https://www.vetmed.wisc.edu/cancer-crusaders/

Cancer Crusaders

How today’s canine patients help to advance better cancer therapies for pets and people

Rossi, a seven-year-old Alaskan Malamute, visits UW Veterinary Care for treatment as part of an oncology clinical trial

Rex, a five-year-old Cane Corso weighing in at 100 pounds, had a summer to remember in 2018.

Swimming in Lake Michigan, enjoying walks in the woods, dipping his feet into a nearby creek, and relishing adventure after adventure. All the while adapting to life on three legs.

“Me and Rex had probably the best summer of our lives once he got his leg amputated,” says owner Trevor Smithson. “We did so many fun things together.”

Rex’s left hind leg was amputated in July due to osteosarcoma, a type of bone cancer, and he began chemotherapy soon after. A few months later, it was discovered that Rex’s cancer had spread to his lungs. In the new year, cancerous tumors were found in two of Rex’s other legs.

Rex, a five-year-old Cane Corso battling osteosarcoma

Rex and Smithson have faced each diagnosis with a brave spirit and a goodwill that may one day help other patients — both dogs and people — facing similar situations. As part of Rex’s treatment regimen, he has taken part in several clinical studies — investigational trials of novel, potentially more effective treatment options with applications in veterinary and human medicine.

The UW School of Veterinary Medicine (SVM) is an early and national leader in this field of research, known as comparative oncology, studying naturally occurring cancers in pets as models for human disease. The goal is to advance new cancer therapies and diagnostics that could benefit animals and people. The decoding of the canine genome in 2005 spurred a larger effort among researchers to apply a comparative, “one medicine” approach to better understand, diagnose, and treat diseases with a genetic basis, such as cancer.

“The answer to cancer may be walking beside us,” notes David Vail, professor and Barbara A. Suran Chair in Comparative Oncology at the SVM.

Past clinical studies in oncology at the SVM have yielded new immunotherapy drugs in research first led by Greg MacEwen, one of the school’s founding faculty members; chemotherapy and radiotherapy treatments with better effectiveness and less toxicity; and revolutionary new technologies. For example, successful clinical trials in pet dogs with nasal tumors at UW Veterinary Care in the early 2000s, shepherded by Professor Lisa Forrest, led to widespread use of TomoTherapy in human medicine. This state-of-the-art radiation machine built into a CT scanner, developed at UW–Madison, allows for precise delivery of radiation therapy to attack tumors while sparing healthy tissue. More than 500 TomoTherapy units are now installed in human hospitals worldwide and the SVM remains one of only two veterinary medical hospitals in the world to offer this technology.

Conquering Cancer Together

An important goal of comparative oncology clinical trials is to raise the current standard of cancer care. In veterinary and human medicine, recurrence and metastasis (the spread of cancer) for aggressive tumors is “a very real problem,” says Vail. “We have such a long way to go both in physician-based and veterinarian-based oncology.”

“For some very aggressive cancers, we truly don’t have a good standard of care or the standard of care available fails our patients in that we’re not achieving high cure rates,” he adds. “Having the opportunity to use and apply this one medicine approach more globally in all species will allow us to help humans with cancer, while also helping our veterinary patients. It’s a huge need that we are working to move forward.”

Cancer by the numbersDogs and people not only share similar cancer rates — about one in four dogs and one in three people will develop cancer in their lifetime — but naturally occurring tumors in dogs and other companion animals often share almost identical characteristics to human cancers in terms of biological behavior, therapeutic response, metastasis, and more.

What sets dogs apart, as those who have loved and lost a canine companion know all too well, is their shorter lifespan, which also speeds the cellular clock. Cancers tend to develop, spread, and grow faster in dogs.

“You talk about one dog year equals seven people years; the same holds true for cancers,” says Vail. “Things progress quicker and occur at an earlier age. Chronologically, everything is compressed.”

This abbreviated timeline, while heartbreaking for an affected dog’s family, means that oncologists can determine much more quickly whether a cancer treatment works or doesn’t work. This is an important advantage of clinical trials in client-owned pets, potentially accelerating the development of better cancer therapies more rapidly and less expensively.

At Great Cost

According to Vail, it currently takes an average of 10 to 15 years and a cost of approximately $1.5 billion per drug to develop a new FDA-approved oncology medicine. Some cancer drugs can cost human patients more than $100,000 for a year’s treatment. Contributing to this toll in time and money is the high number of drug candidates that fail in human clinical trials. Only about five percent of oncology therapies make it from first-in-human clinical studies to final drug approval.

“Where we feel comparative oncology can really help is by including companion species in this preclinical work, as they may better recapitulate the human condition than artificial rodent models,” says Vail.

