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ICMJE criteria for authorship read and met: IKG MP CM CK. Agree with the manuscript's results and conclusions: CM. Wrote the first draft of the paper: IKG. Contributed to the writing of the paper: IKG MP CK.
Despite evidence of drug efficacy in mouse models of cancer, many novel anti-cancer agents fail in human cancer patients because of unacceptable toxicity or poor efficacy . Naturally occurring tumors in dogs and other animals have clinical and biological similarities to human cancers that are difficult to replicate in other model systems. A recently launched cooperative effort, the National Cancer Institute's (NCI's) Comparative Oncology Trials Consortium (COTC; http://ccr.cancer.gov/resources/cop/COTC.asp), now provides infrastructure and resources needed to integrate these naturally occurring cancer models into the development of new human cancer drugs, devices, and imaging techniques.
Murine cancer models have been extremely useful for analyzing the biology of pathways involved in cancer initiation, promotion, and progression. However, they frequently do not adequately represent many of the features that define cancer in humans, including long periods of latency, genomic instability, and the heterogeneity of both tumor cells and their surrounding microenvironment. Most importantly, the complex biology of cancer recurrence and metastasis, integral to outcomes in human patients, are not appreciably reproduced in the conventional mouse models used in cancer drug development. Furthermore, in many cases, there has been inadequate consideration of relevant exposures for new drugs that are evaluated in mice. The development and approval of novel cancer drugs is lengthy and expensive –; therefore, additional models that better represent the human disease are needed.
Current drug development pathways are frequently unidirectional. Novel agents are assessed in conventional preclinical models of efficacy and toxicity before moving into human clinical trials where they either fail or succeed. Particularly with novel targeted therapies the conventional paradigms of toxicity studies conducted in healthy animals followed by Phase I and Phase II human trials leave unanswered many important questions on the “best use” of these drugs . Translational drug development studies in pet dogs with cancer provide an opportunity to answer these questions by serving as an intermediary between conventional preclinical models and human clinical trials –. In these dogs, cancers develop naturally in the context of an intact immune system and with a syngeneic host and tumor microenvironment. Similar environmental, nutrition, age, sex, and reproductive factors lead to tumor development and progression in human and canine cancers. They share similar features such as histologic appearance, tumor genetics, biological behavior, molecular targets, therapeutic response, and unfortunately, acquired resistance, recurrence, and metastasis.
Clinical trials in pet dogs are not constrained by traditional Phase I, Phase II, and Phase III trial designs. This allows novel agents to be offered to pet dogs before conventional therapies or during the period of minimal residual disease. Pet owners are highly motivated to seek novel options for management of cancer in their pets, especially if conventional treatments do not meet their goals. A pet owner's decision to pursue an investigational treatment is often influenced by the risks associated with this therapy compared to conventional therapy, as well as their expectations for outcomes and reduced costs for care provided by an investigational trial. Additionally, many pet owners are motivated by the opportunity to contribute to the advancement of cancer treatment for future human and canine patients.
The study of cancer biology and therapy in animals with naturally occurring cancers, referred to as comparative oncology, is not a novel concept. Indeed, over the last 30–40 years investigators have used this approach to make important contributions to the understanding and practice of human oncology in fields such as basic tumor biology and immunology –, radiation biology , hyperthermia , and systemic therapies for a variety of cancers including osteosarcoma, lymphoma, melanoma, and others ,–. One historical limitation to the widespread use and integration of the comparative approach has been a lack of infrastructure to coordinate animal health professionals with the human oncology community, drug developers, and basic scientists.
The COTC was launched through the intramural NCI's Center for Cancer Research–Comparative Oncology Program. The COTC operates as a collaborative effort between the NCI and extramural academic comparative oncology centers and functions to design and execute clinical trials in dogs with cancer in collaboration with the pharmaceutical industry and nongovernmental groups interested in cancer drug development. Support for the oversight and management of the COTC comes from the NCI. Trial sponsors, most often pharmaceutical companies, support the clinical costs of studies conducted by the COTC academic centers. The goal of this effort is to answer biological questions that can inform the development path of novel agents for future use in human cancer patients in a timely and integrated manner. Trials conducted by the COTC are designed to include clinical and biological endpoints, i.e., pharmacokinetics and pharmacodynamics, so as to optimally inform the design of early phase human trials. Trials are carried out at COTC member institutions, which currently include 18 veterinary academic centers, currently in the United States.
