The Bidirectional Flow of Comparative Cancer Trials: Are People Just Big Dogs?
David M. Vail, DVM, DACVIM (Oncology)
Several aspects of companion animal disease make for attractive comparative models. The idea of testing drugs in dogs and cats dates at least as far back as 1922 when Banting & Best treated a critically ill 14-year old diabetic with insulin after first investigating its use in dogs at the University of Toronto. The use of animals for the preclinical study of cancer therapeutics also has a long history, and important information has been gained regarding new and innovative therapies. Preclinical modeling in companion animal trials can serve as a bridge between in vitro or small animal (rodent) models and physician-based human clinical trials. The companion animal model provides unique opportunities for translational cancer research and is the ideal bridging step to implementation of project methodologies into use in human clinical trials.
Historically, the majority of this work has been performed on inbred rodent models and laboratory -derived canine populations. Working with inbred populations in controlled, artificial laboratory environments raises some degree of concern over the applicability of information as it relates to naturally occurring tumors in people and indeed naturally occurring tumors in companion animal pets. Many of these concerns may be allayed through the study of naturally occurring tumors in our companion animal population, (i.e., dog and cat pet population). Companion animals with naturally occurring tumors, although presently underutilized, better recapitulate tumor biology and responsiveness to therapy and therefore have and should continue to provide an excellent opportunity to investigate many aspects of malignancy from etiology to treatment. We believe that the integration of companion animal investigational trials provide the mechanism to seize these opportunities and ultimately fulfill the NCI charter of "eliminating the suffering and death due to cancer" in humans as well as pet populations. We, as veterinarians, must ensure an eye towards the flow of this information being bidirectional and returning benefit to companion animal species and not exclusively physician-based oncology. At the end of the day, we are veterinarians after all and we want to ensure our own patients benefit from the discoveries and developments that result from these clinical investigations.
Advantages of Companion Animal Models
Shared Common Environment
Companion animals share a common environment with people and represent a more natural outbred population. Exposure to environmental carcinogens should, therefore, be similar to that in people. In support of this, evidence exists that environmental factors may play a role in the development of canine nasal tumors,1 bladder tumors,2 and lymphoma,3-5 and asbestos exposure has been associated with the development of canine mesothelioma.6
Spontaneous Tumor Development
Malignancies in companion animals develop spontaneously, whereas experimental laboratory models utilize induced tumors either through exposure to known carcinogens or transplantation, often in the presence of artificially induced immunologic modification. Tumors implanted in genetically identical, immunologically compromised rodent systems lack the heterogeneity and immunosurveillance capabilities that make companion animal models better to recapitulate the human cancer experience.
High Incidence of Cancer and More Rapid Progression
Nearly half of all households in the United States include a companion animal. This places approximately 74 million dogs and 90 million cats at risk for developing cancers in the United States.7 Cancer is the number one cause of death overall in dogs, likely attributable to the lack of significant atherosclerosis-associated cardiovascular disease in this species. In a necropsy series of 2,000 dogs, 23% of all dogs, regardless of age, and 45% of dogs 10 years of age or older died of cancer.8 Estimates of age adjusted overall cancer incidence rates per 100,000 individuals/year at risk, are 381 for dogs and 264 for cats; comparable to approximately 300 for humans (National Cancer Institute SEER Program).8 Incidence rates for certain malignancies in companion animals (e.g., canine osteosarcoma, non-Hodgkin's lymphoma [NHL]) are higher than those observed in people, providing a large population for study. Conversely, certain other neoplasms, such as hemangiosarcoma (angiosarcoma) and mast cell neoplasia, are extremely rare in humans but abundant in companion animals, allowing meaningful clinical data to be generated in tumor types with "orphan" status in humans.9-12 Tumors in companion animals generally progress at a more rapid rate than their human counterparts. This time-course is both long enough to allow comparison of response durations, but short enough to ensure rapid accrual of data.
By virtue of their body size, sample collection (i.e., serum, urine, cerebrospinal fluid, multiple tissue samples), surgical interventions, imaging and novel drug delivery systems are more readily applied to companion animals than in rodent models. Repeated sampling of biological fluids and tissues before and at various times after novel treatment interventions are not practical in rodents but are safe and practical in companion animals. Abundant tumor tissue is generally available for bench-derived molecular analysis, and often tissues can be submitted to several investigators concurrently. Species body size also allows a commonality of imaging techniques to be used to stage tumors and monitor treatment response. Our recent work with the development of inhalational drug delivery systems, PET/CT imaging systems for monitoring treatment response, and Tomotherapy® radiation delivery systems all serve to illustrate the advantages of a larger body size.
