Liu said. “It’s not perfect, but anything more than 50 percent is good enough to eliminate most dry mouth symptoms and greatly improve quality of life.” The next step will be to test such gene therapy in large animal models and to improve the method’s effectiveness by better understanding and boosting the downstream beneficial effects of Hedgehog signaling in irradiated salivary glands.

The second method of restoring function is related to the first, but it involves using adult stem cell products to deliver genes or proteins into salivary glands. “They can be thought of as a kind of natural nanoparticles,” Liu said. “These products are more tolerable and much safer than viral vectors commonly used for gene therapies.” In addition, these products themselves can promote tissue repair and alleviate radiation damage of salivary glands to some extent.

Finally, in a third approach, Liu and his team have had some success repurposing old, already approved drugs, to treat dry mouth syndrome. In this case, blood pressure medications might turn out to be an important piece of the puzzle, as they have shown some success in relieving radiotherapy damage in other organs and also target molecules related to such damage in salivary gland.

“I’ve had patients write me directly and ask how my research is going and if there are clinical trials,” Liu said. “Repurposing already-approved blood pressure drugs, in combination with gene therapy, may be the best approach, but there’s still more work to be done.”