While important for studying cancer biology, the mouse models of cancer that are often used in medical research — immunosuppressed, with tumors that have been implanted — lack many characteristics of human cancers. Thus, there is a disconnect between the number of anti-cancer therapeutics that work in mouse models versus in human patients, says Mark Albertini, an associate professor of medicine at UW–Madison and chief of oncology at the William S. Middleton Memorial Veterans Hospital.

“In contrast, many human clinical trials have benefited from the translational dog model,” he says.

Successful clinical trials in dogs with nasal tumors at UW Veterinary Care, shepherded by Professor Lisa Forrest, led to widespread use of TomoTherapy in human medicine

Cancer arising in dogs naturally,

“is genetically closer to the human condition, where each person is genetically distinct and their cancers are the same,” adds Jacques Galipeau, the Don and Marilyn Anderson Professor in Oncology and associate dean for therapeutics development at the UW School of Medicine and Public Health. In laboratory rodent models, all mice are genetically identical, he explains. “Though you can treat 100 mice, it is more like treating a single mouse a hundred times. Treating cancer in dogs is a more robust, reality-based test of innovative treatments.”

Moreover, Galipeau says, researchers can deploy novel cancer treatments in client-owned animals at a rate that far outpaces the regulatory, pharmaceutical, and cost constraints of human studies. (Clinical trials in companion animals must meet their own strict criteria and are rigorously executed. All studies conducted at the SVM are reviewed and approved by the school’s Animal Care and Use committee to assure minimal risk to the patient and to guarantee that animal welfare requirements of the National Institutes of Health and Food and Drug Administration are met.)

“Our canine clientele can benefit from ethically sound, FDA-compliant clinical trials of therapeutic innovations far quicker and more cheaply than is achievable in humans,” Galipeau notes. “Lessons learned in dogs subsequently inform the best path to pursue in equivalent studies in people — hence the ‘comparative therapeutics’ angle.”

This bidirectional flow of new technologies and therapies is critical for veterinarians such as Vail. “Yes, we’re informing human clinical trials, but at the end of the day we are veterinarians and it’s really important to ensure that our veterinary patients are benefiting as well,” he says.

A Chance to Help Children

Osteosarcoma, a highly aggressive and painful bone cancer, has long been a poster child for the potential of comparative oncology, according to Vail. This disease affects both dogs and people and shares the same metastatic pattern and genetic profile between the two species.

In humans, osteosarcoma tends to occur in children, preteens, and teenagers.

“It is a devastating disease,” Vail says. Only about 800 cases are diagnosed annually in North America, which has led to the disease being understudied in human medicine, he says. “It’s essentially been orphaned because there are so few patients.”

In dogs, however, the disease is far more common, often affecting the long bones of large breed dogs. More than 20,000 new cases are seen each year in North America. Despite therapy (limb amputation plus chemotherapy), most dogs succumb to the disease within a year of diagnosis due to cancer spreading to other parts of the body.

Gus, a 9-year-old Rhodesian Ridgeback mix who recently completed treatment for osteosarcoma, is participating in an oncology clinical trial at UW Veterinary Care

The large number of patients seen in veterinary medicine allows researchers to evaluate new therapeutics in a way that wouldn’t be possible by studying humans alone.

“Median survival for a dog with standard of care therapy is one year and median time to progression in kids, when the disease starts to worsen or spread, is about five years,” Vail explains. “So we get information that much quicker.”

SVM oncologists are working to uncover osteosarcoma’s underlying causes and develop more effective therapies. The school is one of several sites, for example, now investigating a new approach to stimulate the body’s own immune system to attack any remaining tumor cells in osteosarcoma patients. This clinical trial is sponsored by the Morris Animal Foundation and the National Cancer Institute as part of an innovative 5/5/5 initiative to test five drugs, in five years, for approximately $5 million.

Dogs participating in the trial receive a vaccine made from the bacteria Listeria monocytogenes, which has been genetically modified to express a tumor protein found in many cancer cells, including canine bone cancer cells. When injected into the bloodstream, this modified Listeria stimulates the immune system to attack cells expressing the specific tumor protein. The goal is to delay or prevent the spread of cancer following removal of the primary bone cancer tumor and chemotherapy.

Veterinarians Serving Veterans

The SVM has also just launched a four-year trial of a new immunotherapy treatment for malignant melanoma. A common skin cancer in humans and a common oral cancer in dogs, melanoma frequently spreads within the body, resulting in poor survival rates once it reaches distant sites.