Similar Biology and Tumor Genetics
Companion animal cancers more closely resemble human cancers than rodent models in terms of size, cell kinetics, and biologic variables such as hypoxia, angiogenesis, perfusion, apoptosis and clonal variation.13-15 Indeed tumors in our companion animal species often possess the same molecular targets that show promise for novel anticancer therapy. For example, a variety of protein kinase signaling systems important to human cancer development and progression, have been detected and modulated in canine and feline tumors. Biological regulation of tumor senescence involving telomere length in companion animals more closely follows human cancer biology in comparison to rodent systems. Additionally, the recent elucidation of the canine genome and the commitment to cooperative ventures between several academic, federal, and private sector development groups, provide us with a phenomenal point of opportunity to serve as a bridge between in vitro or small animal (rodent) models and physician-based human clinical trials. The dog has been recently added to the list of post-genomic mapped species and is known to have greater homology and synteny with the human genome than do rodents.16,17 With this genomic map in hand the dog is now positioned to advance our understanding of disease in many important ways. Greater than 500,000 SNPs are identified and > 100 microsatellite markers identify 85 different breeds. Canine specific LOH and gene expression and tissue microarrays now exist. Commercially available gene expression chips that are annotated, and include >20,000 sequences (Genbank, dbEST, LION) are currently available. Additionally, hepatic enzyme homology is 2 orders of magnitude more similar to people than are rodents and pharmacokinetic/pharmacodynamic investigations will likely better parallel the human experience. Indeed, we have investigated novel anticancer prodrugs in pet dogs with cancer that could not be completed in rodent systems that lack the enzymatic machinery to convert these agents to their active metabolites. Further support comes from the fact that tumor responsiveness in tumor-bearing companion animals to currently available chemotherapeutics closely mirrors activity in human cancer patients.
Clinical Trial Mechanics
The relative cost of veterinary-based trials, while of the highest caliber, is substantially less than physician-based trials. These trials can be performed in the pre-IND (investigational new drug) setting without the necessity of GMP drug constraints in many situations. Veterinary patients tend to be less heavily pretreated, with better performance status at study entry than are most humans entered into phase I trials. This allows investigations to proceed in patients that are more likely to tolerate interventions and with tumors that are more likely to be responsive as the cellular death pathways are still intact. In addition, an expanding animal rights movement is making investigations with laboratory animals more difficult. Provided that well-designed, humane guidelines are adhered to, clinical trials involving companion animals may be more acceptable. Because the "standard of care" is not established for many tumors encountered in the veterinary profession, more latitude in prospective clinical trials is allowable, and it is easier and morally acceptable to attempt new and innovative treatment strategies. Importantly, such latitude should not be abused, and present-day veterinary institutions consistently use informed client consent and institutional review boards to ensure study design and ethical standards are maintained. In general, clinical trials using veterinary patients can be completed at significantly less expense than similar human clinical trials. Professional services, clinical pathology, and diagnostic imaging, although of the highest quality, are of lower cost in comparison.
Client Enthusiasm for Investigational Trials
Experience with veterinary clientele provides further evidence for the companion animal as a model. Most companion animal caregivers are highly motivated and actively seek innovative and promising new therapies to vanquish their companions' cancer and are gratified with honest and aggressive attempts at cure or palliation. As a whole, either through personal experience with family members and friends, or media coverage of available and leading-edge therapy, they demand the highest quality of care. Because most trials involve a significant financial incentive, access to the highest quality of medicine, the possibility of an effective therapy when none exists, or the offer of additional therapy if the novel investigative approach does not result in measurable response, these trials often represent a "win-win" situation for the caregiver. Many clients are also driven to involvement with the hope of ultimately enhancing the treatment of cancer in people and future generations of companion animals. Largely due to these points, clinical oncology departments at many academic institutions have been very successful in the past in entering patients into clinical trials that involve invasive procedures and multiple hospital visits. Compliance with treatment and recheck visits is exceptional, and autopsy compliance approaches 90%, significantly better than most human clinical trials.
