New research offers hope for osteosarcoma patients

One of the most common bone cancers in dogs, especially in large or giant breeds, is osteosarcoma. It’s not only painful and aggressive, but it often metastasizes to the lungs early. While treatments, like amputation and chemotherapy, can slow the progression of disease, there is no cure.

There is, however, new hope for improved outcomes in canine osteosarcoma patients thanks to research out of Colorado State University’s Flint Animal Cancer Center.

Dan Regan, DVM, PhD, is the Principal Investigator of the Investigational Pathology Lab at the Flint Animal Cancer Center. He recently received an R37 Method to Extend Research in Time (MERIT) Award from the National Institutes of Health (NIH), which will provide him with long-term support for his work on stopping this aggressive cancer from spreading to the lungs.

“One of the larger major grant mechanisms for the NIH is an R01 award … and those are typically five years,” Regan said. But a MERIT award essentially turns the grant from a five-year to a seven-year award. “At the end of the five years, you still need to apply for those additional two years and demonstrate progress,” he said, “but it’s pretty nice to give you that extended time of support. You can really kind of longitudinally focus on something and drill down to make an impact.”

A historical hypothesis

Regan’s interest in cancer research came from personal experience. Just before he entered veterinary school, his father was diagnosed with cancer.

“Once I got into the field of immunology, I realized how important the immune response was in cancer as well,” he said. “And this idea that the immune response also kind of dictates the pathogenesis of cancer was really interesting to me.”

That’s really what drove the research today. He’s intrigued by the concept that a tumor growing in its primary location can signal through the blood to manipulate distant future sites of metastasis—and change their composition—before actually arriving and metastasizing there.

“It’s called the pre-metastatic niche. It’s essentially like, if you’re climbing Mount Everest and you have these Sherpas that go in front of you. They set up the ropes, and they set up camp, and they get hot food and tea going for you, and you just kind of follow their pathway there and arrive at these hospitable locations,” he explained. “That’s how these tumors could co-opt normal cells in your body systematically, to kind of prepare distant sites before the arrival of a single tumor cell.”

One of the biggest keys to this process is the immune response, which, he said, “kind of blew my mind.”

The other important aspect to note is that certain primary tumors tend to metastasize to specific distant sites. This idea, known as the seed and soil hypothesis, was put forward in the late 1800s by Stephen Paget, who hypothesized that breast cancer did not spread randomly, but, in his studies, tended to spread to the brain, lungs, or bones. “They weren’t spreading to other organs with a high blood supply, like the liver or kidney,” Regan said.

When Regan arrived at CSU, he paired up with mentors, like Steve Dow, DVM, PhD, Flint Animal Cancer Center’s Principal Investigator at the Laboratory for Immunotherapy, who helped him investigate the seed and soil hypothesis as it pertained to bone cancer and dogs to understand why it spreads so readily and specifically to the lungs. “That’s essentially what this grant is still pursuing,” he said.

Monocytes and metastasis

Early in his career, Regan worked with Dow to investigate a particular type of cell called a monocyte.

“It’s an immune cell, a white blood cell. It looked like, as these tumor cells would arrive in the lung, they would make a soluble molecule that would essentially act like a hormone through your bloodstream to call in a bunch of these monocytes—or these immune cells—into the lung,” he explained.

“These monocytes, they’re really good if you need to fight an infection in your body or something like that. You need these monocytes,” he said, “but then the cancer cells, as they were arriving in the lung, would co-opt them and call them in and they would facilitate colonization in the lung and growth of these metastases.”

With that understanding, Regan and Dow investigated that as a component of the metastatic niche of bone cancer in the lung and came up with a therapy to target those specific cells.

“And when we blocked their recruitment, actually these dogs did a lot better,” Regan said. “We could actually reduce the growth of these lung metastases in dogs with bone cancer. And now that therapy is being tested in kids with bone cancer at children’s hospitals in LA, Atlanta, and right here in Colorado.”

Figuring out the fibroblasts

With this grant, and with other smaller grants the team has received, they’ve worked to build preliminary data showing the correlation between fibroblasts and metastases.