This investigational drug will be tested in dogs with melanoma at UW Veterinary Care and in a related study of human melanoma patients. The project is led by Albertini, who in addition to his roles at the Veterans Hospital and UW Health directs the Comprehensive Melanoma Clinic at the UW Carbone Cancer Center. He and Vail have worked collaboratively for several years to identify new melanoma treatments. This latest study is funded by the Department of Veterans Affairs; veterans who have served in the Middle East experience sunlight exposure and melanoma at rates higher than the general population.

With the treatments and novel therapeutics that we look at, the types of things that work in the dog tend to work in people, and the types of things that work in people tend to work in dogs.”

David Vail, professor and Barbara A. Suran Chair in Comparative Oncology

“This is the first Veterans Administration-funded companion animal trial,” says Vail. “We see a lot of malignant melanoma in canine populations — in our clinic, almost daily — and this granting agency recognized the value of the comparative approach.”

The study involves injecting an immune stimulant directly into melanoma tumors to turn the cancerous tumor, while still in the body, into its own anti-cancer vaccine. The treatment may allow patients with melanoma to live longer or even be cured.

“We know that in a tumor developing in a person or dog, it’s no longer presenting as foreign to the immune system, otherwise the immune system would do the job it’s supposed to do,” Vail explains. “We’re trying to trick it back and make the tumor immunogenic again, provoking an immune response.”

MRI and CT scans of dogs who have received the treatment show promising preliminary results. “The tumor becomes very quiet after immunotherapy, with fewer cancer cells dividing,” says Vail. “Importantly, the lymph node, which is kind of the immune fort that gets turned on to attack the tumor and send in anti-cancer cells, becomes more active.”

SVM researchers are collaborating with oncologists at the Carbone Cancer Center to develop novel ways of using advanced medical imaging to determine which patients are benefiting from immunotherapy and which are not — an emerging need as more and more immunotherapies are deployed across cancer types. “That’s important because these drugs are very expensive and they do have side effects,” Vail says.

Gaining Momentum

Writing in The Veterinary Journal, Vail and coauthor Douglas Thamm of Colorado State University note that “a new era of clinical trial awareness, brought on by new consortia and cooperative groups, is beginning.”

The Comparative Oncology Program at the National Cancer Institute and the Comparative Oncology Trials Consortium, of which the SVM is a founding member, are among the initiatives that have emerged to bring researchers together and provide needed resources.

In 2015, a national workshop hosted by the Institute of Medicine’s National Cancer Policy Forum served to build momentum among scientists, veterinarians, physicians, and the general public toward greater integration of pet clinical trials into translational cancer research.

Last year, the Open Philanthropic Project awarded a $6 million grant for the largest clinical study conducted to date for canine cancer. This five-year trial, being performed at the SVM and two other institutions, will test a novel vaccine strategy for the prevention, rather than the treatment, of many types of cancer in dogs — a potential paradigm shift in veterinary and human medicine.

Trevor Smithson and his dog Rex

Most recently, the V Foundation for Cancer Research launched a grant-making program to accelerate comparative oncology research through grants to five top veterinary schools, including the UW School of Veterinary Medicine, paired with five leading human cancer centers. As part of this effort, the SVM has partnered with the UW Carbone Cancer Center to form the Comparative Oncology Working Group, together conducting studies and clinical trials aimed at more efficient cancer prevention, diagnosis, and treatments for pets and people.

Vail says the thousands of pets and pet owners that take part in the school’s oncology clinical studies are critical partners in advancing this work, “helping to push the envelope as far as what can be done to prevent and treat cancer in the future.”

“Our clients come to us demanding high-quality care and access to novel therapeutics and novel technologies,” he says. “They’re highly motivated.”

For Smithson, who has logged countless miles driving from Chicago to the University of Illinois, Ohio State University, and then to UW to allow Rex to participate in oncology clinical trials, the novel therapies have offered optimism in Rex’s battle with cancer. “It’s always good to have a little hope blown into your sails,” he says.

The decision to enroll in the trials hasn’t always been easy for Smithson, who says Rex’s quality of life has guided his decisions. “If Rex didn’t want to live, we wouldn’t have even considered it.”

“I talked to him quite a little bit about this, even before he had his leg amputation, and said ‘If you want to live and you want to fight, I’ll fight with you. And if you don’t want to do it, I’m not going to make you.’ Because there’s no point in doing all this if he’s not happy,” Smithson adds. “But he still finds it in him to wag his tail, eat his food, and chew on his toys. As much as he’s been through, it hasn’t hampered his spirit one bit.”

Meghan Lepisto

Editor’s note: We regret to share that Rex, featured in this article, passed away in March following a courageous battle with cancer.

Categories: Medical Sciences News, On Call, Research News, School News, UW Veterinary Care News.