Not Lost in Translation: How Study of Diseases in Our Pets Can Benefit Them and Us

Abstract

Practice-changing medical discovery requires preclinical and clinical assessment be carried out using appropriate disease models. There is growing awareness of companion animals with naturally-occurring disease as such models. They offer significant advantages over more traditional in vivo models of induced disease. This review describes current efforts to promote translation of discoveries between human and veterinary medicine in order to more rapidly and efficiently make progress in improving the health of all human and animal patients.

Case Presentation

The patient sat in the exam room, uneasy in the hospital surroundings as I delivered the diagnosis: osteosarcoma. The family stared in disbelief as we reviewed the images together and their questions reflected the unfairness of the situation. Why him? Why so young? As I began to talk about treatment options, prognosis, and quality of life issues, the young patient was noticeably detached from the conversation—unable to comprehend the issues with which his family was already grappling. When presented with the option of clinical trials, some organized through the National Cancer Institute, there was a mixed reaction: concern about trying something unproven and hope that this new treatment would provide a better outcome; not just in this case but for those diagnosed in years to come. Eager to pursue the most cutting-edge therapy, the family agreed to speak with the Clinical Trials Coordinator that afternoon. They would leave the hospital weighing options to be discussed further when results of staging procedures were known. Complicating all of this was the fact that the patient was uninsured.

Introduction

This is a difficult situation all too familiar in pediatric practice. However, in this case the patient was a 45-kg Rottweiler and the hospital is the Veterinary Medical Teaching Hospital at the University of Missouri. But before you dismiss the story as irrelevant to your medical practice, consider the following: pet dogs are at approximately ten-fold risk of developing naturally-occurring osteosarcoma compared to people; genetic mutations involved in development of osteosarcoma are shared across species; therapy studies conducted using pet dogs with osteosarcoma have led to advances in limb-sparing procedures for people; and current clinical trials for canine osteosarcoma include investigation of inhalant chemotherapy, small molecule inhibitors, and novel immunotherapy approaches (http://www.vetcancertrials.org).^1–3 Many of these have direct translational application to human oncology.⁴

The Comparative Oncology Trials Consortium

The University of Missouri was one of the eight original institutions selected for inclusion in the National Cancer Institute’s Comparative Oncology Trials Consortium (COTC) (https://ccrod.cancer.gov/confluence/display/CCRCOPWeb/Home), the goal of which is to design and execute clinical trials in dogs with naturally-occurring cancer to assess novel therapies for translation to human patients.⁵

Since its inception in 2003, the Comparative Oncology Program, and specifically the COTC, has initiated 18 trials and has grown to 20 member institutions in North America. All member institutions must meet strict staffing criteria and have both CT and MRI imaging equipment, a dedicated clinical trials coordinator, tissue banking capability, radiation therapy on site, and demonstrated expertise in electronic data reporting.

The first trial conducted through COTC (COTC001) evaluated a targeted AAV-phage vector designed to deliver tumor necrosis factor (RGD-A-TNF) to α_Vβ₃ integrins on tumor vasculature endothelium. This dose-escalation trial enrolled cohorts of three dogs (n = 24) to determine the optimal safe dose (5 × 10¹² transducing units administered intravenously) of RGD-A-TNF.⁶ A unique feature of this trial that would have been impossible in a human clinical trial was the ability to demonstrate selective targeting of tumor-associated vasculature and sparing of normal vasculature via serial biopsy of both tumor and normal tissue. Why would someone seek to enroll their pet in a clinical trial? The answer sometimes lies in the fact that health insurance and prescription plans are uncommon for veterinary patients and standard-of-care is less well-defined. Thus, treatment options for veterinary patients can vary widely and financial constraints are often the determining factor when medical decisions are made.

