Of Dogs and Men: Lessons on the Fight Against Cancer
In a story featured early last year, the NCI Cancer Bulletin highlighted a program, then just getting underway, that helps answer human clinical research questions through studies that include pet dogs that have developed naturally occurring cancers. Now the program has convened a Comparative Oncology Trials Consortium (COTC), led by Dr. Chand Khanna of NCI's Center for Cancer Research (CCR), and several of the participating institutions are nearing the end of their first trial.
"CCR has added value to cancer research by taking on this responsibility, bringing people from the pharmaceutical industry, the federal government, and the veterinary community together," says Dr. Khanna. "I think this is quite important. It's one of the ways the intramural program at NCI is valuable. We can respond quickly and coordinate large projects successfully."
COTC includes 14 veterinary teaching hospitals across the country. All members have met strict staffing criteria and have MRI and CT imaging equipment, a dedicated clinical trial coordinator, tissue banking capability, onsite radiation therapy, and experience in electronic data reporting.
"Our clinical trials are monitored and reported on the same bioinformatics backbone that exists for human clinical trials," says Dr. Khanna. He notes that the technological platforms they use all comply with NCI technology initiatives, such as caBIG™, and that a parallel program, the Canine Comparative Oncology and Genomics Consortium, is guiding their tissue-banking efforts so that the potential of tissues collected in these trials can be maximized.
COTC's inaugural study is testing the targeted delivery of the cytokine TNF-alpha to tumor blood vessels in dogs. The TNF-alpha gene is delivered through viruses that are labeled with arginine-glycine-aspartic acid, a combination of amino acids that "sticks" to proteins found prominently in tumor vasculature. COTC investigators at the veterinary schools of the University of Tennessee, Colorado State University, the University of Missouri, and the University of Pennsylvania are participanting in this first canine clinical trial.
Dr. Steven K. Libutti, head of CCR's Tumor Angiogenesis Section in the Surgery Branch, developed the biological rationale for the study. He says that there are early indications that the targeted vector is reaching its desired destination and is not causing toxicity in the dogs. Full results will likely be published before the end of this year. "If we can confirm tumor targeting, this will make the vector extremely interesting to us for use in human clinical trials," he says.
There are distinct advantages to studies that evaluate novel human clinical agents in canines. Dogs are genetically more similar to humans than are mice, and because of their large body size, their physiology lends itself to human comparison. Also, dogs naturally develop many of the same cancers that people develop, while lab mice must be genetically engineered or triggered to develop these diseases.
Naturally occurring tumors consist of cells that are genetically diverse. The consequences of this diversity include disease recurrence and emergent resistance to therapy, problems frequently encountered in human cancer patients. Another result is metastasis, which occurs naturally in dogs with cancer, as it does in humans.
In addition to the comparable complexity of their tumor biology, an advantage of testing clinical interventions in dogs is that investigators can perform serial biopsies before and after treatment to see how a new agent is affecting the tumor over time - something that's difficult to do in human trials.
"We have some really exciting opportunities as a result of this initiative," says Dr. Khanna. He notes that the consortium is engaged in conversations with the Food and Drug Administration (FDA) about how data from the COTC trials could be included in the drug development pathway for new human drugs.
"One aspect of this discussion is when it's appropriate for canine trials to be conducted, and when it is not," says Dr. Khanna. "Our goal is to determine how these complex, relatively expensive, large-animal studies can complement mouse and other preclinical models and optimize the drug development process."
In the current trial, Dr. Libutti notes that if it demonstrates targeting of spontaneous tumors in dogs, "we can potentially study the activity of a wide variety of agents that have the potential to be active in the local tumor microenvironment. Such therapies may be beneficial both to the pet animals with tumors, as well as to our patients.
"It's an excellent example of how dogs can truly be man's best friend," he says. "In this case, both man and dog have the potential to benefit."
By Brittany Moya del Pino