Information & Impacts
Here are some examples of our research and the impact it has on companion animal health
Comparative Oncology: Bridging Cancer Research in People and Pets at UC Davis
A unique cancer clinical trial is underway through a partnership between UC Davis Comprehensive Cancer Center and UC Davis Veterinary Medicine Center for Companion Animal Health (@UCDavisVetMed). The idea is to treat canines with cancer with an inhaled immunotherapy using the protein interleukin-15 that triggers the body’s natural defense responses. The clinical trial is working so well on some pet dogs in Northern California that UC Davis scientists are hoping to try it on people soon. Tyson, a part English mastiff, part pit bull, is happily participating in what is called comparative oncology as, not a four-legged, but a three-legged patient. One of his hind legs was amputated shortly after a bone cancer diagnosis. The treatment he is getting at UC Davis has him back enjoying life at full speed with his family more than a year after being given only a couple months to live.
Thermal ablation offers a minimally invasive treatment for cancer
In the human medical field, the use of tumor ablation technologies to treat a variety of cancers has been growing. But information on these minimally invasive methods in veterinary patients remains extremely limited. Researchers at the school are attempting to develop that body of knowledge, by focusing on thermal ablation in cats and dogs.
Thermal ablation offers a minimally invasive treatment for cancer.
Tissue ablation by a variety of methods has existed in the medical field for about a century, but it wasn’t until a few decades ago that the technique became more commonplace. Significant advancements with these procedures have been ongoing since then, especially with the application of more controlled and predictable image-guided tumor ablation techniques to treat primary and metastatic tumors and for pain palliation.
Here’s how the procedure works: A veterinary patient is placed under general anesthesia and ablation probes are placed in a minimally invasive way into the pet’s mass using imaging guidance, such as computed tomography or ultrasound. Ablation, or killing of the tumor cells, is then performed using thermal, chemical or electrical methods. With thermal ablation, the procedure directly changes the temperature of the lesion with either heating (microwave ablation) or freezing (cryoablation) for the purpose of causing cells to die.
UC Davis researchers are currently evaluating the outcome of cryoablation and microwave ablation. An equipment grant from the CCAH has facilitated the development of a microwave ablation program. To date, our researchers have completed a study on cryoablation in dogs with nasal tumors, and found this approach very successful in reducing tumor volume among these patients. Because of this success, the school continues to offer the technique as a clinical service to canine nasal cancer patients, and is expanding its evaluation of other types of cancer.
Dr. Michele Steffey, an assistant professor in the Department of Surgical and Radiological Sciences, is leading the current studies on thermal ablation. Depending on the tumor type and location, these treatment methods may be primarily palliative -- relieving signs for a limited amount of time -- but researchers hope that for treated patients these methods may be used to improve quality of life, as well as longevity. Veterinary patients that would benefit most from these types of treatments include those with smaller, localized masses that are deeper in tissues (for example, masses in the liver, kidney, adrenal, bone or lung), but not all patients are optimal candidates. Tumors that are very large or that are very near the skin are not likely to be amenable to these types of ablation.
Researchers hope to develop better therapies for canine cancers
Over the past few years, researchers at the school have been investigating what are called “cell-signaling pathways” in hopes of developing more targeted therapies for canine cancers. The traditional therapy route often uses cytotoxic chemotherapy, which involves putting toxins into the body to stop or slow cancer cells. The problem is that most canine cancers are not cured with chemotherapy alone — within many tumors exists a small population of cells that are resistant to standard treatments, and those cells are the hardest to kill.
Dr. Robert Rebhun, associate director of the CCAH, and his colleagues have published two recent studies (both funded by the CCAH’s competitive faculty grants program) related to cancer in dogs. The team has focused on osteosarcoma in dogs as both a way to understand this cancer in canines and as an animal model for humans. With osteosarcoma in dogs, the primary tumor can usually be addressed effectively through removal or radiation. The more-worrisome problem is that most of these cancers metastasize and spread to the lungs. The prognosis for these patients remains poor. Identifying and targeting therapy-resistant tumor cells is a major step to improving the standard of care.