Comparative oncology trials can answer many questions within a single study. The serial collection of tumor and normal tissue biopsies and fluids from the same animal before, during, and after exposure to an investigational agent is feasible. This sequential sampling allows the study of tissue (tumor and/or surrounding normal tissues) endpoints that may be linked to surrogate imaging or circulating biomarkers, as a function of drug exposure or therapeutic response, in ways that are often difficult or unacceptable in human trials. To ensure the integration of such biological endpoints in these studies the COTC Pharmacodynamic (PD) Core was developed (http://ccr.cancer.gov/resources/cop/scientists/pharmacodynamic.asp). The COTC PD Core provides infrastructure to support the development, validation, and assessment of pharmacokinetic, pharmacodynamic, and biological endpoints within COTC trials. Through the COTC and its PD Core, the opportunity now exists to rapidly accrue pet dogs with cancer to clinical trials that are detailed and biologically intensive (http://ccr.cancer.gov/resources/cop/COTC.asp). The first completed consortium trial was recently published  and a 12th trial is currently under development. In the interest of open access to this approach and its data, the COTC plans to publish its trials in the journal PLoS ONE.
Dogs have historically been useful, informative models in the development and discovery of many novel cancer therapeutic strategies. The efficacy of liposomal muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) in dogs with osteosarcoma served as part of the rationale for its evaluation in Phase III studies in children. Indeed, similar results with L-MTP-PE have been observed in both dogs and children ,. Dogs have been used to develop and evaluate surgical limb sparing techniques  and were valuable models in the investigation of the combination of hyperthermia with radiation ,. Dogs have also been included in the development of novel targeted anticancer agents ,.
The similarities between dog and human cancers are increasingly being realized. The publicly available canine genome has propelled comparative genomics studies. Such studies have shown significant homology between dog and human for recognized cancer-associated genes including MET, IGF1R, mTOR, and KIT . Not surprisingly, cytogenetic abnormalities that define human cancers, i.e., BCR-Abl translocations in chronic myelogenous leukemia and RB1 deletions in chronic lymphocytic leukemia have been found in comparable canine cancers . These and other examples have been recently reviewed elsewhere .
Integrating the comparative approach has the opportunity to improve the development path of new cancer drugs (Figure 1). Drugs that may be less likely to succeed in early human clinical trials may be identified and culled early. For example, the addition of comparative oncology studies in the preclinical setting will eliminate drugs with an unfavorable therapeutic index or inferior target modulation attributes, thus identifying agents most likely to succeed in human Phase I trials. Comparative studies performed during or after human Phase I studies may focus on pharmacokinetic/pharmacodynamic endpoints, classify responding patient subsets, and identify optimal drug combinations. These data may eliminate inactive drugs before Phase II human trials and optimize the design of these trials. Furthermore, the integration of studies using pet dogs with cancer provides a unique opportunity to assess efficacy in the adjuvant or minimal residual disease setting and, in so doing, may prioritize those agents most likely to be effective as Phase III human cancer agents. Collectively, the elimination of inferior drugs early in development will reduce drug attrition in later phases of human clinical development and result in fewer human participants entering trials with potentially ineffective or unsafe drugs. By reducing the number of drugs entering each phase of drug development and increasing the success rate in Phase III trials, an integrated approach can substantially decrease the costs and risks of drug development (Figure 1).
As with all novel approaches and perspectives, integrating studies with pet dogs with cancer into the development pathway is associated with some hesitation and perception of risk. One of the goals of the COTC is to define and address perceived risks and actual challenges and to mitigate them when possible.
The increasing availability of banked canine tumors and associated “omic” annotations for these cancers will allow for rapid identification of valid tumor targets in canine cancers. To this end, a second community initiative, the Canine Comparative Oncology and Genomics Consortium (CCOGC; http://www.ccogc.net/) was recently developed to facilitate strategic partnerships and collaborations across a diversity of these disciplines and to develop a tissue biospecimen repository. This repository has initiated sample collections and expects to provide tissues to the community in late 2009.
Proceeding forward, the COTC plans to increase awareness of the applications of the comparative approach. Through this effort a greater understanding about the diseases and treatment agents that are best suited to this approach will be developed; a broader integration of this approach into the drug development and approval process is expected to emerge; and an acceleration of the development of effective new anticancer agents, devices, and imaging techniques will occur. We believe that such efforts will advance the quality of care for both human and veterinary cancer patients.
The authors have declared that no competing interests exist.
No specific funding was received for this piece.