Originally published in the Fall 2018 issue of Act Against Cancer.
Kirsten Limesand, PhD, professor of nutritional sciences in the University of Arizona College of Agriculture and Life Sciences, never expected to study dry mouth for a living, but she’s happy with where her career path has taken her.
As a graduate student, Dr. Limesand explored how insects transmit viruses from one host to another — work that involved dissecting mosquitoes’ salivary glands. She cites that skill as one of the biggest reasons she landed a job investigating saliva production. If their new hire could dissect a mosquito salivary gland, the reasoning went, she would have no trouble dissecting a mouse salivary gland. It turned out to be a permanent gig.
“The more time I spent with the project, the more it was clear to me that this was a great research niche,” Dr. Limesand recalls.
Most of us have experienced temporary symptoms of dry mouth, but for head-and-neck cancer survivors who have completed chemoradiation, it could be a permanent part of life, bringing a collection of unpleasant symptoms along for the ride.
“Most people don’t think about saliva being important — until you don’t have it,” says Dr. Limesand. “It’s like living in the desert in July all the time.”
Saliva contains proteins that kick-start the digestion process and protect our teeth and gums. It moistens our mouth and makes food easier to swallow. Without it, meals may lose their luster and oral health can take a nosedive.
“Foods, especially those that are dry — bread, meat — become difficult to eat,” says Panayiotis Savvides, MD, PhD, MPH, section leader for the UA Cancer Center Head and Neck Program and medical director of the Clinical Trials Office at the UA Cancer Center in Phoenix. “They have to modify their diet to be able to swallow.”
“Eating is no longer pleasurable,” adds Dr. Limesand. “If I have a mouth full of canker sores and have to go to the dentist all the time so I don’t lose my teeth, life is pretty miserable.”
Although no cure exists for post-chemoradiation dry mouth, treatments are available, including oral lubricants, saliva substitutes and saliva stimulants, but they cannot fix the root cause: a damaged salivary gland.
“Many patients are being cured — but they always have a water bottle with them,” says Dr. Savvides. “If we cannot solve their problem, we feel powerless.”
Cleaning up the mess
The United States is in the midst of a head-and-neck cancer epidemic, and the patient profile has shifted from heavy drinkers and smokers to younger people whose cancers were caused by human papillomavirus (HPV). While an epidemic is bad news, the good news is that these patients have a better prognosis.
“Most people don’t think about saliva being important — until you don’t have it.”
“On average, they are younger, healthier — because they’re not smokers — and they respond better to treatment,” says Dr. Savvides. “They are expected to live 30 or 40 more years, so the long-term side effects are important. It’s a bigger issue than if you’re treating an 80-year-old whose life expectancy is five years or so.”
Patients usually are treated with a combination of chemotherapy and radiation — chemoradiation.
“The typical treatment with radiation is done daily, Monday through Friday, for almost six-and-a-half weeks,” Dr. Savvides says. “As they accumulate more radiation, one of the long-term side effects is a reduction in saliva production. For some patients, it lasts the remainder of their life.”
Although radiation is crucial for destroying tumors in the head and neck, the salivary gland may be an innocent bystander. Over the course of treatment, it absorbs more and more radiation, and the closer it is to the tumor site, the more damage it sustains. After treatment, a salivary gland might lose its ability to produce saliva or manufacture its protective proteins.
Fortunately, UA Cancer Center researchers are devoted to finding a cure for post-chemoradiation dry mouth — and hope they have struck gold in the form of a drug called everolimus, which already is used to treat other types of cancer.
Although previously approved by the FDA for its tumor-suppressing properties, everolimus could have another function that would help head-and-neck cancer survivors. It might activate autophagy, which Dr. Limesand describes as “a cellular recycling process.”
Autophagy breaks down damaged components of cells and misfolded proteins, clearing the way for the body to rebuild itself in the wake of injury. Radiation, however, is thought to obstruct autophagy, leaving a damaged salivary gland unable to clean up the mess and “reopen for business.” Dr. Limesand found that a drug called temsirolimus, a “sister compound” of everolimus, activates autophagy in mice, leading to restored salivary function. She hopes clinical trials in humans will show that everolimus can “send the damaged tissue down the road to heal itself.”
