Investigating Cancer Treatments’ Effects on the Heart and Blood Vessels

Tufts’ human and veterinary medical researchers collaborate to prevent and better treat cardiovascular damage in people and pets who have survived cancer
Vicky Yang examines a large brown dog on an examining table, with a student helping. Tufts’ human and veterinary medical researchers collaborate to prevent and better treat cardiovascular damage in people and pets who have survived cancer
When physicians and basic scientists have a research idea, “they’re thinking about how to bring dogs into their studies,” said Vicky Yang, left, here in 2018 examining a dog with a Cummings student. Photo: Alonso Nichols
December 14, 2020

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An explosion in cancer therapies over the past decade has greatly improved people’s chances of surviving cancer. There are upward of 16 million human cancer survivors in the U.S. today—and that number is expected to grow substantially over the next five to 10 years.

The development of new targeted therapies has even transformed some once-terminal cancers into health conditions that can be managed more like a chronic disease. “That is a huge success story,” said Iris Jaffe, cardiologist and executive director of the Molecular Cardiology Research Institute (MCRI) at Tufts Medical Center.

However, some advances in cancer treatment have come at a cost, Jaffe said. Most of the new cancer therapies were studied in cancer patients who otherwise might have died from their cancer. The drugs were approved based on the survival data demonstrating their efficacy for treating tumors and metastasis.

“If we see some benefit with the drug identified from our research study in the canine cancer patients, the next step would be a clinical trial in humans,” said Iris Jaffe.“Now, in many cases, we put patients on these drugs for life. And we’re discovering that many novel cancer therapies cause heart and blood-vessel side effects that were unanticipated when those drugs were first approved,” she said.

These long-term side effects are particularly problematic for the youngest patients. Childhood-cancer survivors have a six-fold higher rate of developing cardiovascular disease 15 to 20 years later than those who haven’t gone through treatments. “If you were a 10-year-old when you had cancer, that means you may be dealing with heart disease when you’re only 25 or 30,” said Jaffe, the Elisa Kent Mendelsohn Professor of Molecular Cardiology at Tufts University School of Medicine.

This medical quandary has led to an emerging field of medicine called cardio-oncology, which is dedicated to managing and studying heart and blood-vessel problems caused by cancer treatment.

In Tufts’ Cardio-Oncology Research Group—which was formed in October 2017 by Jaffe within the MCRI—cardiologists and biomedical researchers are taking a unique approach to the problem. They’re working closely with veterinarians to better understand and treat cancer therapies’ effects on the heart through studies in both people at Tufts Medical Center and pets at Cummings School of Veterinary Medicine.

Going to the Dogs

As the life-extending benefits of the new generation of cancer drugs reached veterinary clinics—adding an estimated average of 6 to 24 months of life to a typical pet dog treated for cancer—the risk of long-term cardiovascular side effects also rose. Some traditional chemotherapies such as doxorubicin, which also is used in human medicine, already are well known to cause long-term heart damage in dogs.

Cheryl LondonThat’s why Cheryl London, V90, a veterinary oncologist well known for doing comparisons across species, was all ears when Jaffe approached her in April 2018, proposing a truly multidisciplinary approach to answering the questions raised by the Cardio-Oncology Research Group

London—the Anne Engen and Dusty Professor in Comparative Oncology at Cummings School—is leading a study in dogs looking at whether immunotherapy can help the body fight lymphoma using far less-toxic doses of doxorubicin.

The clinical trial is being funded by part of a five-year, $2.5 million grant from the National Cancer Institute of the National Institutes of Health through the Cancer Moonshot initiative. Her colleague, veterinary cardiologist Vicky Yang, V09, led a team of Cummings School researchers who identified a potential biomarker that’s an early indicator of heart damage being caused by this common chemotherapy.

With many new cancer therapies poised to enter veterinary clinics, London and Yang also are concerned about the long-term side effects of the comparable human drugs. For example, the oral cancer treatment toceranib (Palladia)—the first cancer therapy approved specifically for dogs—is analogous to sunitnib, a cancer treatment that often causes high blood pressure in people.

Given their patients’ potential for shared complications, London and Yang eagerly joined forces with their counterparts researching human medicine.

