Transdisciplinary collaborations essential to tackling cancer

Veterinarians and engineers team up to treat osteosarcoma

By Mindy Quigley

A dynamic collaboration between researchers in the veterinary college’s new Animal Cancer Care and Research Center and Virginia Tech’s Department of Biomedical Engineering and Mechanics has attracted substantial funding for a unique approach to treating osteosarcoma, a notoriously painful and aggressive bone cancer that primarily afflicts large-breed dogs, children, and adolescents.

Led by oncologic surgeon Joanne Tuohy, assistant professor in the Department of Small Animal Clinical Sciences, and biomedical engineer Eli Vlaisavljevich, assistant professor in the College of Engineering, the interdisciplinary team is working to refine a type of ultrasound technology, histotripsy, for the treatment of various canine cancers.

Typically requiring amputation of the affected limb and follow-up chemotherapy, treatment for osteosarcoma can be challenging for some pet owners, but the alternative — death due to tumor pain and metastasis — is far worse. And while treatment protocols and life expectancies haven’t meaningfully improved in several decades, Tuohy is encouraged that histotripsy has the potential to help both dogs and humans with osteosarcoma.

“Cancer clinical trials offer exciting opportunities to advance treatments,” Tuohy said. “But these trials require patience, coordination, and solid cooperation among researchers, clinicians, owners, referring veterinarians, and, of course, the patients themselves.”

One such patient is Balian, a 6-year-old Alaskan malamute that was diagnosed with osteosarcoma in February. Informed of the study by family friend Andrea Cangin ’98, Balian’s owner, Jake Polverini, was immediately on board. “Once we had accepted the fact that he was going to lose his leg,” Polverini said, “we wanted to help make sure a future dog wouldn’t lose a leg. No dog should have to go through this.”

Histotripsy, the technology used in the study, focuses ultrasound beams to non-invasively create cavitation bubble clouds, mechanically breaking down cells inside a defined area. The technique doesn’t use heat, an attribute that helps avoid damage to surrounding tissues.

“Even though this is what I do every day, I still think it sounds like sci-fi to be able to destroy tumors without making any incisions,” said Vlaisavljevich, whose lab explores a range of physical mechanisms through which ultrasound interacts with tissues in the body, including cancerous tumors.

When the ultrasound technology breaks apart the tumor cells, they release proteins, and the body’s immune system begins to recognize them as invaders. A strong enough immune response could even begin to recognize and attack metastatic growths or regrowth of the same tumor, which is highly desirable with an aggressively metastatic cancer like osteosarcoma that kills the majority of patients by its propensity to spread throughout the lungs.

Although histotripsy and related ultrasound-based immunotherapies are being developed for use in humans, there is little data on their use in dogs or on these types of tumors. As a result, Vlaisavljevich and Tuohy have designed a series of clinical studies that, if successful, will support the use of histotripsy as a treatment for canine osteosarcoma. Both Vlaisavljevich and Tuohy are members of Virginia Tech's Cancer Research Alliance.

The team’s first study, conducted two years ago with local veterinarians and owners, tested histotripsy on the amputated limbs of tumor-bearing dogs. Because the researchers were not treating live patients — referred to as ex vivo, literally “outside a living body” — they were able to validate that the approach would be safe and would provoke the kind of immune response needed for success.

On the heels of the first study’s positive results, a grant from the American Kennel Club moved the study to the next phase — in vivo, or inside the bodies of dogs affected by osteosarcoma.

In this phase, the researchers perform the histotripsy treatment before surgically removing the dog’s affected leg as part of standard-of-care treatment. They then test whether the ablation effects they were able to measure in the amputated legs will surface in a living dog.

Crucially, the treatment is overseen by a team of highly trained experts at the Animal Cancer Center, and the cost to owners is largely subsidized by research funding. The experience and expertise of the center’s clinical staff ensure that most “tripods,” as post-amputation dogs are affectionately known, do well, even if they have preexisting conditions, such as obesity or orthopedic disease.

A case in point is Balian, whose amputation took place in early March. “He’s bouncing around, hopping through the yard like a champ,” said Polverini. “He still makes friends everywhere he goes.”

Funded by grants from the Focused Ultrasound Foundation and the National Institutes of Health, the next phases of the study will undertake additional immune system evaluations, examining more markers, using different modalities to identify markers, and investigating immune function across different points in time.

The work is meticulous, time-consuming, and rarely glamourous. Obstacles like slow enrollment in the study and technical glitches can be frustrating because the research team is acutely aware of how desperate both canine and human patients are for effective, new therapies.

The next round of studies, which will also provide funding to help offset the cost of treatment, will again enroll dogs with osteosarcoma and will run for the next several years.

Although the ultimate goal is to avoid amputation entirely by offering the histotripsy treatment alone, Tuohy cautions that immunotherapy will likely be part of a multimodal approach, not a replacement for all other therapies. “If there’s one thing we’ve learned about cancer in the past half-century, it’s that we must be humble,” she said. “We don’t expect to find a silver bullet in cancer treatment with the technologies available.”

Vlaisavljevich, whose mother died of liver cancer when he was 4 years old, agrees. “Clinical research can be difficult,” he said, “and there are no sure things.” However, the incremental progress, the collaboration with a passionate interdisciplinary team, and especially the success stories of patients who have been helped by his research give him hope: “This is an extremely rewarding job. You’ve got to use setbacks to inspire you to keep going.”

— Mindy Quigley is clinical trials coordinator in VA-MD Vet Med’s Department of Small Animal Clinical Sciences.