The upside to this economic dilemma is that clinical trials investigating new treatment options are often a win-win for pet owners and clinical researchers. The incentive to pet owners is three-fold: 1) trial funding means that pet dogs are treated at minimal expense to the owners, 2) trials offer cutting-edge therapy not available elsewhere, and 3) the opportunity to contribute to “the greater good” is attractive in terms of both altruism and the chance to turn individual misfortune into opportunity for future patients. The value of the latter cannot be overestimated. The sense of empowerment provided by turning a frightening diagnosis into an opportunity to advance the field of oncology in ways that could have tangible benefits for humans and animals affected by cancer is highly motivating for many people enrolling their pets in veterinary clinical trials.

In the case of the COTC001 trial, pre- and post-treatment biopsy of normal and tumor tissue confirmed targeting of the α_Vβ₃ integrins on tumor vasculature. Repetitive dosing in a cohort of 14 dogs using the defined optimal dose was well tolerated and led to objective tumor regression in two dogs (14%) and stable disease in six dogs (43%). The study findings were used to inform decisions in design of ongoing Phase I clinical trials in humans. Other COTC studies that are currently underway are facilitating protocol optimization and elucidating mechanism of action for novel anti-cancer therapies that will undoubtedly enter human clinical trials if success is demonstrated in canine models of spontaneously-occurring cancer.

The key to successful translational studies is the appropriate choice of disease model and who better to choose that model than Mother Nature? While the phrase “cancer researcher” has traditionally conjured visions of laboratory personnel assessing tumor response in rodents with artificially-induced tumors, animals with naturally-occurring cancer offer distinct advantages. Rodent models of human cancers either develop within an incompetent immune system as xenografts or arise artificially homogeneic in knockout models. They lack heterogeneity, progress rapidly, and may not recapitulate the tumor microenvironment found in human cancers to the degree that spontaneously occurring cancer in companion animals does. The internal and external environments in which cancer develops in pets share similarities with those of people. The environments encompass everything from exposure to carcinogens to fluctuations in hormone levels. Given the abundance of examples where cures in rodents have not translated to effective therapies in people, this side-step of medical discovery into the field of companion animal medicine offers a logical new path.

Beyond the applications of canine disease models to cancer drug development, the field of comparative medicine extends into many other disciplines including neurology, infectious disease, immunology, cardiology, orthopedics, and ophthalmology to name just a few. Researchers at the University of Missouri’s College of Veterinary Medicine have gained international recognition as leaders in the study of animal models of retinal degeneration, asthma, degenerative neurological disease, and osteoarthritis. Mizzou researchers have modified existing technology to validate these animal models with comparative genomics and epigenomics, flow cytometry, ex vivo immunological evaluations, and bioengineering.

The concept of comparative medicine is gaining interest of late, both in the scientific literature and in the lay press. In articles from the New York Times to the New England Journal of Medicine this past year, authors have given examples of medical discoveries that have crossed species boundaries, benefitting patients of the two-legged and four-legged varieties.^7,8 In her newly published book, “Zoobiquity, What Animals Can Teach Us About Health and the Science of Healing,” cardiologist Barbara Natterson-Horowitz coins the term “zoobiquity” to describe what she calls the “fusion of veterinary, human and evolutionary medicine.”⁹ She describes the tremendous potential for advancement of medical science if barriers between physicians, veterinarians and evolutionary biologists are broken down, stating “we are uniquely situated to explore the animal-human overlap where it matters most urgently - in the effort to heal our patients.” Admittedly, when veterinarians use the phrase “patient” to refer to a pet presented for medical care, our physician counterparts do a double-take. But the reality is that precisely the same technology and treatment options found in local hospitals for human patients are available at academic and referral institutions for veterinary patients. In certain specialties such as veterinary oncology, drugs marketed for use in people are routinely prescribed for use in pets, as comparable veterinary-labeled drugs do not exist. Ignoring that the patient is a dog or a cat, the underlying etiology and pathology are similar, demanding the same diagnostics and drugs.

Efficient and rapid scientific discovery through comparative genomics are enhanced by clinicians and researchers sharing knowledge between human and veterinary medicine.

