Dogs that have oral squamous cell carcinomas often need surgeries that disfigure their jaws and lower their quality of life - and in 20% of dogs diagnosed, the cancer has metastasized to a point where surgery is no longer an option.
A team, including Cornell researchers across five departments and institutes, has found that an FDA-approved drug used in humans can be "remarkably effective," researchers said, in treating the cancer, which is the most common oral epithelial malignancy in dogs. The drug substantially inhibited the growth of the tumors in mouse models and in dogs enrolled in a clinical trial. One dog's tumor nearly disappeared in a matter of weeks.
"It's a super exciting clinical tool that we now have available," said Santiago Peralta, associate professor of dentistry and oral surgery in the College of Veterinary Medicine (CVM) and senior author of the study, published Feb. 27 in Scientific Reports. "We are already getting calls and emails from colleagues and from dog owners from all over the world."
The drug, trametinib, targets a downstream component of the RAS signaling pathway, which regulates cell growth and which is implicated in a number of human and animal cancers. Approved for the treatment of melanoma in humans, trametinib has been found to be safe for use in dogs and relatively inexpensive - a month's worth of treatment is around $100 to $200 depending on the size of the dog.
To test the drug, researchers created new cell lines from the tumors of dogs diagnosed in the clinic. They tested a number of therapeutic agents on the cells and then moved to mouse models, where trametinib was particularly effective.
"I've never seen results like that in mice before," said first author and research associate William Katt. "And I was blown away when we saw the results in the dogs - being on a project that made it to the clinic and seeing the tumor nearly vanish in a couple of weeks was delightfully surprising."
At the time the paper was submitted, the ongoing clinical trial had just begun, with only four dogs enrolled; it's now at 20. The researchers included the preliminary data because it was so encouraging. Of the four dogs, only two responded to trametinib, but the response was significant, with one dog showing 80% tumor regression and another 40% regression.
"What we're seeing is that some dogs or some tumors are susceptible to this treatment whereas others are not," Peralta said. "But now with more dogs in the trial, we're seeing several cases where the response is remarkable."
Peralta and others are currently following up to try to understand the divergent tumor responses - research that could shed light on the RAS pathway and have implications across cancers and species.
The original cell lines created for the experiment could also spur more research. Katt plans to add the cell lines to open-access depositories for other researchers' use.
"When you do work on human cancers, there's a huge toolbox to work with," Katt said. "The first thing I did for this study was to look for existing cell cultures out there for these canine cancers, but there was basically nothing. Now that we have them, we hope to make good use of these tools."
Peralta said he doesn't expect trametinib to cure the oral cancers completely, but that it could be used to shrink them before surgery and result in less destructive interventions and improved quality of life.
"There's often this window of opportunity between diagnosis and surgery - treating the dog in this window makes sense because, what if the tumor responds?" he said. "It sets everyone up for success."
Katt emphasized that the research was a team effort leveraging Cornell's strengths and breadth.
"This speaks very positively to what we can do almost entirely in-house," he said, "and to just how much leverage and scientific power we have, with the collective wisdom and expertise and facilities on this campus."
Co-authors of the study include CVM researchers Cheryl E. Balkman, clinical professor of oncology; research support specialists Scott D. Butler and Michael Byron; Patrick C. Carney, assistant professor of community practice service; Amy B. Todd-Donato, assistant professor of diagnostic imaging and radiology; veterinary resident Matthew E. Drozd; Gerald E. Duhamel, professor of anatomic pathology; Jacquelyn M. Evans, assistant professor of biomedical sciences; Nadine Fiani, associate clinical professor of dentistry and oral surgery; senior research associate Jessica J. Hayward; Kelly R. Hume, associate professor of oncology; postdoctoral researcher Elizabeth S. Moore; PATh Project Manager Rishi Puri; Skylar R. Sylvester, assistant clinical professor of medical oncology; lab manager Suzin M. Webb; Andrew C. White, associate professor of biomedical sciences; Alexandra L. Wright, assistant clinical professor of dentistry and oral surgery; and Richard A. Cerione, Distinguished Professor of Arts and Science in Chemistry. Additional authors include Jennifer K. Grenier, director of genomics in the Cornell Institute of Biotechnology; Jordan C. Ford and Sydney L. Warshaw of Prism Veterinary Dentistry in New York City; and Kristiina Keikinheimo of the University of Turku.
The study was supported with funding from the Cornell Richard P. Riney Canine Health Center, the National Cancer Institute and the Maritza and Reino Salonen Foundation.