Attacking the Problem from Multiple Fronts

The Cardio-Oncology Research Group secured more than $3 million in funding from the National Institutes of Health (NIH) to launch a multidisciplinary study entitled Credentialing a Cross-Species Platform to Investigate Cancer Therapy-Associated Cardiovascular Toxicity. The study seeks to determine the mechanisms driving cancer treatments’ toxic effects, develop an early diagnostic for cardiovascular dysfunction, and assess possible preventative therapies.

The researchers are looking at two drugs in pets and people: toceranib, which causes high blood pressure, and doxorubicin, which causes heart failure—in dogs being treated for cancer at the Henry & Lois Foster Hospital for Small Animals, and their human-medicine equivalents in people being treated at Tufts Medical Center.

In human and canine patients, clinicians are comparing ultrasounds of the heart called echocardiograms over time and blood pressure measurements against the results of blood tests to identify molecular changes that may serve as early indicators of cardiovascular side effects.

The study has already yielded new evidence of a cancer treatment’s effect on dogs. Pets’ blood pressure usually is not taken routinely as part of oncology follow-ups the way it is in people, said Yang, a research assistant professor at Cummings School. However, when veterinarians started checking blood pressure in dogs treated with toceranib as part of the studies done in collaboration with the Tufts physicians, they noticed that some canine patients were developing high blood pressure, just like many human patients treated with sunitnib do, Yang said.

While in human medicine cardiologists turn to existing blood-pressure medications to try to bring patients’ blood pressure down, so they can continue their cancer treatments, the approach is not based on any evidence.

“We don’t really know the biological mechanism that’s causing the high blood pressure, and there have been no clinical trials to show whether one drug is better than another,” said Jaffe. 

Now the group is comparing the cardioprotective benefits of two blood-pressure medications in dogs treated with toceranib as part of the NIH-funded study. The findings could have practice-changing implications for pets and people alike. 

“If we see some benefit with the drug identified from our research study in the canine cancer patients, the next step would be a clinical trial in humans,” said Jaffe. “We already have cardio-oncologists taking care of patients at Tufts Medical Center, so we could pretty rapidly follow up on any promising approach in people.”

Moving Further, Faster

Howard Chen, an assistant professor of medicine at Tufts School of Medicine and investigator in the MCRI at Tufts Medical Center, expects the cross-species nature of Tufts’ research to help translate his own laboratory findings into new diagnostics and treatments far more quickly.

A pre-clinical researcher, Chen is partnering with Yang on a complementary study funded by a Tufts Collaborates seed grant. Their research aims to determine whether molecular imaging can reveal biological changes in the heart caused by cancer treatments well before there has been a change in the organ’s structure or function.

“Oncologists monitor cardiac function now as a routine follow-up in their patients, but it’s hard to predict which patients will go on to develop cardiac problems and when,” said Chen. “Existing medical imaging technology only provides anatomical information, so it can’t tell doctors if there’s a problem until cardiac function is already impaired. At that point, oncologists’ only choice is to stop the chemotherapy, which is not what anyone wants, because then the cancer will come back.”

Chen has identified pathways in cardiac muscle cells that appear to be affected by cancer treatment in mice. He’s now using canine cardiac tissue from Cummings School’s deceased-body-donation program—through which pet owners may donate their animals’ bodies to research that helps animals and people—to study if it’s possible to see changes in those cells under magnetic resonance imaging (MRI). Chen’s findings could be directly applied to human patients.

Yang said she’s thrilled how the pace of the veterinary research seems to be accelerating as a result of working so closely with physicians and basic scientists. “They’re getting really excited about what we do,” Yang said. “Whenever they have an idea, they’re thinking about how to bring dogs into their studies.”

The collaboration across human and veterinary medicine has “really been spectacular” agreed Jaffe. She noted that the cardio-oncology team has made rapid advances, secured multiple large NIH grants, and brought together senior investigators and junior investigators, providing “great opportunities for mentoring.”

“I think we owe a lot of our success to having the veterinary school involved,” Jaffe said. “By demonstrating safety and efficacy in dogs—real cancer patients—we will not only help these pets and their owners, but we’ll be able to translate these findings into people faster through this uniquely Tufts collaboration.”

Genevieve Rajewski can be reached at genevieve.rajewski@tufts.edu.