No animals today are as intertwined with humans as dogs. Since the domestication of their wolf ancestors over 10,000 years ago, our canine companions have grown to become intimate parts of our lives and our families. As any dog owner will assure you, they share our joys, our sorrows, and seemingly even our thoughts.
Another thing we share, unfortunately, is cancer.
In the United States, cancer claims one of every four human lives each year and is the leading cause of death in domestic dogs. However, because of the similarity of some of our cancers, treatments that work in humans sometimes work in dogs, and vice versa. Cures for one of us can mean cures for both of us.
It was with that in mind that CRI Scientific Advisory Council associate director Ellen Puré, Ph.D., of the University of Pennsylvania School of Veterinary Medicine, helped launch the Penn Vet Cancer Center in 2016. Under Puré’s leadership, the center aims to take basic discoveries and use them to develop more effective ways to treat and even prevent cancer in all species.
To discuss how best to achieve this mission, human and veterinary oncology experts from across the country met this past month in Philadelphia for the inaugural Penn Vet Cancer Center symposium.
The sheer scope of the efforts provided immense hope for the future. In addition to cutting edge treatments, there was an important emphasis on maximizing the benefits of the relationship between basic research and clinical application.
Therefore, while the value of newly developed cancer treatments was highlighted, perhaps the most inspiring aspects of the symposium were the ambitious ideas for how we can more reliably translate breakthroughs between our two species and better sustain innovation in the long run—to ensure continued advances for both of us for the foreseeable future.
“You are a lot more like your dog than that mouse”
Essentially all of the breakthroughs that have helped cancer patients over the last several decades were made possible by studying cancer in animals, and mice are still the main way we evaluate new treatments for humans.
As the experts emphasized, however, we’ve learned much more about cancer in the past few decades, and we now know that studying spontaneous cancers in dogs offers several advantages over mice. Above all, mice don’t get cancer like we do. In fact, tumors in the lab are often induced artificially. Other times, mice are altered—“humanized”—to try to better mimic human cancers.
In contrast, dogs and humans develop cancer naturally. Compared to mice, whose tumors develop in a matter of days, many of our cancers develop over a period of years, gradually accumulating the mutations required to become malignant.
One of the pioneers in studying cancers that spontaneously arise in animals like dogs and cats was CRI’s first scientific and medical director, Lloyd J. Old, M.D., who helped establish the Donaldson-Atwood Cancer Clinic at the Animal Medical Center (AMC) in New York City in 1975.
As Nicola J. Mason, Ph.D., an associate professor of medicine & pathobiology at Penn Vet, put it previously, “Genetically, you are a lot more like your dog than that mouse running around a cage in the lab. Where dogs really stand out is in the way they generate tumors and react to treatments, which is a lot like people.” (NOTE: No dogs are given cancer experimentally—all studies involve dogs who have developed cancer naturally and are seen as “patients.”)
The unique ancestry of dogs provides another benefit when it comes to tackling cancer. While all dogs are of the same species, selective breeding has produced a wide variety of different breeds—over 400 are now recognized. Each has their own unique set of genes, and because cancer is, at its core, a genetic disease, different breeds are predisposed to different types of cancer.
Lymphoma is more likely to affect golden retrievers, whereas glioma, a form of brain cancer, is more prominent in Boston terriers, boxers, and bulldogs. A form of cancer called squamous cell carcinoma occurs more often in standard poodles—but only those with black fur.
Deciphering these links can allow researchers to take very complex diseases and begin to break down how individual genes contribute to various forms of cancer, according to Elaine Ostrander, Ph.D., chief of the Cancer Genetics and Comparative Genomics Branch at the National Institutes of Health as well as the leader of the Dog Genome Project.
For example, in dogs with invasive bladder cancer—which Scotties, Westies, and Shelties are twenty times more likely to get compared to other breeds—Ostrander found that 85% carried a mutation in a gene called BRAF, and this was the same mutation that we see very commonly in human tumors.
