Translational Research: Dogs and Humans Nearly Interchangeable in the Laboratory


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Wendy Levin, MD

Michael Kastan, MD, PhD

Matthew Breen, PhD

Recently, there has been renewed interest in studying tumors that spontaneously develop as a result of aging in companion animals (dogs mostly), because they share many characteristics with human cancers.

—Michael Kastan, MD, PhD

“Between animal and human medicine there is no dividing line—nor should there be. The object is different but the experience obtained constitutes the basis of all medicine.”

— Rudolf Virchow (1821–1902)

 

Everyone has seen photographs of people who look like their dogs: the young woman with long straight hair and a thin face and her Afghan hound, the square-faced codger with an underslung jaw sitting cheek by jowl with his English bulldog, the middle-aged woman with curly hair hugging her grey poodle. However, according to the scientists who spoke at the National Cancer Policy Forum’s workshop, “The Role of Clinical Studies for Pets With Naturally Occurring Tumors in Translational Cancer Research,” we resemble our doggie pals in far deeper ways than just furry bellies and goofy grins.

Michael Kastan, MD, PhD, Executive Director, Duke Cancer Institute, described how dogs could serve well as preclinical models—for humans and for themselves. “Many novel drug candidates fail human clinical trials despite evidence of efficacy in murine model, because mice often lack key characteristics of human cancer, such as long latency, genomic instability, and heterogeneity among tumor cells and the surrounding microenvironment.” In fact, only 11% of antineoplastic drugs that showed efficacy in mice were approved for human use.

Drug Development

“Oncology drug development is extremely expensive, crowded, and fiercely competitive,” said Anne Keane, JD, Director of Regulatory Affairs, Achaogen, San Francisco. There are more than 800 oncology compounds currently in the pipeline, 576 in late phase II and III trials, and a total of about 5,000 ongoing oncology drug studies.

Moreover, the competition for research money is intense, and the time it takes to get a drug from the lab to market is critical. Ms. Keane said that even a 1-month delay can mean millions of dollars of lost revenue each month. Human trials are fraught with problems from beginning to end. They take, on average, 70% longer than anticipated, patient recruitment is slow and unsteady (particularly in pediatrics), and they almost always cost more than the original estimate.

Lee J. Helman, MD, Senior Investigator, National Cancer Institute (NCI) Pediatric Oncology Branch: Cancer, said drug development attrition rates are significantly higher in oncology than in other therapeutic areas—a 5% success rate compared with 20% for cardiovascular drugs. In fact, 70% of oncology drugs that enter phase II studies fail to move to phase III trials, and 59% of phase III drugs fail to gain approval—more often due to a lack of efficacy than to toxicity. There have been many attempts to solve the problem, most to no avail. Therefore, Chand Khanna, DVM, PhD, NCI Consultant, NCI Pediatric Oncology Branch, stated that a comparative and integrated approach to cancer drug development may be a solution.

Dogs May Be More Than Companions

“Recently, there has been renewed interest in studying tumors that spontaneously develop as a result of aging in companion animals (dogs mostly), because they share many characteristics with human cancers, such as histologic appearance; tumor genetics; biologic behavior; molecular targets; therapeutic response; and acquired resistance, recurrence, and metastasis,” said Dr. Kastan.

Cancer is common in pets—80 million dogs and 90 million cats. Of U.S households, 47% own at least one dog, and every year, a million of them are treated for cancer. The disease kills 50% of dogs aged 10 and older and 33% of younger ones. One-third of cats die of their cancer. Pet owners, especially men for some reason, because they are so attached to these family members, are highly motivated to enroll pets in clinical studies.

Wendy Levin, MD, Vice President, Clinical Development, Fate Therapeutics, San Diego, said that companion animals are large and outbred, thus showing strong genetic similarities to humans. Their cancers occur naturally, as do those of humans, and they are immune-competent and syngeneic. Other characteristics that make them ideal subjects in cancer trials include relevant tumor histology and genetics, tumor heterogeneity, biology of metastasis, relevant response to chemotherapy, and compressed times for disease progression.

At the same time that human drugs are progressing from preclinical studies through three phases of clinical trials, tumor-bearing dog studies can determine activity, toxicity, pharmacokinetics, and pharmacodynamics (preclinical and phase I), as well as dose, regimen, schedule, biomarkers, responding histologies, and combination therapies (phases II and III).