Viewing diseases with this lens, the similarities become obvious. Infectious diseases, endocrinopathies, toxicities, and immune-mediated diseases share causes and clinical signs across species. Most canine patients come from large “families” of siblings/littermates, often with defined pedigree information available through kennel clubs such as the American Kennel Club. This facilitates the genetic mapping of disease susceptibility traits by breed, enhancing the power of comparative studies to elucidate underlying genetic causes. If one breed is uniquely susceptible to Disease X and another breed rarely affected, comparing the genomics of these two breeds to the rest of the population often defines the underlying etiology for Disease X, as well as giving clues as to how to manage or mitigate it.

Compatibilities in Genomic Studies

The field of genomics was bolstered in 1989 when the National Center for Human Genome Research was established in response to the charge to map the human genome as part of the International Human Genome Project. With sequencing of the human genome completed in 2003, biomedical research has experienced the opening of a floodgate of opportunities for discovery in areas as broad and varied as understanding genetic mechanisms of disease to developing a more sustainable food supply. Fast forward to 2005 when the completion of a genome sequence of the domestic dog expanded the horizons of comparative medical genomics. Opportunities for efficient and rapid scientific discovery through comparative genomics are now limited only by the imagination of clinicians and researchers and the shared knowledge between human and veterinary medicine. An inherited cancerous disease in German Shepherd dogs, renal cystadenocarcinoma and dermatofibromatosis, is found to be caused by a mutation in the gene for folliculin, bearing a striking clinical similarity to the human disease, Birt-Hogg-Dube syndrome.¹⁰ A form of progressive retinal atrophy (Leber’s congenital amaurosis type 2) that leads to blindness shortly after birth shares a similar genetic mutation between dogs and people. Using gene therapy to restore the RPE65 protein that is lost through the mutation restored vision in affected dogs and led to subsequent successful therapy in people.^11,12 Veterinary neurologists, geneticists, and physicians at the University of Missouri have worked together to identify the genetic cause of degenerative myelopathy in dogs that is analogous to human amyotrophic lateral sclerosis (aka, Lou Gehrig’s Disease).¹³ NIH funding for a University of Missouri-led therapy trial in affected dogs was announced in September 2012. Clearly, the pace of scientific discovery and medical innovation has quickened and we are well positioned to lead the way in this critical endeavor.

One Health/One Medicine

Few sites in the U.S. can boast the atmosphere of creative, innovative and collaborative research found at the University of Missouri. The phrase “One Health/One Medicine” refers to the sharing of resources, knowledge and effort toward the common goal of improving the health and well-being of all species. This One Health/ One Medicine concept is a key component of the MU’s strategic plan. The presence of a School of Medicine, School of Nursing, College of Veterinary Medicine, University Hospital and Clinics, Center for Clinical Research, Life Sciences Center, and tremendous strength in basic science research, biomedical innovation, and bioinformatics makes MU an ideal setting in which to translate medical discovery from idea to clinical implementation efficiently and at a pace to have a real impact on patients in our lifetime. This translational approach is being extended to other sites throughout the State. University of Missouri is partnering with other Missouri academic centers, the Kansas City Area Life Sciences Institute, the Institute for Conservation Medicine, the St. Louis Zoo, and the “Animal Health Corridor” extending west along I-70 and connecting MU veterinary and human medical researchers and clinicians with animal health companies and academic institutions in Kansas City.

We are also reaching outside of the state to Kansas State University’s College of Veterinary Medicine and the University of Kansas to speed clinical translation of novel diagnostic and therapeutic approaches. We are rapidly moving towards a day when the patient in the examining room with osteosarcoma will receive better news of individualized therapy developed in comparative trials. Through One Health/One Medicine efforts, whether the patient is human or canine will matter less than the underlying, shared disease mechanisms for therapy decision making.

Biography

Carolyn J. Henry, DVM, MS, DACVIM, is in the Department of Internal Medicine, Hematology/Oncology Division and Department of Veterinary Medicine and Surgery. Jeffrey N. Bryan, DVM, PhD, is in the Department of Veterinary Medicine and Surgery. Both are at the University of Missouri.

Contact: HenryC@missouri.edu