Thus, by learning more about mutated BRAF and how to address its impact in dogs, it could enable useful strategies to be developed for humans, too. “Suddenly, we have a new system in which to study an old trend,” Ostrander said.
“It’s unacceptable that we don’t have better treatments”
Osteosarcoma is an aggressive form of bone cancer that affects children as well as large dog breeds such as Great Danes and German shepherds. “It really is striking how similar the disease is in canine populations and children,” noted Kristy L. Weber, M.D., director of the Penn Sarcoma Program.
Unfortunately, treatment options—amputation, chemotherapy, radiation—are pretty abysmal, especially once the disease has metastasized, or spread to other organs.
“It’s unacceptable that we don’t have better treatments,” Weber continued. “We’ve been dealing with osteosarcoma for a long time. We’ve had the chemo in place since 1990. The same chemo we’re using now. We haven’t made any progress.”
Fortunately, one type of immunotherapy—a relatively new class of treatments that utilize the immune system—has shown recent promise against the disease in dogs and could potentially help humans, too.
In this case, the immunotherapy—developed by UPenn’s Yvonne J. Paterson, Ph.D., while being funded by the Cancer Research Institute (CRI)—involves genetically modified bacteria and takes advantage of the fact that about half of all osteosarcomas have abnormally high levels of a protein called HER2, a protein also associated with cancers of the breast, stomach, and ovaries in humans.
In 2012, an Old English Sheepdog named Dexter (below) became one of the first dogs treated with this new approach (along with chemotherapy and amputation) in a Penn Vet clinical trial led by Mason. By injecting the HER2-positive bacteria into Dexter, doctors taught his immune system to seek out and destroy anything that looked like the bacteria, including the HER2-positive tumor cells.
More than five years after Dexter received this immunotherapy, he’s still alive and cancer-free.
As the trial continued, the immunotherapy’s benefits became clear. The dogs that received it were more than twice as likely to survive at least two years compared to those that received only the standard treatment. While historically only 28% of dogs with osteosarcoma survive at least two years, 67% of those treated with this immunotherapy reached that mark.
Based on the remarkable results in dogs, clinical trials are now in progress to see if this immunotherapy approach will work against osteosarcoma in children, who still have few promising options.
“I don’t think we’re ever going back”
Over 100 years ago, Dr. William B. Coley first demonstrated the benefits of cancer immunotherapy, coincidentally also by employing bacteria in humans with sarcoma. However, once chemotherapy and radiation came along, it was nearly forgotten and almost never became a part of mainstream medicine.
“This is a field that started in the late 1890s and then got ‘debunked,’” noted Puré.
Only in the past few decades—once our technology could help scientists finally grasp the immune system’s complexity—did immunotherapy’s incredible power against cancer become clear, “[thanks to] the Cancer Research Institute, who supported this field when no one else did,” Puré noted.
“Cancer immunotherapy was a concept that was challenged until about 10 to 15 years ago,” added Robert H. Vonderheide, M.D., D.Phil., the director of UPenn’s Abramson Cancer Center who also serves on the CRI Scientific Advisory Council along with Puré. “People thought ‘well there’s really no interaction between cancer and the immune system’ but now we understand there really is.”
“I don’t think we’re ever going back,” Puré proclaimed.
Most recently, much of the buzz has surrounded CAR T cells, immune cells named for the customized chimeric antigen receptors they’re equipped with that enhance their ability to target and eliminate cancer cells.
The first two versions of these synthetic “living drugs” were approved in the last several months for leukemia and lymphoma after responses were seen in more than four of every five patients who were treated. Spurred by the success of CAR T cell immunotherapy in humans, the Penn Vet Cancer Center recently launched the first canine clinical trial using this approach for dogs with lymphoma. Harley the boxer (below) was one of the first dogs to be treated.
Several modern immunotherapy approaches have been especially effective for human patients. Overall, the most widely used class of immunotherapy is checkpoint inhibitors (also referred to as checkpoint blockade). These checkpoint immunotherapies work by preventing tumor-targeting T cells from becoming “exhausted,” and thus enable them to continue carrying out their cancer-killing activity. Already they’ve been approved by the FDA for ten different types of cancers and can be used to treat any solid tumor that is characterized by an unstable genome.