Comparative Oncology Consortia

Translational studies in pets, known as comparative oncology, can be a useful intermediary between traditional preclinical models and human clinical trials. After drug approval, comparative oncology can provide additional information about safety, dosage, and regimen. The main goal is to answer biologic questions about the development paths of new treatments for future use in human patients with cancer.

The Comparative Oncology Trials Consortium (COTC), which is managed by the NCI Center for Cancer Research Comparative Oncology Program, provides an infrastructure and resources to integrate clinical trials for pets into development of new drugs, devices, and imaging techniques for human cancers. Trials are conducted by 20 veterinary academic centers, which provide owner education and obtain informed consent for research that eventually benefits both animals and humans. Progress to date includes 19 initiated letters of intent, 11 initiated study protocols, 9 studies completed (with 3 published), and 7 more in progress.

“Trials conducted by COTC are pharmacokinetically and pharmacodynamically integrated into the design of human phase I and phase II human trials,” said Dr. Kastan.

The Canine Comparative Oncology and Genomics Consortium (CCOGC), also part of the NCI Center for Cancer Research, was established in 2007 to facilitate strategic partnerships and collaborations to study cancer in dogs. The Pfizer-CCOGC Biospecimen Repository has amassed 60,000 specimens from about 2,000 canine patients with cancer of more than 100 breeds—52% male and 48% female. They include seven types of cancer (osteosarcoma, lymphoma, melanoma, pulmonary tumors, mast cell tumors, soft-tissue sarcomas, and hemangiosarcomas) and nine types of specimens, among them frozen tumor tissue, plasma, and normal tissue. The CCOGC has developed a mechanism to share reagents and resources as well as to develop a biospecimen repository, which is accessible to the public based on scientific merit.

The FDA Animal Testing Rule

The U.S Food and Drug Administration (FDA) has established a rule about animal testing as a surrogate for approval of drugs and biologics when human efficacy studies are neither ethical nor feasible. Stipulations of the rule follow:

  • There is a reasonably well-understood pathophysiologic mechanism.
  • The study outcome is clearly related to the desired benefit in humans (reduced morbidity/mortality).
  • Effective dosage in humans can be extrapolated from the pharmacokinetics in animals.
  • Animal testing is not designed merely as a shortcut to approval.
  • After adequate and well-controlled animal tests, the results of which establish that a product is reasonably likely to provide clinical benefit in humans, safety must still be demonstrated in human subjects.

Dogs Eat, Play, and Sleep With Us

The vast majority of human cancers are the result of environmental exposures, and because pets share our environment (breathe the same air, chase tennis balls on lawns that we fertilize, swim in the same lakes, eat some of the same food, and possibly sleep in the same bed), they too are heir to the same cancers. Different breeds are susceptible to different cancers, said Dr. Kastan, and these differences can provide insight into how environmental exposure can lead to cancer development.

So too can biobanks, said Matthew Breen, PhD, Oscar J. Fletcher Distinguished Professor of Comparative Oncology Genetics, North Carolina State University, College of Veterinary Medicine. They are critical for several reasons. First, research involving canine genetic or genomic information analyzed using biologic specimens from well-annotated patients is key to understanding complex diseases such as cancer. Second, these data are critical to advancing cancer detection, diagnosis, prognosis, intervention, treatment, and prevention. Third, establishing and sharing canine biologic samples and information derived from their analysis can create maximal research efficiency.

Key elements of an effective biobank include specimen selection and storage for a variety of purposes, access to the specimens and patient data by researchers, and a workable data-sharing plan. These factors are critical, of course, but the animals from whom these samples are taken are our family members, and most pet owners are utterly besotted by their “babies.”

“Think of them as child patients,” said Patricia Olson, DVM, PhD, Independent Advisor on Animal Health and Welfare. She asked a number of questions that researchers should take into consideration:

  • Is the trial in question designed to prevent disease or provide a new therapy?
  • Who will serve as an independent advocate for the animal during a trial?
  • Animals cannot give consent; therefore, what are appropriate safeguards to ensure their welfare?
  • Should conventional therapy ever be delayed for an animal participating in a trial?
  • What are the limits on tissue and blood collections?
  • Do companion animals benefit from clinical research, especially phases 0 and I? ■

Disclosures: Ms. Keane, Drs. Kastan, Helman, Khanna, Levin, Breen, and Olson reported no potential conflicts of interest.

 



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