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October 21, 2021 – About a decade ago, several research groups began studying how the drug propranolol, a commonly used beta blocker that is used to treat heart disease in people and in dogs, could be used to fight cancer, especially cancers of blood vessels or vascular tumors. Because propranolol appeared to inhibit the growth of a rare vascular tumor in humans known as angiosarcoma, researchers also wondered if propranolol could be used to treat hemangiosarcoma, an aggressive cancer in dogs that looks and acts remarkably like human angiosarcoma.

Early cell culture studies showed that propranolol killed both angiosarcoma cells and canine hemangiosarcoma cells and limited tumor growth. Veterinarians wondered if propranolol could be the much-needed tool they’d been looking for to help treat hemangiosarcoma in dogs.

A few veterinarians began giving propranolol to their patients, adding it to standard-of-care treatments for hemangiosarcoma, which includes surgery and chemotherapy. What the veterinary community observed was encouraging but inconsistent - the drug seemed to work well in some dogs with hemangiosarcoma but not others. Researchers and veterinarians wanted to know why.

Is Hemangiosarcoma One Disease – or More?

Dr. Erin Dickerson, a Morris Animal Foundation-funded researcher from the University of Minnesota, and her colleagues believe the answer lies within the tumor itself. Hemangiosarcoma, like many cancers, comes in different forms or subtypes. It’s not just one disease, even though it has always been treated like one.

“Our early research found at least three different types of hemangiosarcoma,” said Dr. Dickerson. “This discovery and the fact that some dogs appear to respond well to the addition of propranolol to current treatment approaches led us to our current thinking that maybe propranolol is only going to work on a subset of dogs with a certain tumor subtype with certain genetic mutations.”

Dr. Dickerson said that in human oncology, cancers like breast cancer have many different subtypes and these subtypes often respond to different treatment strategies. If the same situation occurs in dogs with hemangiosarcoma, it could explain the difference in responses seen in clinical cases.

Back to the Basics

To find out if their hypothesis was true, Dr. Dickerson and her team had to begin with the basics. They wanted to know more about how hemangiosarcoma cells respond to propranolol in the lab and how propranolol responded when it was combined with chemotherapy drugs. Was it safe to combine the drugs and did they work better together or alone? Only after collecting these data could they safely test their theory of how propranolol worked in dogs with different subtypes of hemangiosarcoma.

In her most recent Foundation-funded study, Dr. Dickerson and her colleagues are investigating the effect of adding propranolol to the drug doxorubicin, the standard-of-care chemotherapy for dogs with hemangiosarcoma. They also want to learn if propranolol could help reduce chemotherapy resistance, a major roadblock for many cancer treatments.

“Almost any tumor treated with chemotherapy will develop resistance to that drug,” said Dr. Dickerson. “You can kill some cancer cells with the chemotherapy and not others. There are always some cells that have different ways to work around the effects of the drug. Cancers are basically parasites that want to survive, and they often figure out how to do that.”

In a recently published paper, Dr. Dickerson and her team showed administration of propranolol can help sensitize hemangiosarcoma cells to the effects of doxorubicin. In their study, Dr. Dickerson’s team treated cells with propranolol and doxorubicin. While some cells remained resistant, data suggest the addition of propranolol did help kill more tumor cells and may have helped block some of the strategies cancer cells use to develop drug resistance.

The team also conducted synergy studies, looking for favorable reactions when propranolol and doxorubicin were added to the cell culture at the same time. The good news is propranolol works well with doxorubicin and together these drugs should kill cancer cells more effectively. The team is now expanding their laboratory work to study other beta-blocking agents.

From Lab to Clinical Trials

With new data in hand, Dr. Dickerson and her team are working on next research steps.

“We have to be careful how we interpret laboratory study results, because we’re looking at cells in a dish,” said Dr. Dickerson. “And what happens in a dish and what happens in a dog or a person can be very different. We are now translating our results into other study models. We also are conducting a clinical trial in dogs, now that we have data showing the combination of propranolol and doxorubicin can kill hemangiosarcoma cells in the lab.”

The team has translated their findings to the clinic and is enrolling dogs with early stage splenic hemangiosarcoma to test the combination of propranolol with doxorubicin. Dr. Dickerson and her colleagues hope to have preliminary results next year. Their findings will help the team learn more about what makes hemangiosarcoma more responsive to propranolol or the combination of propranolol and doxorubicin. Analysis of blood and tumor samples from dogs in the study may also shed light on tumor subtypes and their role in how some dogs respond better to propranolol than others.

“We hope propranolol will be a promising new treatment for some dogs diagnosed with hemangiosarcoma,” said Dr. Dickerson. “But it probably won’t be a treatment for every dog. That’s a very common situation when it comes to cancer treatments.”

Findings from Dr. Dickerson’s Morris Animal Foundation-funded studies are helping inform current and future clinical trials of propranolol as an adjunct treatment for hemangiosarcoma. If we understand more about how the disease works, and if subtypes are an important factor that alters the course of disease in some dogs, researchers can continue to discover new avenues to stop or slow this deadly cancer.

Learn more about Morris Animal Foundation and our health studies for dogs, as well as cats, horses and wildlife. When we support groundbreaking work, like that of Dr. Dickerson and her team at the University of Minnesota, we can help owners and veterinarians provide optimal care for pets to help them live longer, healthier lives – and maybe beat a deadly cancer.