One approach is to identify pathways to access this population of resistant cells. The researchers began by examining the signaling pathway that transmits the information needed for embryonic cells to properly develop. Take this analogy: This particular signaling pathway is like a light switch, located outside a cell; when the signal gets turned on, it triggers the nucleus of the cell to either survive or proliferate — neither of which we want cancer cells to do. Sometimes the light switch can get stuck on. Through a series of experiments, UC Davis researchers figured out how to turn off that switch.
As their research progressed, the team discovered that the switch is working fine, but that another portion of the cell-signaling pathway is stuck on. A protein called “BMI-1” then became the focus of their second study. Researchers found that BMI1 is nearly always expressed at high levels in the dog’s primary tumor and in the lesions in the lungs. BMI1 appears to play a critical role in the development or progression of cancer, and causes cancer cells to resist chemotherapy. If they could inhibit BMI1 — thereby making osteosarcoma cells more sensitive to the effects of chemotherapy — then this could become an effective treatment in dogs whose cancer has spread to their lungs.
While progress on osteosarcoma is incremental, and this project is not ready for clinical application yet, our research “is laying the groundwork for which signaling pathways are important, and this provides the basic science to ultimately help guide translational studies for dog and human health,” Rebhun says.
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Vets investigate improved formulation of chemotherapy drug for dogs
The School of Veterinary Medicine and the School of Medicine are collaborating on a clinical trial to evaluate a novel formulation of doxorubicin that may help the drug better penetrate a tumor, decrease tumor resistance to the medication, and lower the frequency and severity of side effects.
Doxorubicin is a highly effective chemotherapy drug for treating lymphoma both in people and dogs. It also works against sarcomas and carcinomas. But there’s a drawback. “It’s a great drug, but it’s associated with some significant side effects. Toxicity to the heart is often the limiting side effect,” says Dr. Jenna Burton, an assistant professor of clinical oncology in the Department of Surgical and Radiological Sciences. Burton is based at the CCAH.
In addition to heart toxicity, doxorubicin can temporarily upset a patient’s stomach. These problems limit the dose of doxorubicin that can be administered to patients undergoing cancer treatment, and demonstrate the need for less-toxic formulations.
To address these side effects, Burton and Joyce Lee, an assistant adjunct professor in the Department of Internal Medicine, Division of Hematology and Oncology at the medical school, have loaded the drug into nanoparticles, called micelles. These are extremely small drug carriers intended to better penetrate into the tumor because of their small size. So, hopefully, the efficacy of this chemotherapy drug can be increased.
Because doxorubicin is contained within these little packages, less of the drug gets released into the blood system, which means normal cells and tissues won’t experience as much toxicity. Our investigators are specifically evaluating the doxorubicin dose that can be administered and the safety of the micelle formulation when given to dogs with lymphoma.
The next steps of the trial involve the process of labeling the packages with specific molecules that can help the drug home to the tumor, instead of passively diffusing into it. The results of this trial on dogs could have potential impacts for cats and people undergoing cancer treatment.
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Improved lymph-node mapping would help detect cancer spread in dogs
Mast cell tumors are a very common skin tumor in dogs. Successful treatments and potential cures depend on the ability of veterinarians to accurately detect the extent of the disease present at the time of diagnosis. The CCAH recently funded a study to improve this process: The research focuses on mapping lymph nodes to find the one most likely to show any cancer spread.
When mast cell tumors metastasize, or spread, they commonly travel to nearby lymph nodes, which can impact the prognosis for dogs with this type of cancer, explains Dr. Michele Steffey, the faculty adviser on the study. Currently, veterinarians commonly evaluate the lymph nodes for evidence of cancer, using fine-needle aspirates and cytology (looking at cells spread out on a slide). But there’s a drawback: “While minimally invasive, aspiration cytology only samples a very small part of the lymph node and can miss a diagnosis of lymph node metastasis in a concerning number of patients,” according to Stephanie Majeski, a resident in the school’s Soft Tissue Surgery Service.
Steffey and Majeski are focusing on sentinel lymph node mapping, which is becoming more common in the treatment of cancers in humans. The sentinel lymph node is the primary lymph node most likely to show evidence of metastatic disease if there is any. This lymph node can then be removed during surgery and evaluated microscopically to determine if the cancer has spread within the lymphatic system.
