MAN'S BEST FRIEND, AND THEN SOME
Collaboration bridges gap in animal-human medicine
Outside the UC Davis Center for Companion Animal Health lies a memorial walk honoring beloved dogs and cats that have battled cancer under the care of veterinarians at the state-of-the-art pet hospital. One inlaid brick dedicated to Marley by his owner, Kirk Fornoff, reads: "At first they need us, and then we need them."
The affectionate pit bull terrier had succumbed to an aggressive form of lymphoma, one of several cancer types shared by dogs and humans. Fornoff's words fittingly describe the sentiment among a team of UC Davis clinicians who believe our four-legged companions deserve the best available care, and also champion the idea that advances in cancer treatment for pets will ultimately benefit human patients, as well.
The roots of this homegrown, progressive approach toward translational medicine were laid down by the collaborative environment fostered between two of UC Davis' renowned resources – its National Cancer Institute-designated cancer center and the School of Veterinary Medicine. It was this strong interdisciplinary culture that allowed Michael Kent, an expert in radiation and medical oncology at the Center for Companion Animal Health, to put that sentiment into practice.
"I think that dogs can become a more important model in trying to unlock different treatments and cures for cancer," says Kent. "We're hoping that by using the dog as a model first, we're able to come up with more rational therapeutic trials that can then go on to people."
Spontaneous tumors that arise in pets mimic human cancers much more closely than the transplanted human tumors typically studied in laboratory mice. With a more natural and genetically similar model to follow, Kent argues, potential breakthrough therapies backed by pets are then more likely to work in people.
A practicing veterinarian at UC Davis since 1999, Kent completed the Mentored Clinical Research Training Program a few years ago through the Clinical Translational Science Center. The National Institutes of Health-supported initiative was designed to foster innovative and collaborative research across the UC Davis campus. There, he picked up the skills he needed to translate the most promising research from the bench-top to his patients' "cage side" through clinical trials. But he could not do it alone.
"We try to nurture the skills, attitudes and behaviors that promote team science," says program director Fred Meyers, executive associate dean of the UC Davis School of Medicine. "The major advances in cancer research have really happened because of people working collaboratively, but it's been a relatively rare occurrence, and we're trying to accelerate that."
Meyers says Kent was one of the program's star pupils embodying the principles for successfully bridging the gap between animal and human medicine.
"Dr. Kent is highly competent by himself, but he also possesses the interpersonal skills and willingness to work with people of other backgrounds and disciplines to form new teams that will advance science a lot faster than it otherwise would," he adds.
During his training, Kent connected with several UC Davis Cancer Center clinicians over shared research interests. One of the budding relationships was with professor and Chief of Hematology and Oncology Kit Lam, an expert in targeted drug therapies for cancer.
Kent is now bringing a novel drug delivery approach developed by Lam to canine patients suffering from lymphoma, an often lethal cancer in pets for which chemotherapy is the preferred, life-extending treatment.
Lam and his group have packaged chemotherapeutic drugs into nanoparticles that can easily pass through the leaky blood vessels that nourish many solid tumors to deliver a powerful, toxic blow.
"You can potentially increase the amount of drug delivered to the tumor site and less to normal organs," Lam says, adding that the treatment can be tailored to deliver other drugs for many cancer types. "In that way, the drug will be more effective and there will be fewer side effects."
Kent and his colleagues at the Center for Companion Animal Health have just closed their first clinical trial in dogs using a nanoparticle formulation of paclitaxel, a drug used to treat lung, ovarian and breast cancer in humans. While their main goal was to identify safe guidelines for delivering the new therapeutic agent, Kent believes the project shows a lot of promise in benefiting his patients.
"For dogs, we've never actually been able to use paclitaxel before because they often get allergic reactions," he said. "In this new formulation, we may have found a less toxic form of the drug."
Kent looks forward to starting the next run of clinical testing, this time with an enhanced concoction of the nanoparticle vehicle coated with a peptide – named by Lam "LLP2A" – that singles out and binds specifically to the surface of both human and canine lymphoma cells rather than healthy ones.
"These canine trials will provide a basis for helping decide if this is worth going on to human trials," Kent adds.
Ralph deVere White, director of the UC Davis Cancer Center and a urology professor, says that Kent's work is especially valuable in an environment where working both as a clinician and researcher is a very demanding challenge.
"We are very lucky that Michael possesses both qualities," he says. "However, in Michael's case his work benefits both his patients and our patients. We hope our work will equally benefit his patients and keep our four-legged companions safe."
Along with veterinary radiologists Allison Zwingenberger and Erik Wisner, Kent also has started using the targeting agent LLP2A to image and locate lymphomas in dogs. If proven successful, doctors could use the approach to improve tumor staging and devise better customized treatments for their patients.
Kent's own research strongly reflects his view that spontaneous cancers in dogs offer an excellent model for studying human cancers and devising improved, safer treatments that will benefit both. While genetic similarities between the two species are evident, Kent and other researchers are finding that many of the important pathways that are mutated or changed in human cancers – such as the p53 tumor suppressor – are similarly altered in dog cancers.
Kent recently found that a common cancer survival pathway in humans also is activated in canine osteosarcoma and melanoma. Drugs called mTOR inhibitors that target this pathway have gained traction through clinical trials in the past few years as promising treatments for human sarcomas. As part of the NCI-headed Comparative Oncology Trials Consortium, Kent helped UC Davis complete one of the first nationwide clinical trials to deliver mTOR inhibitors in dogs with osteosarcoma. He is now looking at the drug's efficacy for treating melanoma and as a potential agent for sensitizing canine tumors to radiation therapy.
With deVere White and his colleagues, Kent has started a new project to compare molecular signatures in an invasive form of bladder cancer that is hard to detect in dogs and difficult to treat in both dogs and humans.
DeVere White explains that standard therapy for patients with cancer that has invaded the bladder wall muscle is chemotherapy followed by bladder removal. "The problem is that only 50 percent of patients benefit from the chemotherapy, and we cannot tell prior to administering the chemotherapy which patient will or will not benefit," he says.
The hope is that before chemotherapy treatment, tumors can be removed and genetically analyzed to distinguish the responders from the non-responders.
"It seems like the course of this disease can be very similar between dogs and people," says Kent, "so if we can find a good model for the disease, my patients can benefit, and then hopefully down the road people can benefit, too."