“These fibroblasts are like these connective tissue cells in the lung that provide all the structural support,” Regan said. “They’re normally, natively present in your lung and in all tissues of your body.”

However, although they’re native to the body, they also appear to sit at the top of the hierarchy of the metastatic niche, he said, “and they might be one of the first cells that are kind of co-opted by these tumor cells to start changing that lung soil, or that lung environment. They might be the ones that make these molecules that call in the monocytes.”

With that understanding, they looked at how, instead of solely trying to stop the monocyte recruitment or that one piece, they could start at the top and take out the fibroblasts.

A dual target

“When you’re looking at developing drugs, they often target some sort of biological process or molecule,” Regan explained. “And so, we found this protein: Focal adhesion kinase or FAK, which is kind of a signaling protein.”

While digging into what was happening with the fibroblasts, they found that this protein was hyper-activated both in the fibroblasts of the lung and in the tumor cells themselves. “It was kind of this potential dual target, where you have a molecule that both the cancer cells themselves are dependent on for survival and proliferation, but also the soil needs to reorganize and promote metastasis.”

Basically, targeting the FAK molecule enabled them to go after both the soil and the seed.

Determining the right drugs

At the moment, Regan said they’re looking at which existing FAK inhibitor drug they want to use for a trial, as well as how to dose it, but they have plans to partner with the Comparative Oncology Trials Consortium (COTC) run by Amy LeBlanc at the National Cancer Institute.

They hope “to run a large national, multisite trial in dogs with osteosarcoma where we hope to enroll roughly 75 patients,  and see if we add this FAK inhibitor drug on to current standard of care, to see if we can slow down the rate or reduce the number of dogs that develop metastatic disease.”

If all goes to plan, this trial should open up within the next year.

“Along the way, obviously we’ll be looking to see, do we improve outcomes for these dogs?  Safety is always at the top of our minds,” he said. “Is this well tolerated ,because we’re going to be combining it with chemotherapy that’s the current standard of care.”

Additionally, he said they’ll be doing a number of immune correlative analyses, “basically taking samples from these canine patients, both pre- and post-drug therapy, and looking at, are we changing some of these components of the immune system and the metastatic niche?”

They’re also hoping to better understand whether there’s anything in a dog’s blood or tumor that might predict how they’d respond to the therapy.

Because FAK inhibitor drugs are already in use for other cancers in humans, like ovarian and pancreatic cancer, the drugs already exist, but choosing the right one has come with some roadblocks. “In the early days, we started with a FAK inhibitor drug which was, at the time, seeming to be fairly heavily investigated,” he said. However, it had solubility issues and stopped being developed for clinical use, so they were forced to switch to a different drug.

FAK to the future

By the time this research is complete and the funding has ended, Regan hopes that we’ll have a new standard of care for dogs with osteosarcoma, where they can get this drug along with chemotherapy.

“And, instead of 30% of dogs with bone cancer developing fatal lung metastatic disease immediately after chemotherapy, then around four months into their treatment schedules, now, only 10-15% of dogs with bone cancer are getting this fatal metastatic disease,” he said. “I mean, if we can make that even lower? If we can cut that in half? Awesome. That would be a huge inroad.”

Not only does he hope to see this therapy drastically reduce the number of dogs developing this fatal metastatic lung disease, but, with that data, he believes it could pave the way for another human clinical trial.

“Not long ago, this was kind of a death sentence for these animals,” he said. “You’d maybe send them home on supportive care and pain management. And to think that’s no longer the case—even with our current standard of care, many of these patients do really, really well with amputation and standard of care chemotherapy. Pursuing treatment is important. And even when the tumor does come back, or it does metastasize to the lungs, we have more options now than we did.”

For veterinarians with patients who might benefit from this trial, or vets who have questions about any of their oncology patients, Regan highlights the free consultation service at Flint Animal Care Center at CSU. “It’s staffed by veterinary nurses who interact with our surgical, radiation, and medical oncology specialists,” he said. “They speak to both clients or referring veterinarians—or both—and can offer advice on next steps, potential open trials for enrollment, and more.”

 

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