Weaknesses of Companion Animal Modeling
Certainly no system is perfect and not all biological questions can be answered by any one model. Companion animal investigational trials do require larger quantities of "clean" drug to be manufactured in comparison to rodent models; however, as stated earlier, GMP quality drug is not a requirement for initial investigations. Target biology is not uniformly identical in all species and some initial proof-of-target investigations must precede most trials. Additionally, the spectrum of cancer histologies in companion species differs from humans; classically, people tend to get more carcinomas than sarcomas while our companion species tend to have a reverse incidence. This caveat can be irrelevant, however, if the molecular target is the same despite the histology. This latter point is best illustrated by mast cell tumors, which while very common in dogs and extremely rare in people, are often affected by signal pathways (e.g., c-Kit) that are relevant to a much more varied group of human malignancies. Another obstacle to investigation in the past has been the relative lack of biological reagents and monoclonal antibodies for the canine species in comparison to rodent species. This is becoming less relevant as availability grows. Finally, the position of companion animal modeling with respect to regulatory oversight (i.e., FDA) and acceptability and application to future human trials has been an issue that has given corporate biotech and the pharmaceutical industry some pause for concern. This continues to be a moving target and future collaborations with the FDA regarding what data regarding efficacy and toxicity should be relevant are currently ongoing.
Methods to Enhance Bidirectional Flow of Information Gained
As previously mentioned, our wish is not to have important data generated in companion animals and indeed promising drug and therapeutic strategies that are developed solely benefit physician-based oncology. We strive to ensure important breakthroughs and advanced treatments flow back into veterinary-based oncology standard-of-care. Ultimately, all therapies developed and marketed for human patients will be available by off-label use to veterinarians and veterinary patients; however, these often are at excessively high cost, at least until patents expire and more economical generic products become available. Approaches to ensure more rapid and economical access to veterinary markets include ensuring cross-talk between the human and animal health divisions of major pharmaceutical companies early in drug investigation, promoting a "second to lead" approach (see below), and communicating successes with smaller veterinary based pharmaceutical and marketing companies. In the former case, when drug development leads to a product that may not be suitable for use in humans for various reasons (e.g., other alternatives already exist, uncommon tumor incidence), a superior, more common, or acceptable veterinary use may exist and communication between the human and veterinary development groups can result in shifting the market focus. In the latter case, recent negotiations with veterinary based drug marketers have resulted in groups moving for FDA licensure of drugs with indications specific for veterinary species resulting in formulations (e.g., dosing size) becoming available that are better suited to companion animal species.
The "Second-to-Lead" Approach
In today's rapidly accelerating drug development environment, most pharmaceutical companies take advantage of accelerating the process of chemical synthesis methods to the extent that it is now possible to produce compound libraries to screen for novel bioactivities. This powerful new technology has begun to help pharmaceutical companies find new drug candidates quickly, save significant money in preclinical development costs and ultimately change their fundamental approach to drug discovery. The result is that rather than one particular drug being available for investigation, a "library" of similar drugs is codiscovered that have nearly identical structure and function. In this case, moving one forward through the human health division and another in parallel through the animal health division has several advantages. Investigations in one can serve to inform development of the other in clinical trials without compromising marketing strategies that will allow less expensive and species-licensed products to become available to companion animals. This is best illustrated in the current development of small molecule tyrosine kinase signaling pathway inhibitors, where second-to-lead molecules are currently being field-tested in veterinary patients prior to licensure in companion animal species.
1. Reif JS, et al. Am J Epidemiol 1998;47:488.
2. Glickman LS, et al. J Toxicol Environ Health 1989; 28:407.
3. Gavazza A, et al. J Vet Intern Med 2001; 15:190.
4. Hayes HM, et al. J Natl Cancer Inst 1991; 83:1226.
5. Reif JS, et al. Am J Epidemiol 1995; 141:352.
6. Glickman LT, et al. Environ Res 1983; 32:305.
7. Vail DM, et al. Cancer Invest 2000;18:781.
8. Bronson RT. Am J Vet Res 1982; 43:2057.
9. Dorn CR, et al. J Natl Cancer Inst 1968;40:307-318.
10. Dorn CR. Comp Cont Ed Pract Vet 1976;12:307-312.
11. Priester WA, et al. Natl Cancer Inst Monogr No. 54. Washington DC: US Government Printing Office:152, 1980.
12. Teclaw R, et al. J Am Vet Med Assoc 1988;201:1725.
13. Vail DM, et al. In Teicher BA, Andrews PA (eds): Anticancer Drug Development Guide, 2nd Edition. Totowa, NJ, Humana Press Inc., 2004, pp259.
14. Khanna C, et al. Nature Biotechnology 2006;24:1065-1066.
15. Paoloni M, et al. Nature Rev Cancer 2008;8:7.
16. Parker HG, et al. Science 2004;304:1160.
17. Sutter NB, et al. Nature Rev Genetics 2004;5:900.