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Researchers turn to canine clinical trials to advance cancer therapies

Wednesday, March 30, 2016

This is an excerpt of a piece that appeared in JAMA. Read the full article here.

Kristy Richards, M.D., Ph.D.Kristy Richards, M.D., Ph.D. About 6 million dogs are diagnosed with cancer each year, and more than half of dogs older than 10 years will develop cancers such as osteosarcoma, lymphoma, or melanoma. But the heartbreaking diagnosis for dog owners is a treasure trove of potential data for oncology researchers. In clinical trials at academic research centers across the country, veterinarians and physicians are studying how pet dogs respond to cancer therapies and analyzing the genetic makeup of these tumors. Although medicine and veterinary medicine, for the most part, have been viewed as two different worlds, with little exchange of information between the two, that is beginning to change.

"We’ve come a long way in the last 10 years in understanding what we know and don’t know about canine cancers to define the type of questions that can be efficiently answered within that model,” observed Amy K. LeBlanc, DVM, director of the National Cancer Institute’s (NCI’s) Comparative Oncology Program (COP).

In recognition of the potential utility of canine cancer models, the NCI established COP in 2003 to promote comparative oncology research. The NCI also created the Comparative Oncology Trials Consortium (COTC) to manage comparative oncology clinical trials conducted at a network of 20 academic veterinary medical centers. And just last year, the National Academy of Medicine held a workshop on comparative oncology and issued a report addressing how to best integrate clinical trials of pets with naturally occurring cancers into human oncology research.

There’s even been interest in exploring tumor biology in nondomesticated animals such as elephants to better understand mechanisms of cancer suppression (Abegglen LM et al. JAMA. 2015;314[17]:1850-1860).

The surge in comparative oncology research may be due to a convergence of factors, noted Will Eward, DVM, MD, an assistant professor of orthopaedic surgery at Duke University School of Medicine, who researches and treats sarcoma in both human and furry, four-legged canine patients.

“I don’t know if as pet insurance becomes more common, more people are seeking high-end treatment [for pets], or if we’ve reached a critical mass of researchers who are looking at humans and other species,” said Eward.

Canine clinical trials in progress or completed are already demonstrating the value of comparative oncology.

For example, noted LeBlanc, a canine clinical trial of the immunocytokine NHS-IL12 as a therapy for treating dogs with melanoma yielded useful information on the drug’s safety and efficacy (Paoloni M et al.PLoS One. doi:10.1371/journal.pone.0129954 [published online June 19, 2015]). The data on the drug’s efficacy were key to the study sponsor’s decision to go ahead with a phase 1 clinical trial, she said.

“That data helped support an investigational drug application for a [human] clinical trial that is going on at [National Institutes of Health],” LeBlanc said. “The principal investigator commented how helpful it was to have the dog data.”

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Researchers at Cornell University College of Veterinary Medicine are planning to study whether a combination of 2 new promising drugs is more effective in treating lymphoma in dogs than each drug alone. Such a clinical trial in humans is currently impossible because neither drug has been thoroughly studied individually, said Kristy Richards, MD, PhD, an associate professor of oncology at Weill Cornell Medical College and an associate professor of biomedical sciences at Cornell University College of Veterinary Medicine, who leads the research.

“With the dogs, we can say ‘We think the combination will be best’ and go forward [to human trials] with that,” said Richards, who prefers not to name the drugs until the trial begins.

As an oncologist, Richards said she is sometimes asked why she’s conducting research on dogs. Her response: the results of canine studies may help facilitate the development of treatments for humans.

“I love the fact that the [dog] subjects benefit from the research, but my primary motivation is that I want to cure people with lymphoma,” said Richards. “[With dogs] they relapse faster, the kinetics of their disease are faster, we can take biopsies easier.”

“We have all these potential study subjects sitting there… why not use that to help speed things up?” she added.

Researchers are also looking at genetic data to help pinpoint mutations most likely to cause certain types of cancer. The canine genome, which was sequenced in 2005, has provided a foundation for future research on the genetic underpinnings of diseases also common in humans (Lindblad-Toh K et al. Nature. 2005;438:803-819). Due to selective breeding of dogs over the centuries, many purebreds are susceptible to specific diseases that can be linked back to inheritable germline mutations. Given the large number of breeds and their shared ancestry, inheritable germline mutations associated with complex diseases such as cancer are easier to identify in purebred dogs than in human populations.

At Duke, for example, Eward and his research team have been doing genetic sequencing on human and canine osteosarcoma tumors and comparing the somatic, or nonheritable, genetic mutations common to both.

“That number of 5 genes that are common to osteosarcoma in dogs and humans matters because if you have a huge number [of mutations in] like 3000 genes, it’s kind of hard to figure out which of the 3000 genes to study. If you boil it down to 5 genes, it’s a much more reasonable thing to study,” said Eward, who noted that the research has not yet been published.

Richards and her team are taking a similar approach, sequencing tumors from 100 dogs with lymphoma to compare both germline and somatic genetic mutations in these tumors with those found in human lymphoma tumors. Their work builds on an earlier study by other researchers that found somatic mutations in the gene TRAF3 in about 30% of canine lymphoma and TRAF3 deletions in about 9% of human diffuse large B-cell lymphoma tumors (Bushell KR et al. Blood. 2015;125[6]:999-1005).

“The germline mutations will help us learn more about the biology of cancer predisposition and oncogenesis, and the somatic mutations, especially the ones in shared pathways, will help us learn more about cancer formation and progression but also provide good therapeutic targets,” said Richards.

The team will also compare human and canine clinical data such as disease stage, tumor phenotype, and progression-free survival, she said.

Like any clinical trial model, canine trials are not a cure-all to speed new treatments.

“It’s never been our position that the dog should be in every single drug development [process],” said LeBlanc. “It’s irresponsible to believe that the dog will solve all the drug development problems.”

One limitation is dogs’ size: they’re larger than mice and require larger drug doses, which increases a trial’s cost. Canine clinical trials also take longer than mouse model trials.

In addition, pharmaceutical companies may be reluctant to sponsor a canine clinical trial, fearing that an adverse effect that occurs in a dog might derail clinical trials in humans, Richards noted.

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