Could Fido Fetch A Cure?

When Mike and Lois Wirtel woke one Saturday morning to find their dog’s neck swollen behind his ears, they thought something must have bitten him. After all, Moses, a six-year-old black Labrador retriever, spent most of his time outside—chasing squirrels and playing with his three canine siblings on the Wirtels’ rural land outside of Moscow Mills, Mo.

So they were shocked when their veterinarian told them Moses’s swollen neck was probably a sign of cancer. Like many owners of the approximately 4 million dogs diagnosed with cancer in the U.S. each year, the Wirtels were given two options: treat Moses’s symptoms and keep him comfortable or take a biopsy, confirm the diagnosis, and treat him with one of the few cancer drugs available for dogs.

“To me, it’s no different than if I would have had cancer,” says Lois Wirtel, recalling their decision to treat the disease. “It was a no-brainer. He’s a family member.”

The biopsy revealed that Moses had lymphoma. Approved chemotherapy regimens for the disease could give Moses perhaps another year of life. Unsatisfied with that grim prognosis, the Wirtels looked for alternatives.

What they found was a clinical trial at the University of Missouri, where Moses could be treated with a new class of chemotherapy agents called indenoisoquinolines. The veterinary hospital conducting the trial was a 90-minute drive away, but they were happy to go the distance if it meant more time with Moses.

The Wirtels were surprised and pleased to find that Moses might not be the only one to benefit from trying the new drugs. The trial is part of a collaboration between researchers at the nation’s top veterinary hospitals and the National Institutes of Health: the Comparative Oncology Trials Consortium (COTC). The effort recruits “pet parents” to enroll their dogs in clinical trials to test emerging cancer therapies that, if successful, could be used in humans.

The dogs that researchers study are not typical lab rats (or, in Moses’s case, lab labs); they’re patients. Unlike preclinical mouse or rat models, which are engineered to develop cancer, these dogs develop tumors spontaneously—just like we do.

Those passionate about the field of comparative oncology—the practice of studying naturally occuring cancer in animals to discover insights and treatments that benefit both animals and people—claim that running clinical trials on dogs with cancer is a win-win. Trials may save the lives of beloved family pets, while the data collected can be used to inform drug development for human patients.

Although the pharmaceutical industry has long considered whether dogs could be useful models for cancer, it’s only been in the past decade that drug companies have put resources behind these studies. But the concept of Fido as a model for human disease is still finding its footing, and ethical and regulatory challenges abound.

As for the Wirtels, who report that Moses is doing well after a round of indeno­isoquinolines, they are proud to participate. “They informed us right off the bat what this was about and who it would go on to benefit,” Mike Wirtel says. “I lost my mom to cancer, so I think anything that helps everybody out is not a bad deal.”

The Mouse And The Trap

Earlier this summer, cancer experts convened at the Institute of Medicine for a two-day forum where they discussed the possibilities, challenges, and growing momentum of translating cancer research in pet dogs to possible cures in people.

A common theme across many of the presentations was how dogs could be used to help improve the success rate in late-stage cancer drug development. According to the Tufts Center for the Study of Drug Development, the clinical approval rate as of 2013 for cancer drugs was a mere 13%, with many of the failures occurring in Phase II and III clinical trials, when cancer compounds are tested for efficacy in humans (Clin. Pharmacol. Ther., DOI: 10.1038/clpt.2013.117).

A major reason agents fail so late in the game is that animal models of cancer in the lab don’t adequately reflect the complexity of the disease in nature. Tumors—abnormal, rapidly growing masses that grab hold in our tissues—grow their own vasculature, adapt to the body’s defenses and medicines’ assaults, and range in genetic composition from one cell to the next. They’re not easy to re-create.

For now, the gold standard for testing cancer drugs is the mouse xenograft, in which malignant human tissue is transplanted into a mouse. This method exploits the lab mouse’s relative low cost, short life span, controlled lifestyle, and genetic similarity to humans to reliably screen out compounds that may have looked promising in a petri dish but don’t actually shrink tumors in a living animal.

But testing on mice still lets duds slip through. The problem: The implanted tumors just aren’t the formidable opponents researchers are up against in humans. Unlike a complex human tumor, mouse tumors are more likely to be genetically homogeneous—meaning if a drug can kill one cell in a tumor, it’s likely to kill the others. And regardless of the tumor type, the mouse xenograft is placed right on the animal’s back, which is convenient but not where most human tumors occur. For these reasons, cancer in lab mice tends to be deceptively simpler to treat. As late cancer researcher Judah Folkman would tell reporters, “If you have cancer and you are a mouse, we can take good care of you.”

Certainly, the mouse has taught us and will continue to teach us valuable insights about cancer, and few advocates of comparative oncology trials suggest that the dog can take its place. But in dogs with naturally occurring cancers, researchers see an opportunity to make drug development more efficient.

“Big pharmaceutical companies have come to us and said, ‘We want to get more involved in this because we believe that there’s an opportunity for us to succeed if we take this approach and fold it into all the other stuff we do,’ ” says Amy LeBlanc, a veterinary oncologist and director of COTC. She emphasizes that the mouse model will remain an important part of preclinical cancer drug trials. But valuable information gleaned from dog trials can help human trials run more smoothly.