Interestingly enough, before either checkpoints or CAR T cells gained approval, one of cancer immunotherapy’s first clinical milestones occurred in dogs. In 1999, Jedd D. Wolchok, M.D., Ph.D., the chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center, received support from CRI to investigate a vaccine for humans with melanoma.
But as the trial stalled for logistical reasons, Wolchok thought that treating dogs with melanoma might be a good way to advance the science—and might make it easier to receive regulatory approval—so he teamed up with Philip Bergman, D.V.M., Ph.D., D.A.C.V.I.M., of the previously mentioned Donaldson-Atwood Cancer Clinic, to launch a clinical trial in dogs.
From 2000 to 2007 they treated approximately 500 dogs after surgery with the DNA-based vaccine, which targeted a protein called tyrosinase. They found that the vaccine significantly increased survival compared to surgery alone. In 2010 the vaccine, now known as ONCEPTTM, became the first cancer vaccine to be approved in the United States.
In addition to helping dogs, it also helped promote a favorable perception of immunotherapy as a treatment for humans. Months later, an immunotherapy vaccine was approved for humans with prostate cancer. According to Wolchok, "There’s no question that the success of the animal trials did a lot to speed up the approval process of the human trials.”
“But what happens if there are no T cells?”
Despite this success, immunotherapy still doesn’t work as well as we’d like. It’s not effective against all cancer types or even for all patients with immunotherapy-responsive cancer types. Rather than replacing surgery, chemotherapy, and radiation, it’s become clear that combining immunotherapies with these traditional treatments in complementary ways will prove a more effective strategy.
”What we’re beginning to understand,” continued Vonderheide, “is that the patients who respond to checkpoint blockade are the ones who have formed this T cell response. The [cancer-fighting] T cells are right there and ready to go but they’re exhausted. We give them checkpoints and we get a result. But what happens if there are no T cells?”
That question is especially relevant for a man whose specialty is treating pancreatic cancer, which is notorious for its ability to keep T cells out and, as a result, resist immunotherapy.
Vonderheide’s solution involves targeting a pathway called CD40. It’s found on specialized immune cells that orchestrate overall immune responses by telling T cells—the “foot soldiers”—what to attack. By activating CD40 in the presence of cancer, it was reasoned, one might be able to drive a T cell response against tumors.
Although the approach appeared promising in mice, Vonderheide was still unsure how this approach would translate to humans because of the nature of this type of medicine. Drugs designed to activate certain pathways, such as CD40, are known as agonists and are much different than drugs that are designed to block the activity of certain pathways. “Those are the typical drugs in medicine. We don’t have that many agonists.”
After being informed by a member of the Penn Vet faculty about another opportunity to study his treatment in dogs with lymphoma, he began collaborating with Mason and Karin U. Sorenmo, D.V.M., on a clinical trial in dogs.
“[In the canine clinical trial] we learned that there really is the ability to… exploit the CD40 pathway. That was the first proof of principle that we needed to take things further,” Vonderheide explained.
Now, he’s leading a pancreatic cancer clinical trial to test this CD40-based approach, in combination with chemotherapy and checkpoint immunotherapy, in humans. “This wouldn’t have been possible without the Cancer Research Institute, who really gave us what it took to get this over the goal line to start the study.” While the trial only began this past year, the early results are quite promising, according to Vonderheide.
“The first was a mistake and the second was the correct clinical trial”
Immunotherapy relies on the immune system’s crucial cancer-fighting capabilities, but some types of immune cells are often recruited by, and manipulated into protecting, tumors. Some even appear to promote the metastatic tumor growth responsible for the majority of cancer-related deaths. Consequently, preventing their recruitment to tumors could potentially disrupt one of cancer’s most dangerous tricks.