In humans, sentinel lymph node mapping uses what’s called nuclear scintigraphy, which is expensive and requires injection of radioactive substances (requiring very specialized equipment, is highly regulated, and carries the risk of radiation exposure to patients and hospital personnel). Consequently, the technique is rarely used in veterinary medicine. “Developing a method of mapping that is accurate but more accessible to veterinary practitioners could improve the accuracy of cancer diagnoses and treatment recommendations for a large number of veterinary patients,” according to the researchers.
Steffey and Majeski will evaluate different mapping methods in an effort to advance the quality of care and treatment recommendations that veterinarians provide to canine cancer patients.
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Researchers probe risks associated with chemo drug compounding
Compounding — or the customized preparation of drugs that are not commercially available from the manufacturer in the desired formulation or strength — is becoming more common in veterinary medicine. Compounded drugs, which are not regulated by the FDA, can be created in any capsule size, which could, in theory, enable safer and more accurate dosing.
But a new study spearheaded by UC Davis veterinary researchers found that compounded chemotherapy drugs are not always as consistent or as accurate as their labels claim, which can unintentionally lead to suboptimal treatment and possibly even put animals at risk.
In late 2013, UC Davis veterinarians noticed that dogs prescribed the compounded version of CCNU — a chemotherapy drug used to treat a range of cancers, including mast cell tumors and lymphoma — were not experiencing the predictable drop in white blood cells associated with the drug. When they compared the blood work of the animals prescribed the compounded CCNU to the records of animals treated with the FDA-approved version, the differences were significant. While 100 percent of the animals treated with the FDA-approved CCNU saw a decrease in white cell count, only one in four animals treated with the compounded CCNU showed any decline in these cells.
“Ultimately, we found that both the incidence and the severity of those counts were dramatically less than what we would expect to see,” says Dr. Robert Rebhun, associate professor of medical oncology, and one of the authors of the study.
Further analyses of the compounded CCNU capsules found that the concentrations varied widely and could be as low as 50 percent of what the compounded medication was labeled to contain. The study’s findings raise concerns about the potential to underdose or overdose animals that are treated with compounded chemotherapy. Inaccurate dosing is especially dangerous when it comes to chemotherapy drugs because the margin of safety is very narrow. “If there is a drug that we can’t really afford to have be ‘off,’ it’s chemotherapy,” Rebhun says.
Another investigation is now underway looking into four or five other chemotherapy drugs; this research is funded by the CCAH and is being led by Dr. Jenna Burton. In the meantime, veterinarians and owners should weigh the pros and cons of compounding and be aware of the risks associated with opting for a compounded drug. “There is no doubt that there needs to be better oversight in the production and sale of compounded drugs,” Rebhun says. “But, for now, raising awareness of the issues with compounded drugs is critical, and that is our primary goal.”
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Cancer impacts animals and people
Cancer strikes animals and people alike. Comparative oncologists in the school are working with physician-scientists at medical schools to reveal new knowledge about the root causes of this challenging disease – tumor genetics, molecular targets, biological behavior and response to therapy. With a One Health approach that takes into account animal, human and environmental factors, veterinary faculty are translating scientific discovery into effective treatments for animals and humans.
Experts in chemotherapy, radiation oncology, surgery, imaging, genetics, pathology and other disciplines pioneer new veterinary treatments while providing outstanding patient care at our veterinary hospital
Tackling canine and human lymphoma
Treating dogs with naturally occurring cancers such as lymphoma, which also affects humans, provides a bridge to discovery to benefit both species. In 2011, veterinary and medical colleagues identified the protein that may promote the formation of lymphoma and other cancers by inhibiting a tumor-suppressing gene. The protein may be a potential target for diagnosis and treatment of lymphoma in humans and animals.
Bold treatment for brain tumors
Results from specialized veterinary studies in dogs enabled physician-scientists at UC San Francisco to introduce a novel therapy for glioblastoma into phase-one clinical trials in humans. The technique, which involves neurosurgery, a specialized infusion machine and simultaneous guidance from magnetic resonance imaging, has safely and effectively delivered liposomal drugs directly to inoperable tumors inside the brains of canine patients with naturally occurring tumors.