The Mouse And The Trap

Cancer is not merely a human problem. This revelation quickly dawns at a public presentation about comparative oncology. “In the first five or 10 minutes of my presentation,” says North Carolina State University genomics researcher Matthew Breen, “somebody will always raise their hand and say, ‘I’m sorry, but you’re saying that dogs get cancer?’ ”

Indeed they do. Any organism that is multicellular and grows by cell division can have that process spin out of control. And for reasons genetics researchers are just beginning to pin down, some organisms are more likely to develop cancer than others. Dogs are one of them.

After years of inbreeding, certain kinds of dogs develop specific cancers with startling frequency. For instance, golden retrievers—one of the most popular dog breeds in the U.S.—are particularly prone to hemangiosarcomas, a highly invasive cancer of the blood vessels that kills about two in 10 goldens. Likewise, Scottish terriers have an 18- to 20-fold increased risk of developing a certain form of bladder cancer.

Although heartbreaking for owners, the phenomena help researchers such as Breen understand how genetics figure into the development of cancer. And the more genes researchers identify as playing a role in cancer, the more clues they will have to help them find promising drug targets.

At the Institute of Medicine workshop in June, Breen encouraged the crowd to think of dogs and other animals as “rearrangements of the same collection of ancestrally related genes.” “Shuffle the deck,” he said, “and you’re a human being. Shuffle the deck differently, and you’re a dog.”

Dogs have 78 chromosomes, while humans have 46. Despite this difference, dogs are still more genetically related to us than mice, which have 40 chromosomes. In fact, dogs share a majority of our genetic material, a similarity that allows researchers to use the location of a dog’s cancer gene to track down an analogous gene in humans.

For example, cancer experts believe mutations in human chromosome 22 may lead to certain brain tumors. Three sections of the 500-gene chromosome are similar to regions on three separate, smaller dog chromosomes, Breen explained. In 2009, researchers in Breen’s lab found that mutations on only one of these dog chromosomes were likely to cause brain cancer in dogs.

This insight allowed scientists to prioritize research on the 10 genes from the aberrant dog chromosome that the species had in common and let them avoid the task of raking through 500 genes. This approach may save researchers time and money, Breen told the audience at the workshop.

A New Type of Trial

Though many scientists are excited by the opportunities such studies create, participants still need convincing. Proponents have to persuade drug developers that the trials are an innovative solution to their late-stage failure problem. They also must convince dog owners to trust the health of their four-legged friends to a program whose mission is to advance cancer research in humans.

Like any new scientific idea, comparative oncology trials that use dogs as models for human disease need a good sales pitch, according to COTC’s LeBlanc. “You put animals and research in the same sentence, and people have a really visceral reaction to that. We have to make sure people understand what the goals are,” she says. “The intent of our studies is to help advance human health,” she continues, but the data collected in these studies inevitably help experts learn about cancer in both species. And veterinary science could use more information about cancer and other animal diseases for which treatments are sorely needed (C&EN, Aug. 10/17, page 39).

These research goals are explained during a consent process, in which a dog’s owner and a veterinary clinician sit down to discuss the particulars of the trial. LeBlanc concedes that some pet owners don’t like the idea of entering their dog into an experiment and opt for approved treatments instead. Others decide against participating because they prefer not to put their pet through chemotherapy.

But for many, the clinical trials are an appealing option: Participating dogs receive interventions that represent the latest developments in cancer research, the data will ultimately help humans, and—for the most part—expenses are covered.

“We’re not doing things to animals. We’re doing things for animals that will not only benefit them but their pet parents as well as people with cancer and cancer researchers,” says Gerald S. Post, a veterinarian and founder of the Animal Cancer Foundation. “In my mind, there’s nothing morally ambiguous about comparative oncology.”

Pharmaceutical industry executives echo the sentiment. “One of the opportunities that the companion dog model offers is the ability to, in a very ethical way, evaluate the efficacy of a novel therapeutic,” Gilead Sciences Senior Director Daniel Tumas told the audience at the Institute of Medicine.

But even if drugmakers and dog owners are interested, comparative oncology trials can be logistically difficult. Only 22 U.S. veterinary hospitals participate in the program, ruling out the option for owners who live far from a trial site. Those in the field also worry the trials are too under the radar to get adequate support from the human medical community. But with inclusive forums such as June’s well-attended workshop, that’s beginning to change.

Those who have had a good experience with the trials also seem happy to spread the word. “I hope everybody takes part in it. It’s far from a selfish thing,” says Terry Chrudinsky of Davis, Calif. Chrudinsky found out about the trials because his dog, a two-year-old vizsla named Orko, was already being treated by a veterinary center running trials.

An avid mountain climber and biker, Chrudinsky would often take Orko on outdoor adventures. When the young dog began limping on his hind leg, Chrudinsky assumed Orko must have injured his knee racing alongside his owner’s mountain bike.

He says he’s glad he was already sitting on the floor with Orko in his lap when the vet delivered the news: Orko had osteosarcoma, and if he was to have any chance of survival, his leg would need to be removed. “It was pure shock,” Chrudinsky remembers.

Even after the surgery, the cancer spread to Orko’s lungs. Though devastating, the metastasis allowed Orko to qualify for a COTC trial of rapamycin, a compound that has shown promising results in people with osteosarcoma but has not yet been approved to treat the disease. Orko finished out the trial but passed away from his disease in late July.

Knowing there might be beneficiaries—especially young children with bone cancer—from the data Orko helped researchers collect was the one silver lining Chrudinsky took from an otherwise traumatic experience. “His taking part in the study gave me something to focus on,” he says. “It had a very positive effect on me.”