Testing the hypothesis
Clinical trial participants receive excellent care from their physicians, who know they have to be extra vigilant in monitoring their patients’ treatment.
“When we use standard of care, we have a lot of experience using the drug,” says Dr. Savvides. “In clinical trials, that experience can be very limited. We have to be a lot more thoughtful and be prepared for surprises.”
Many investigator-initiated trials at the UA Cancer Center are funded by the Clinical Research Oversight Council (CROC). Helmed by a team of experienced UA Cancer Center scientists, CROC is responsible for evaluating the merit of research proposals and divvying up resources to support them, and is funded in part by donors.
“It’s difficult to secure funding,” says Dr. Savvides. “We received the drug free of charge from the company, but having seed money from donors allows these concepts to move forward.”
Thanks to CROC support and gifts from donors, Dr. Limesand’s laboratory-driven hypothesis will be tested in the clinic. Dr. Savvides designed and recently opened the trial at the UA Cancer Center in Phoenix. It is a pilot study, formally known as a “phase zero” clinical trial, and will enroll only 10 to 16 patients.
“It’s a proof of principle,” Dr. Savvides explains. “We want to show that everolimus does what we think it’s going to do.”
One of the advantages of investigating alternative uses for an FDA-approved drug is that there are already piles of toxicity data, allowing the team to skip phase I testing. After the pilot study, if they receive positive results, researchers will advance to phase II trials.
“If everolimus had not already been approved for humans, it would have had to go through extensive regulatory and experimental processes before we could start testing it to see if it could restore salivary function,” Dr. Savvides says. “That process could take five years or more.”
The team will measure both volume and composition of participants’ saliva, using a suction tube inserted into the mouth — “very similar to when you go to the dentist,” Dr. Limesand says. The first measurements will be taken before patients start chemoradiation and will be tracked throughout treatment. Afterward, participants will take everolimus for five days, and investigators will see if saliva production bounces back.
In addition to stimulating the production of more saliva, the researchers hope it will improve the composition of saliva.
“Composition plays a major role in how dry these patients feel,” says Dr. Limesand. “If you have proteins to protect from cavities, but not the proteins that moisten the oral cavity, you are going to feel dry even though you have sufficient production.”
The UA Cancer Center is uniquely poised to bring cutting-edge science to patients.
“One of the most exciting aspects of oncology are the major improvements we have seen in our everyday practice,” Dr. Savvides says. “There is constant improvement, and sometimes it’s dramatic. For those of us who have seen the struggles of cured patients, being able to decrease the magnitude of the problem, or completely eliminate it, is inspiring.”
Forging more partnerships
Today, head-and-neck cancer survivors with post-chemoradiation dry mouth have no good options to restore salivary function. Unlike loss of appetite and hair loss, dry mouth might not be a well-known side effect of cancer treatment, but to these patients, the condition is life altering.
“I periodically receive emails from patients,” Dr. Limesand says. “If I weren’t already fully vested before, feeling their angst coming through the text is a good reminder every single day of the need to do something about this problem, because very few options are available.”
Research that addresses unmet patient needs is made possible by UA Cancer Center teamwork. The Clinical Trials Office in Phoenix was launched in 2016, opening a door for collaboration between Tucson and Phoenix. The everolimus trial illustrates how this alliance can make the science stronger and the research faster.
“Some fantastic individuals in Phoenix want to work with us,” Dr. Limesand says. “As the relationship between the two campuses grows, we hope to go to Phoenix more often, even if it’s just going to lunch and talking science. Great ideas sometimes happen on napkins.”
“That interaction is one of the main aspects of a comprehensive cancer center,” Dr. Savvides adds.
By expanding researchers’ pool of potential collaborators, the Tucson-Phoenix partnership builds more links between scientists and clinicians with compatible interests. Dr. Limesand especially values the input she receives from physicians, whose everyday contact with patients helps her “laser in” on research priorities. As a basic scientist, she does not see patients, but she knows improving their lives is the ultimate goal — and a high point of her career is knowing that her laboratory work is being put to the test in the clinic.
“I feel incredibly privileged to witness something that has come from the bench to the clinic,” Dr. Limesand says. “It’s mind-blowing. You almost have to pinch yourself and say it’s real!”