Scientists have long used animals in research. According to the National Association for Biomedical Research, “approximately 95 percent of all laboratory animals are mice and rats.” They’re small, but these little critters share many similarities with humans, so researchers use them to model how new drugs may function and how genetics influence the course of disease. They’re often the go-to choice for medical research because they’re easy to care for and they have a short life cycle. They can be bred to be nearly genetically identical in short order.
Research on mice and rats has told us a lot over the years, but they aren’t a perfect model for humans. Particularly when it comes to cancer research, other animals, namely dogs, may offer an even better view into how cancer works and how they could help us one day break the cancer code.
Called comparative or translational oncology, this field is different from traditional animal research in laboratory rodents in a few ways, says Dr. Kristen Weishaar, a veterinarian and clinical trials director at the Flint Animal Cancer Center at Colorado State University in Fort Collins. “When we do research on cancer in mice and rats, those are tumors that are given to those animals,” meaning that tumor cells are injected into the animal and allowed to grow. “We can test drugs and things like that on those tumors,” and that has provided a lot of information, but in comparative oncology, researchers are investigating “spontaneous cancers. These dogs develop these cancers in the same way people do,” naturally over a long period of time with no injection by the researcher to kick it off.
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Looking at these types of cancers in dogs can help shed light on how environmental factors influence cancer development and treatment. “These dogs are living in the same environment as their humans,” Weishaar says. “They’re drinking the same water, oftentimes eating the same food. The similarity between their cancers is going to be a lot more than what we see with mice and rats.”
In addition, “the DNA differences between dogs and people are a lot fewer than what we see between mice and rats and people. They’re a lot more similar genetically to humans than the rodents are to us,” Weishaar says.
Dr. Cheryl A. London, the Anne Engen and Dusty Professor of Comparative Oncology at the Cummings School of Veterinary Medicine at Tufts University in Grafton, Massachusetts and an associate faculty professor in the College of Veterinary Medicine at The Ohio State University, adds that, just like people, “dogs come in different sizes, they’re exposed to different things, they have different comorbidities and their tumors tend to develop over a long period of time. So they add a different landscape in which to evaluate a therapeutic and optimize it.”
The parallels are many, but London notes that “there are some things we simply can’t do in dogs that you can do in mice.” For example, “you can turn genes on or take genes out and put specific mutations in,” when working with mice and rats, which can tell us a lot of things in a tightly controlled setting, but “what you can’t recapitulate in the mouse is the natural history of disease,” or the long, messy time period over which cancer develops based on a variety of factors including environmental exposures and pressures, risk factors and comorbidities. “You can’t really always mirror that accurately in the mouse,” and these models often lack some of the complexity that makes cancer in humans such a difficult puzzle to solve.
“Cancer tends to be noisy. There are a lot of genetic changes in the tumor itself and lots of responses from the microenvironment that can facilitate tumor growth including the immune system itself,” she explains, so “sometimes it’s hard to figure out what’s important versus what’s not important in that noise. One of the things that including dogs in therapeutic development can do is to help identify patterns that are consistent across species that can help cancel out the noise.”
This points back to a fundamental principle of biology regarding consistency in response across species. “We know that in biology, pathways that drive tissue differentiation drive biologic processes all the way from simple worms to humans,” meaning that the way things work in one species is often very similar in another. By reversing that thought process, researchers are looking to figure out which pathways are relevant to tumor development and what controls a patient’s response to therapy, because that “will likely be conserved across species as well.”
Comparative oncology is all about integrating more species into that therapeutic development process, because the more similarities you can find, “the more you can cancel out the noise,” London says. Dogs won’t supplant another species in cancer research, but adding another species to the investigation “adds one more piece of information to a really complex puzzle,” and hopefully removes some of the trial and error that often accompanies therapeutic development.
The concept is not new.The National Cancer Institute’s Center for Cancer Research launched the Comparative Oncology Program in 2003 to help both pets and people. But recently, this area of research has gained wider attention and funding. “In 2016 the NCI committed some of the Cancer Moonshot funds to this translational immuno-oncology work” to investigate immunotherapies that employ the body’s own immune system to fight cancer, London says. “Some of that involved sequencing a variety of canine tumor genomes to get a better sense of what the genomic landscape looked like and certain cancers that were thought to be close to human cancers. And the second set of studies that are ongoing are related to using dogs with spontaneous or naturally occurring cancers to study novel immunotherapy approaches.”