Veterinary epidemiologists reported in the early 1990s that a small number of cats that had received multiple vaccination injections over time developed sarcomas at the injection sites. This team joined a national task force that investigated and updated veterinary vaccination guidelines to reduce vaccine-associated sarcomas in cats.
Viruses, contaminants and cancer in wildlife
Veterinary pathologists discovered in 1996 that a striking 18 percent of deaths in stranded adult sea lions resulted from tumors in their reproductive and urinary tracts. Faculty observed viral particles later identified as herpesvirus and found that this virus is twice as common in adult male sea lions— infecting 45 percent of them – as in females. This team also explored whether chemical contaminants (PCBs) interact with hormone receptors in the reproductive tracts to promote tumor growth because animals with higher concentrations of PCBs in their blubber were more likely to have died of this type of cancer.
Feline leukemia vaccine
The cat has the highest incidence for lymphoma of any species. Faculty specialists developed a vaccine to protect against feline leukemia virus, which can cause lymphoma in cats.
Canine skin cancer
Veterinary faculty and graduate students teamed up to explore possible links between certain papillomaviruses and cancer. They have isolated in a single dog at least five canine papilloma viruses – one of which may be associated with skin cancer in dogs.
Meeting client demand
The opening of the privately funded CCAH facility in 2004 tripled the teaching hospital’s capacity to treat cancer in pets, enabling the school’s veterinary oncologists to meet increasing client demand for oncology services.
New protocols extend survival in cats
Clinical researchers confirmed that several new combinations of chemotherapy and radiation prolonged survival times in cats with different types of malignancies, including cancers related to feline immunodeficiency virus.
The radiation oncology team, using a linear accelerator that the school adapted especially for small animals and horses, developed the school’s protocol for stereotactic radiosurgery. This precise, non-surgical treatment delivers a single, high dose of targeted x-ray beams to a brain tumor while minimizing radiation to healthy tissue. A specialized frame device and computerized treatment planning ensure the utmost accuracy. Since 2009 when the approach was introduced, scores of patients have benefited from this therapy.
Bringing minimally invasive surgery to hospital patients
Introducing minimally invasive procedures and specialized imaging to locate and remove tumors, the school’s veterinary surgeons now treat animal cancers considered inoperable just a few years ago. Patients recover more quickly and experience fewer complications. Endoscopy and urethral stenting, for example, are being explored in depth only at the School of Veterinary Medicine. Chemoembolization and intraarterial chemotherapy are other innovative approaches to life-saving cancer therapy.
Pivotal findings in cellular biology
Faculty investigators found that a protein critical for cell cycle regulation serves a dual role in cell proliferation and differentiation – and a possible association with certain lymphomas and carcinomas in cats.
Proving the value of comparative studies
Veterinary oncologists provided the first evidence that an experimental oral drug could inhibit the growth of several kinds of malignancies in dogs. The study gave oncologists in human medicine relevant information sooner than could have been learned in human clinical trials. In 2009, the US Food and Drug Administration approved the drug, now known as Palladia, as the first medication developed specifically for the treatment of mast cell tumors in dogs.
UC Davis Veterinary Center for Clinical Trials
In 2013, the school expanded its longstanding comparative clinical trials program into a national initiative, the Veterinary Center for Clinical Trials. The goal is to enhance the quality of life in companion animals while reducing the time required to bring novel therapies, diagnostics and preventive strategies into much-needed human clinical trials. This center takes advantage of the hospital’s large and diverse clinical caseload. Clients whose animals have naturally occurring disease may choose for their pets to receive new drugs, minimally invasive surgical techniques and radiation technology. The coordinator contacts clients across the country and reaches out to pharmaceutical companies interested in partnerships with veterinary scientists.
Translational researchers received acknowledgment in 2013 by the National Cancer Institute for “unique and noteworthy scholarly contributions in the field of cancer drug development.” The clinicians are members of the NCI’s Comparative Oncology Trial Consortium, which includes 20 veterinary schools across the US and Canada.
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