Approximately 6 million dogs and a similar number of cats are diagnosed with cancer in the United States each year, and many of these cases may offer clues to fighting the disease in humans. This promise is what drives the field of comparative oncology, the study of naturally developing cancers in animals as models for human disease. Spontaneous cancers in dogs and cats share many of the same features with specific human cancers, including melanoma; non-Hodgkin lymphoma; leukemia; osteosarcoma; soft tissue sarcomas; and prostate, mammary, lung, head and neck, and bladder carcinomas.
Although studies in comparative oncology have occurred for a number of years, the National Cancer Institute (NCI) launched the Comparative Oncology Program (COP) in 2003 to take advantage of these similarities and further advance the field.
According to veterinary oncologist Chand Khanna, DVM, PhD, who heads the program, COP's initial main goal was to develop a national consortium to complete preclinical trials that evaluate new cancer drugs in pet animals, answering key questions before the therapies move into human clinical trials. That goal led to the creation of the Comparative Oncology Trials Consortium (COTC), a network of 20 veterinary academic medical centers across the country that treat dogs and cats with cancer.
Since the COTC was launched, 9 clinical trials have been completed, and 2 of the agents tested are currently in phase 1 human studies, Dr. Khanna notes. Three of the studies have focused on defining the mechanism of action of rapamycin/rapalog inhibitors of mammalian target of rapamycin (mTOR), and data generated from the trials will be used to prioritize agents for a phase 3 trial in children with osteosarcoma.
“There is a traditional drug development pathway of preclinical studies in rodents and sometimes lab dogs and primates, followed by clinical trials,” says William Kisseberth, DVM, PhD, of the Ohio State University's College of Veterinary Medicine in Columbus, Ohio, one of the COTC sites. “These studies in dogs with spontaneous cancers have the ability to inform and enhance the steps of development along the traditional pathway.”
Dogs Versus Laboratory Mice
One advantage of using dogs with spontaneous cancers versus laboratory mice to answer important research questions about new drugs is that the latter have cancers that have been induced chemically or by genetic manipulation, which differs from how cancer develops in humans. Also, pet dogs live in the same environments as humans, and they can easily undergo some of the same tests, such as imaging and biopsies.
“It allows you to develop questions that are much more relevant as you move into the human clinic,” Dr. Khanna notes. “The studies help you evaluate the therapeutic index of a drug and tolerability in a dog at dosages that are relevant to human translation.” Among some of the key questions that studies in pet animals can help answer are determining effective dose amounts and scheduling, identifying which biomarkers to follow to determine the effectiveness of a drug, and assessing whether drug levels are achieving the desired effect on tumor cells.
Osteosarcoma is one type of cancer that is common in dogs and can provide a good model for human disease. Because dogs have a shorter life span, questions can be answered more quickly than they can in people. Less common among dogs in the United States are carcinomas of the breast and prostate because most dogs are neutered and spayed, which reduces the incidence of these cancers.
Most of the drugs are being developed by pharmaceutical companies or the NCI, and the majority have not yet been approved for use in humans. They currently are either in preclinical development or are being studied in conjunction with early phase 1 or phase 2 human trials.
Pet owners are motivated to participate in the studies for several reasons, notes Susan Lana, DVM, chief of the clinical oncology service at the Colorado State University Veterinary Teaching Hospital and the Animal Cancer Center in Fort Collins, Colorado, another COTC site.
“There may be no good options for treating their pet's particular disease,” she says. “Also, our clinical trials are funded, which helps people access treatments for their pets that they may not otherwise be able to afford.” In addition, she says, many pet owners are interested in helping advance cancer research, both in pets and humans.
Dr. Lana also coordinates the COTC's Pharmacodynamic Core, which is a virtual laboratory that draws on experts across the country to evaluate how drugs are affecting the body, ranging from modulating a target to altering immune cells. “If someone has submitted an application to work on a project, we'll find a lab with the expertise to do the necessary assays,” she says. “Also, as protocols are developed, we help refine them, suggest different endpoints, and determine who best can do the work.”
One current COTC trial is a proof-of-concept study involving personalized medicine. Researchers are attempting to determine whether information can be generated quickly enough from tissue samples to create molecular profiles and enable a treatment decision. “We're trying to determine the practicality of collecting samples and doing complicated assays within 7 days,” Dr. Lana says. “In the future, we would receive the information and a recommendation as to the appropriate treatment based on the genetic signature of the patient.”
Another upcoming trial will evaluate the safety and effectiveness of 3 similar indenoisoquinolines when given to dogs with lymphoma. The study will enroll 80 to 90 dogs and will inform the development of the drugs in human clinical trials. “We see a lot of this disease in dogs, and because our patients aren't cured by chemotherapy, new therapies are always of interest to us,” Dr. Lana says.
Most cancer treatments for dogs are those that are used in humans, Dr. Kisseberth notes. The first approved, targeted, anticancer drug for dogs is toceranib phosphate (Palladia), which is a receptor tyrosine kinase inhibitor. It is very similar to the human drug sunitinib (Sutent); both drugs target tumors with KIT mutations. In humans, sunitinib is used primarily to treat gastrointestinal stromal tumors. In dogs, toceranib phosphate treats mast cell tumors.
Similar to human clinical trials, comparative oncology research is beginning to focus less on matched histologies and more on the shared biology (dysregulation of a pathway or gene) of tumors between dogs and humans. For that reason, researchers in human and veterinary oncology jointly launched the Canine Comparative Oncology and Genomics Consortium (CCOGC). The program's goal is to collect biopsied tumor tissue (with a target of 600 samples from dogs with each histology) to provide a resource for investigators conducting genomic studies.
“A lot of mutations we see in human cancers are similar to those seen in dogs, and we can test these drugs in many of the same signaling pathways that have become dysregulated,” Dr. Kisseberth says. In addition to banking tumor tissue, the CCOGC's biospecimen repository will collect urine and serum samples, which may enable scientists to develop new diagnostic tests for specific cancers, he says.