“We know [these pro-tumor immune cells] express the receptor CCR2. It’s really the major receptor that they use to migrate,” explained Steven Dow, D.V.M., Ph.D., director of the Laboratory for Immune and Regenerative Medicine at Colorado State University.
There was only one problem: there weren’t any drugs on the market that were known to block CCR2. While Dow could have turned his energy toward developing a new drug from scratch, he had a better idea. “We went back to the drawing board.”
Dow’s team used computer modeling to predict if any already-approved drugs might be good candidates. “One of the drugs that was very unexpected at the time was [a drug called Losartan] that’s used for hypertension,” otherwise known as high blood pressure.
After showing that this hypertension drug could indeed block the recruitment of these cells in mice, Dow decided to take his strategy one step further by adding a second immunotherapy drug. By targeting additional immune cells that support cancer through suppression of T cells that would otherwise attack tumors, he hoped that this one-two punch would significantly improve outcomes.
The two drugs given together significantly stopped the growth of tumor metastases and improved survival in mice. They then launched two clinical trials for dogs with osteosarcoma. “The first was a mistake and the second was the correct clinical trial.”
One of the most important aspects of clinical trials evaluating new drugs is dosing. At first, Dow’s team administered the CCR2-targeting drug at the same dose that’s used to treat high blood pressure. But it didn’t work.
So in the second trial, they upped the dose—to ten times the original amount—and witnessed very encouraging results including “several strong, durable responses.” Overall, half the dogs responded to the combination treatment, and more than one in three had their tumors shrink. Importantly, this higher dose didn’t appear to lead to low blood pressure in any of the canine patients either.
Now, in addition to applying this approach earlier in the course of treatment to prevent metastases in the first place, efforts are also under way to apply this treatment to human patients.
“It’s been a very rewarding process for us…being able to use the dog model to validate the approach,” remarked Dow. “The human trial design has really been driven by the results of the dog clinical study, so we’re hopeful we’ll… be able launch this trial next year.”
“…so that it never becomes a true disease”
Approximately half of all men and one out of every three women in the United States will be diagnosed with cancer at some point in their lives. Survival rates vary by cancer type, but one fact remains constant: the earlier cancer is detected and treated, the better the chance of successful treatment.
Unfortunately, in many cancer types symptoms don’t arise until a tumor has already advanced beyond its initial foothold. At that point it’s typically an uphill battle to eliminate it. So, wouldn’t it be great if we had a simple, reliable way to detect cancer as soon as it began to form?
As it turns out, this might be achievable in the near future.
“Most tumors shed cells into the circulation…and you can detect these cells,” noted Jaime Modiano, V.D.M., Ph.D., the Perlman professor of oncology and comparative medicine at the University of Minnesota School of Veterinary Medicine. Additionally, “there’s some evidence that some of these cells may be responsible for tumor progression and metastasis.”
In his effort to develop a method for early detection of these circulating tumor cells, Modiano has been working with a cancer in dogs called hermangiosarcoma. “Think of it as a malignant blood vessel tumor.”
“Survival expectation with best treatment is between three to six months, so without treatment the dogs will die in a few weeks,” Modiano pointed out. “So what are the possible solutions? Well, one really cool [potential] solution is that we can actually prevent this disease before it happens, if we detect the cancer early enough so that it never becomes a true disease.”
Alongside the validation of the model diagnostic test he developed to identify circulating cancer cells, he’s shown the effectiveness of a “very safe, non-toxic drug that seems to kill hemangiosarcoma cells by apparently targeting the tumor-initiating cells.”
This treatment—an engineered toxin known as eBAT—targets cells that express either uPAR or a growth receptor known as EGFR. High levels of both these receptors are also associated with several types of human tumors.
Like Dow’s previously mentioned immunotherapy, eBAT also “seems to quite effectively target inflammatory [cancer-supporting] immune cells within tumors...and appears to shift the microenvironment to something the tumors don’t like,” according to Modiano.
Already, fifty dogs have been treated through two clinical trials. In one trial, almost 40% of the dogs survived at least one year, compared to only 16% who received standard treatment.
