On an early spring morning, Gunther, an unflappable, ginger-colored Terrier mix, pads into an examining room at Tufts University’s Cummings Veterinary Medical Center outside of Boston. Dogs in casts, bandages and plastic cones stream past the room’s open door. Gunther doesn’t seem to care, not even when a large, gray dog passing in the hall lunges through the exam room’s doorway before being reeled back.
Gunther’s owner, contractor Sean Kilcoyne, says the nine-year-old Terrier sleeps on the back of the couch in the sun like a cat, and perches on the middle armrest in his truck as they travel to construction sites. Gunther doesn’t even mind when Kilcoyne’s wife dresses him in costumes, like the mini New England Patriots T-shirt she pulled over his head for the Super Bowl.
It was about then that Kilcoyne noticed a large lump on Gunther’s back, near his tail. It rose almost overnight. By the end of the week, the mound was as big as a half-grapefruit. Their vet had only bad news: the lump was cancerous, a soft tissue sarcoma tumor too large to be removed. Chemotherapy was likely to extend Gunther’s life, but probably only by months. Kilcoyne called his son, who grew up with Gunther. “It doesn’t look good,” Kilcoyne told him, but there was this clinical study at Tufts Medical School they could try.
So, for the past few months, Kilcoyne has brought Gunther to the hospital once a week to receive an experimental treatment. Dr. Cheryl London, a veterinary oncologist at Tufts, is testing a new form of immunotherapy on about a dozen pet dogs with sarcomas. If it works, it could cure Gunther and the other dogs. And if it does that, it might cure people too.
London is one of the pioneers in the growing field of comparative medicine, which looks to our companion animals to find answers to our ailments, from kidney disease to heart failure. Laboratory mice have long been the standard animal model for research, in part because they can be bred quickly and given distinct genetic traits. Yet while that model has produced drugs that cured diseases in lab mice, it has not been nearly as successful in finding cures for humans. More than 80 percent of clinical trials for human patients fail; for cancer, the failure rate is 90 percent. Those studies cost millions, which makes them a huge financial risk for pharmaceutical companies and contributes to the high cost of drug development. That’s why big pharma has retreated from developing drugs for some diseases after multiple trials have failed, London says. Studying disease in pet animals could help change that.
“It’s a win-win for everyone,” London says. “Pets get access to a brand-new therapy, typically at little or no cost. On the human side, we get critical new information.”
There are plenty of reasons why using mice to research human disease is not more successful. The animals are injected with the disease being studied rather than developing it spontaneously. They live in a controlled, sterile environment, and their life span of one to two years is far shorter than the time it takes some humans even to develop a disease. Plus, London points out, mice don’t vomit, so that will never show up as a side effect when testing a drug on them.
Dogs not only are expert vomiters, but also lead lives much more like ours. They share our environment, drinking the same water, breathing the same air. They also share more of our genome than lab mice. Most importantly, like us they get sick spontaneously —the pet dogs in clinical trials are never injected with a disease—and suffer from many of the afflictions that plague humans, from spinal cord injuries to congestive heart failure. They also develop many of the same cancers, including lung, bladder and melanoma, as well as sarcomas.
Soft tissue sarcomas are challenging to treat in dogs and humans. The tumors are often difficult to remove surgically because they grow in problematic locations and can have tentacles that may reach
into joints; chemotherapy often has little effect. London is exploring if a form of immunotherapy might work by trying it on 12 pet dogs with sarcomas.
Jounce Therapeutics, a Cambridge-based biotech that develops cancer treatments, created the experimental approach. The dogs’ tumors are injected with a piece of DNA that, it is hoped, will essentially inspire their immune systems to destroy the sarcomas. If it works in dogs, says Emma Lees, Jounce’s senior vice president of research, it is a good indicator the approach could be used to treat people. Even if the therapy doesn’t work for dogs, London and Jounce may learn something new about the cancer.
The dogs in the study are given an injection of the DNA, and then in the following weeks, are examined for any changes in their health. Abbey Sadowski, a veterinary resident who works with London, takes their vital signs, draws blood and feels their bodies for any new lumps or swollen lymph nodes. The treatments are free. Owners are warned that there could be side effects, but so far, none of the dogs have had any.
Of the pets in the study, Gunther has had one of the most positive responses. After two injections, his sarcoma was hard to see. Sadowski had to pinch the edges with her fingers so she could measure it. She and London thought it might be small enough to remove surgically. To be sure, the Terrier was anesthetized, and his still body disappeared into a CAT scanner. As it whirred, what’s inside Gunther became visible, and the cancer’s secrets were revealed. The sarcoma was like an iceberg: there was far more of it below the skin line, so surgery was still out of the question. They decided to try a third round of the treatment on the Terrier.
