Published On Aug 24, 2016
Loose the Hounds
Prized for more than 10,000 years as loyal companions, domestic dogs now also become a powerful ally in the fight against cancer
For years, scientists have been hopeful that a clever use of a protein called interleukin-12 might nudge the body’s own immune system to attack tumor cells. Treatments that harnessed IL-12 initially showed promise in treating melanoma and renal cell carcinoma, a type of kidney cancer.
But dangerous side effects of IL-12 soon came to the fore, and two deaths from the drug in a 1997 clinical trial all but ended human studies. Rather than abandon the promise of the drug, however, scientists affiliated with the National Cancer Institute and other universities developed a new therapy, NHS-IL12. And the compound is being tested not in people, but in dogs.
Dogs are enjoying a resurgence in the world of comparative oncology, which uses other species to help researchers understand cancer. And while many mammals develop cancer—cattle, pigs and sheep, as well as elephants, to name a few—dogs have several advantages for such studies. As companions to humans in all of their many environments, dogs are exposed to many of the same risks that people encounter. And when dogs get cancer, their people tend to notice right away, which means that a wide range of dog cancers are quickly brought to the attention of veterinarians—and biomedical scientists—for further study. And the biology of the cancers in both species can be surprisingly similar. For example, osteosarcoma, more commonly known as bone cancer, is indistinguishable in people and dogs by both microscopic and genetic analysis.
The availability of dogs with naturally occurring skin cancer meant that researchers looking at NHS-IL12 could study its safety and effectiveness in those animals rather than in mouse models, whose cancer must be artificially created. The results of one study using dogs, published last year in PLOS ONE, proved promising enough to launch the first human trial for NHS-IL12, now in its initial stages.
While the popularity of studying dogs to investigate cancer has risen dramatically in the past two decades, interest in this approach began in the late 1930s when Charles Huggins, then a professor at the University of Chicago, studied the prostate gland in dogs to learn about the causes of prostate cancer in humans. Huggins found that naturally occurring hormones in both dogs and humans prompted the growth of prostate tumors, a discovery that led to effective hormone-based therapies and the Nobel Prize in Physiology or Medicine in 1966.
Part of dogs’ appeal as research subjects today is that they may provide more relevant information than laboratory mice. New cancer therapies are required to be tested on mice or rat models before advancing to human clinical trials, according to U.S. Food and Drug Administration guidelines. But cancers in these animals must be artificially induced, and lack key characteristics of human cancers. For example, laboratory mice are bred to have weakened immune systems to allow human tumor cells to grow. They also are missing natural tumor stroma cells, which help support tumors’ growth, and cancers in mice don’t naturally metastasize like human cancers do. Dog cancers, in contrast, develop spontaneously and organically.
“Mouse models alone don't consistently predict the success of a drug when it finally gets into human trials,” says Amy LeBlanc, director of the NCI’s Comparative Oncology Program. A comparative review of cancer drug development in 2009 by the National Cancer Institute speculated that canine studies could save billions of dollars by providing a more reliable indication of how a drug will behave in humans.
And dogs are also helping to identify specific genes that may increase cancer risks. When Matthew Breen, a professor of genomics at North Carolina State University, analyzed the genomes of cancer biopsies taken from dogs with naturally occurring bladder cancer, he found extra copies of chromosomes 13 and 36, deleted copies of chromosome 19, or a combination of these abnormalities. Collaborators at the University of Utah then compared this data with the genomes of 285 human bladder cancer biopsies to identify which aberrations occurred across both species. The scientists propose that these shared aberrations indicate an evolutionarily conserved mechanism with bladder cancer. By performing this analysis, they found that abnormalities in both species involved the gene PABPC1, which they propose should be investigated further.
To help organize all these efforts, the National Cancer Institute manages the Comparative Oncology Trials Consortium (COTC), a network of 22 academic comparative oncology centers that design and execute clinical trials for dogs with naturally occurring cancers. COTC helps to build partnerships among drug developers, veterinarians, clinicians and oncology researchers.
And humans aren’t the only ones who benefit from this research. Veterinarians currently use several human cancer drugs to treat canine cancers and many comparative oncology trials also provide valuable insights regarding potential new treatments for dogs.
“Cancer is cancer, regardless of the species,” says Rodney Page, a veterinarian and professor at Colorado State University. Page also directs the Flint Animal Cancer Center at Colorado State University, where researchers developed a successful treatment for bone cancer in dogs that is now being used as an experimental therapy in humans with osteosarcoma.
“Dogs suffering from cancer are our patients,” says Page. “Hopefully they are going to provide better answers to the cancer puzzle for both humans and dogs in a faster time frame.”