Abstract SY28-01: Spontaneous cancer in dogs: Opportunities for preclinical evaluation of novel therapies

Spontaneous cancers are common in the pet dog population with estimated 60% of dogs that live to 10 years of age developing neoplasia. These naturally occurring tumors in dogs possess several clinical and molecular features observed in human cancers that are challenging to replicate in experimental systems. Therefore, they represent a unique biological resource to answer critical questions in the development of new cancer diagnostics and therapeutics that are often challenging to evaluate in conventional preclinical models or in human clinical trials (reviewed in [1, 2]). In support of this effort, the NCI has developed the Comparative Oncology Program (http://ccr.nci.nih.gov/resources/cop/) housed within the Center for Cancer Research. The overriding goal of this program is to promote and include companion species with naturally occuring cancesr into preclinical oncology investigations. Components of this program include the Comparative Oncology Trials Consortium (COTC) and the Canine Comparative Oncology and Genomics Consortium (CCOGC). The COTC is an active network of academic comparative oncology centers, centrally managed by the Comparative Oncology Program, that functions to design and execute clinical trials in dogs with cancer to assess novel therapies. The primary purpose of the CCOGC is to populate a biospecimen repository (tissue bank) that can be utilized for future molecular and genetic studies of canine cancers. The COTC has now completed ten studies and several more are scheduled to begin in the next year. Examples include “Evaluation of RGD Targeted Delivery of Phage Expressing TNF-alpha to Tumor Bearing Dogs” and “Evaluation of Immunocytokine Fusion Proteins in Dogs.” The biospecimen repository is now close to being sufficiently populated and release of samples is expected to begin within the next year. Together, these efforts have markedly enhanced the incorporation of dogs into studies intended to support the development of novel treatment strategies for human cancers. Several factors contribute to the suitability of spontaneous canine cancers as a model for human disease. Dogs are an outbred population exposed to environmental factors known to contribute to carcinogenesis, and as such, their tumors closely recapitulate the heterogeneity and tumor-stromal interactions found in human tumors. Unlike most rodent models, cancers in dogs consistently exhibit spontaneous metastases and resistance to standard therapeutics including chemotherapy, immunotherapy and radiation therapy. Furthermore, similar druggable targets, angiogenic pathways, and mechanisms of apoptosis are present in dog cancers (3-6). Dogs that develop cancer possess an intact immune system shaped by both age and previous immune exposure, permitting a more accurate assessment of immunotherapeutic approaches when compared to rodent models. Importantly, given their larger size, diagnostic imaging (PET/CT, MRI) and treatment modalities typically used in humans (hypofractionated radiation therapy), can be routinely employed. Essential for the evaluation of novel therapeutics, the large size of dogs provides an opportunity for repeated tissue and fluid sampling over time with more abundant tissue for analysis than that available in rodent models. A significant challenge associated with many human cancer clinical trials, particularly in the early phases, is the fact that patients have often undergone several prior therapeutic regimens, and as such are heavily pretreated prior to study entry. They may also have significant tumor burdens and a lower performance status thereby influencing the spectrum of clinical toxicities observed. In contrast, clinical trials in pet dogs are performed using a patient population that is less heavily pretreated, has a higher performance status, and exhibits less acquired resistance providing an opportunity to evaluate a novel treatment approach in a setting more likely to demonstrate activity. A feature unique to trials in dogs is that toxicity studies are initially performed in normal laboratory dogs permitting subsequent evaluation in pet dogs with cancer to be initiated close to the predicted maximum tolerated dose, resulting in a more rapid toxicity to activity assessment than occurs in human clinical trials. Lastly, the lack of established standards of care for the treatment of canine cancer allows for early evaluation of therapies in the minimal residual disease setting, providing insight into how a particular treatment may perform in a naturally occurring microscopic metastatic model. The use of spontaneous cancer in dogs to inform the human drug development path is not new. Dogs with lymphoma were used for several years to develop protocols for autologous bone marrow transplantation that are currently used in human patients. More recently, a variety of clinical trials have been undertaken in dogs with cancer that have directly impacted human drug development. These include evaluation of the multitargeted receptor tyrosine kinase inhibitor SU11654 in dogs with cancer (7, 8), targeted AAV-phage vector delivering tumor necrosis factor (RGD-A-TNF) to alphaV integrins on tumor endothelium (9), assessment of the novel acyclic nucleotide analog GS-9219 in dogs with non-Hodgkin9s lymphoma (10, 11), and development of a xenogeneic tyrosinase DNA vaccine for melanoma (12-14). Such studies have helped to define clinical toxicities and safety of targeted therapeutics, to establish pharmacokinetic and pharmacodynamic relationships, and to identify dosing regimens most likely to demonstrate clinical activity. These efforts have laid the groundwork for enhanced integration of dogs with naturally occurring tumors into the development path for new cancer diagnostics and therapeutics. 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Bergman et al., Clin Cancer Res 9, 1284 (Apr, 2003). 14. J. C. Liao et al., Cancer Immun 6, 8 (2006). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY28-01. doi:10.1158/1538-7445.AM2011-SY28-01