“There is this really nice survival that by one and a half years we still have a good proportion of the dogs alive that would otherwise be dead,” exclaimed Modiano. “And again, one and a half years for an animal that lives ten years is a pretty good thing, so we’re making a difference here.”
This novel treatment also offers a notable improvement with respect to side effects.
“My very healthy German shepherd—I would feel perfectly comfortable giving her this stuff, and I would definitely not want to give her [standard chemotherapy].”
But what really excites Modiano is the prospect of combining his early detection method with his innovative eBAT-based therapy to prevent the disease altogether, a goal that will be pursued in an upcoming clinical trial. “The rationale for early detection and prevention is that these therapies are going to be more effective before the tumor actually is a tumor.”
“We’re going to be using this in healthy dogs, so these are dogs at risk but don’t yet have disease. We get blood samples from them, and if we can detect these hemangiosarcoma cells in circulation, owners can then come to the University of Minnesota with some financial assistance and bring their dogs in and we treat them with eBAT and then we test if we made those circulating cancer cells go away.”
Due to hemangiosarcoma being rare in humans, this is “more proof of concept that things can be done,” Modiano emphasized. “This really creates an opportunity to understand how you can do that for many other diseases that are much more common.”
“We’ll have 3,000 stories about these golden retrievers”
“We heard a lot of wonderful scientific discussions today,” began Rodney Page, D.V.M., director of the Flint Animal Cancer Center at Colorado State University, in one of the last talks of the symposium. However, “there’s a whole concept that we haven’t really talked about here.”
While Modiano’s efforts focused on preventing cancer in dogs likely to get it according to historical trends, the ambitious project discussed by Page—“a lifetime study of about 3,000 golden retrievers, from birth to death”—seeks to deepen our understanding even further. He wants to learn what kinds of factors cause disease in the first place.
In addition to taking biological samples—including blood, DNA, hair, urine, stool, and toenails—from every dog every year, the researchers are also seeking to determine how outside factors, such as air and water quality as well as pesticide exposure influence their health.
“As dogs go through their lives and do what they do, we collect information about their activity every year.” Once it’s finished, “we’ll have 3,000 stories about these golden retrievers, what happened to them, and most of the samples that we need to answer questions” about why.
The ongoing study is about 30% complete. Though 62 dogs thus far have died, life also has sprung forth in the form of 800 golden retriever puppies born to the study participants.
“Over the course of the study we may have three or four generations” that will shed light on how various factors affect dogs and their offspring over time. The insights gained could have wide-ranging implications and allow us to not only better protect dogs from certain health hazards, but also use that knowledge to improve the health of human societies.
For example, Page offered, “if we identify a particular heavy metal exposure in a region and try to mitigate that with a particular strategy, then we could perhaps show that that particular strategy works relatively quickly and that it might be useful in similar human populations.”
Beyond any single project, Page also focused on how to improve the field’s overall efforts to advance canine cancer studies and then use that knowledge to help humans.
“How do you rapidly translate data from a few studies into a substantial portfolio that would convince individuals or agencies to actually go forward into human clinical trials,” Page asked.
To do so, “we need to be ready to be successful…and part of it is having significant partnerships and conferences like this.”
In addition to doing a better job communicating the valuable opportunities to both scientific communities and the public, a blueprint that shows how this comparative approach can be carried out—and highlights its value for both veterinary and human oncology experts—will help pave an easier path for other efforts in the future.
“They’re not just models, they’re patients too.”
One successful blueprint was showcased by Amy K. LeBlanc, D.V.M., the director of the Comparative Oncology Program at the National Cancer Institute, and, according to one attendee, the woman who “convinced the National Institutes of Health to allow dogs on campus.”
Stressing that “data-driven research to help bridge the worlds of veterinarian oncology and human oncology is absolutely critical,” LeBlanc revealed how the National Cancer Institute’s Comparative Brain Tumor Consortium is working to do just that “by fully integrating the canine patient into all aspects of neuro-oncologic research.”