There are several diseases in which the experiences of dogs and other animals have been useful, and there are several types of cancer where active research may provide key insights to unlocking important questions about cancer treatment and prevention. “Things like non-Hodgkin’s lymphoma, soft tissue sarcomas, melanoma, even breast cancer, or mammary carcinoma as we call it in dogs,” all have parallels between pets and people, Weishaar says.
The NCI is currently sponsoring several clinical trials across the country through the Comparative Oncology Trials Consortium, an active network of trials being conducted at 22 sites across the United States. One of these trials, anticipated to get underway at CSU in early 2019, is investigating the use of a blood pressure medication called losartan (brand name Cozaar) to suppress the population of inflammatory monocytes, cells that have been identified as being key to the spread of cancer. Inflammatory monocytes “play some role in the development of the primary tumor, but are also more involved with promoting tumor spread or metastases,” Weishaar says. In conjunction with Children’s Hospital Colorado, the study is looking at using losartan to stop the spread of osteosarcoma, a type of bone cancer that’s more common in children.
In dogs, the use of losartan showed that this drug could significantly inhibit the production of inflammatory monocytes. This led to “stabilization of the lung tumors as well as some shrinkage, which is pretty unheard of in the setting of metastatic disease in dogs as well as people. Once the cancer spreads to the lungs, we really don’t have a lot of great options to treat the patient and the prognosis is poor,” whether the patient is canine or human. But based on the results in dogs, this new drug could hold promise for treating metastatic osteosarcoma in people and the clinical trial will investigate whether what’s true for dogs holds true for people. “We’re hoping it has the same benefit in people that we see in our dog patients,” she says.
Immunotherapies like the one being investigated in Colorado are a hot topic in comparative oncology right now. “Immunotherapy is a challenge because it’s hard to mimic the human immune system in mice,” largely because “the immune system has the capacity to learn and change,” London says. The immune system of a person who has two young children in day care, for example, will look quite different from “someone who isn’t exposed to all the germs associated with kids and day care. The landscape of what your immune system looks like is really different depending on what you’ve been exposed to because it can learn and change over time. That creates an underlying heterogeneity that has made it challenging to optimize immunotherapies,” that seek to leverage this system to treat cancer. “The goal has been to take something that’s as close as it can be to humans in terms of heterogeneity and see if we can’t learn a little more,” London explains.
In addition to immunotherapies, other clinical trials are looking at other treatments. Weishaar says a trial currently underway at CSU is looking at a novel application of losartan in combination with chemotherapy to treat hemangiosarcoma, a rapidly moving cancer in the lining of blood vessels that is common in dogs.
Although much of the research currently underway is focusing on dogs, they aren’t the only animals helping us learn more about cancer. “The majority of the clinical trials we have are for dogs, but we do periodically have them for cats,” Weishaar says. “It’s not that we don’t like cats,” she adds, just that her hospital sees more dogs. Plus “we don’t have quite as many tumor types in cats that are comparative to humans. Cats are not small dogs, and a lot of their tumors are very different from what we see in dogs and they behave differently,” so the comparative aspect is a somewhat less frequent occurrence in our feline friends.
Horses have also helped in the search for cancer treatments, Weishaar says. “Most of their cancers are skin-related tumors that can be somewhat similar to the type of tumors humans develop.” But dogs currently are the top choice for comparative oncology studies, in part because of the long-standing, close relationship we have with dogs — when Fido gets sick, we tend to notice that pretty quickly and take him to the vet where he has a chance to be diagnosed potentially earlier than other animals might be.
And, because there’s not the same standard of care issue with pets as there is with humans, that sometimes means animals can access novel therapies sooner, London says. “In human cancer therapy, there are set standards of care that are well established to treat cancer,” and people may not be enrolled in a clinical trial until multiple other treatment regimens have failed. “By the time you get to the trial, your cancer is very different than it was five cycles of treatment before, and a therapy that may have worked well two years ago is now not going to work.” But with animal patients, she says “we have the ability to treat our canine patients up-front with some of these novel therapies so it may give us a better sense of what these treatments do in these patients that haven’t evolved a resistance.”
Comparative or translational medicine holds a lot of promise for one day curing many diseases in both animals and humans, but one of the challenges with clinical trials in animals is that many pet owners are unaware that they exist. As such, if your pet is diagnosed with any disease, ask your doctor whether there are any clinical trials you could pursue. These trials provide cutting edge treatment for pets that could save their lives while also advancing our knowledge of how such treatments could help people down the line. London adds that it’s important to ask before you’ve engaged in another therapy that may render your pet ineligible to participate. “We can learn a lot from our additional family members, meaning our pets, in terms of disease biology,” London says. “There’s a lot that they can teach us.” It seems dogs really are man’s best friend in so many ways.
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