Though London became a vet because she loves animals, now she spends most of her time in labs in downtown Boston, analyzing data or talking on the phone or sitting in meetings. But she can help more animals this way, and also humans, a prospect she never considered years ago when she decided to become a veterinarian. After vet school at Tufts, she joined a private practice in Kennebunkport, Maine. There, she far too often had to break the bad news to pet owners that their dog had cancer. She had little hope to offer. Though cancer is the leading cause of canine death, there are relatively few effective treatments even now. Back then, the primary “treatment” was euthanasia. That set London on a mission. She returned to school to study veterinary oncology at the University of Wisconsin–Madison, and followed that with a doctorate in immunology from Harvard.
It was at Wisconsin in the early ’90s that London first heard about comparative medicine. Veterinarians believed clinical studies with companion animals could inform human medicine, and vice versa. But doctors and pharmacological companies were far less convinced. Even the medical doctors who saw the link didn’t see a practical way to carry out clinical trials with pet dogs, says Dr. George Demetri, director of the Center for Sarcoma and Bone Oncology at Dana-Farber. It was hard enough to get humans to sign up for drug studies.
Then London and other research veterinarians began to change minds. In 2000, when London was an assistant professor at the University of California–Davis, she ran a study on mast cell cancer in dogs. Research in humans and mice had found a specific genetic mutation in mast cell tumors, a type of white-blood-cell cancer rare in people but common in dogs. London’s study found that dogs also had the genetic mutation. Her team went on to help create Palladia, a drug to treat mast cell tumors in dogs, and the first cancer drug specifically approved for dogs. The research also contributed to the development of Sutent, a drug for kidney cancer in humans. Pfizer brought both to market. London went on to study a compound for dogs with lymphoma, which yielded Verdinexor for dogs, now in Phase 2 clinical trials, and informed work on Selinexor for human lymphoma, also in trials.
In the past 10 years, the number of comparative clinical trials has ballooned. There are programs at Tufts, the University of Pennsylvania, Ohio State University, Colorado State University and University of California–Davis, among others. Most studies enroll dogs, though cats are also studied. Many of the programs at veterinary colleges have formalized relationships with human medical research institutions, as Tufts does with Dana-Farber. Though a wide range of diseases is being studied, from the canine equivalent of Alzheimer’s to skin diseases, the bulk of the research is focused on cancer. That’s because early on, veterinarian oncologists saw how veterinary research could inform human research and vice versa, says Dr. David Vail, who designs comparative clinical trials at the University of Wisconsin–Madison, where the use of advance radiation machines was first tested on pet dogs with nasal tumors.
Dr. Cheryl London shares a moment with her patient named Drambuie. His participation in a clinical trial saved him from cancer.
The trend has also been reinforced by the National Cancer Institute (NCI), the federal agency charged with researching cancer in humans, which threw its weight behind comparative oncology starting in 2003. The NCI both provides research money and runs a network of academic research institutes across the country to share information from comparative clinical trials. “It’s an extraordinary time,” says Demetri of Dana-Farber. “We can fundamentally change how we look at developing drugs in people.”
This is equally good news for dogs, according to Dr. Nicole Ehrhart at Colorado State University’s Flint Cancer Center, who studies how to save the limbs of dogs and children with osteosarcomas. Treatments for these cancers can cost in the tens of thousands of dollars, but by participating in the trials, owners can get them for their pets for free. And, finally, diseases in dogs are drawing more research dollars.
“We can continue the fight to find cures,” says Ehrhart. “We can push the envelope.”
In London’s study at Tufts, all the dogs have had different responses to the experimental treatment. Some had no real response, though their tumors quit growing, which is still a kind of progress. One dog’s tumor vanished altogether. Gunther has had the next best reaction, though the sarcoma still lurks inside him. For his third injection, Sadowski used an ultrasound machine to place the needle much deeper. That had no noticeable effect. Though all that’s left on his back is a kind of dimpled outline to the tumor, on the inside, the tumor has changed little.
In June, the Terrier was given two more injections, again using ultrasound to guide the needle far into the tumor. And then Sadowski and London waited to see if that worked. London says she will give Gunther the injections until the Terrier’s tumor shrinks enough to be removed or stops responding.
Whatever happens, London will have learned something about the therapy or about sarcomas that may help both dogs and humans in the future. For now, though, the most immediate question is, will it help Gunther?