One valuable program they launched involves bringing together physicians, veterinarians, and pathologists—experts at identifying signs of disease in tissue—to develop a better consensus of how to characterize and compare brain cancer between the species by analyzing samples from each.
After the veterinarians and physicians first helped enlighten each other regarding “what they see” in their respective cases, they were able to combine their diverse expertise to develop a classification scheme for the brain tumors that they jointly decided on. Furthermore, they were able to come to several important realizations regarding species-specific differences.
“What they came back to us with was really interesting,” said LeBlanc, noting that there were some of “those ‘aha!’ moments where we said ‘okay that’s important we should talk more about why that might be happening.”
Despite the immense work it took to acquire all the tissues and prepare them for analysis, LeBlanc was absolutely thrilled with the engagement.
“This is an exercise that, although painstaking and long and expensive, was really critical to getting buy-in. There’s really no better way to get people to work together than to have them teach each other,” said LeBlanc. “That was the key point, when they got to do a little ‘show and tell’ and really feel like they were all on the same team and that everybody had something important to share.”
Moving forward, “in addition to a clear method of classifying what’s a complex disease, we have now a roadmap for how to do this for other tumor types.”
Beyond a “significant investment in having more conversations,” LeBlanc proposed that “team-building efforts be at the center of what we do. So we need to continue to build those bridges between veterinary and human oncology. We need to continue to maintain the highest standards for that work…as well as the highest standard of care [for dogs] because they’re part of a family.”
“They’re not just models, they’re patients too.”
Where Do We Go From Here?
Above all, the progress showcased at the inaugural Penn Vet Cancer Center symposium should be welcomed news for all dog owners: incredibly bright and brilliant people are exploring a variety of ways to save dogs from cancer. But it’s important to remember that they can’t do it alone. They’ll need help from dog owners—and their dogs—if they are to address the most important questions and develop significant breakthroughs.
Unfortunately, there’s still a critical lack of awareness, and that has led to a lack of participation in important and often valuable clinical opportunities.
“Trial enrollment and trial fulfillment is something that sometimes keeps me up at night. Forty-percent of trials don’t finish because of accrual,” Page explained. “We’re going to have to be extremely cooperative and extremely open to new models of identification, credentialing, and enrollment of patients into clinical trials in order to do that.”
Many institutions, including the Penn Vet Cancer Center and Colorado State’s Flint Animal Cancer Center, have begun doing just that. To encourage participation in these groundbreaking studies, dog owners are offered helpful incentives in many cases. While the incentives often vary from trial to trial, the cost of experimental drugs is almost always covered, and in many cases long-term care and treatment is also provided. There’s also, of course, the fact that one’s dog receives cutting-edge, potentially life-saving medicine.
Furthermore, as mentioned before, the benefits of these canine clinical trials extend far beyond just the dogs being treated in them. They are also the basis for advancing the field as a whole and transforming the landscape of cancer treatment for dogs and humans in general.
A huge component in many of these latest efforts is the emphasis on the basic science because, as Vonderheide put it, “A clinical trial is insufficient unless it is partnered with a deep scientific inspection of what is going on biologically.”
By examining how certain treatments work and under what circumstances, it increases our knowledge of cancer biology as well as its interactions with the immune system. This, in turn, opens up entirely new therapeutic avenues and enables scientists to develop the treatments of the future—those that can truly transform the landscape of cancer treatment as we know it.
For us to successfully get there, it all comes back to what Puré outlined at the beginning of the symposium. “The problems we see in the clinic have to drive what are our highest priorities at the basic level in the laboratories. Then, we bring things that we learn there back to the clinic.” This will allow scientists to take advantage of this “iterative process of improving things and then asking new questions.”
In this way, Puré says, we “make sure … that we get advances in human medicine, help bring them to the veterinary clinic, and then use the vet models to actually facilitate development of new therapies and studies in animals that go on to advance human medicine.”
All photos provided courtesy of PennVet.