Abstract IA5-1: Spontaneous cancer in dogs: Opportunities for preclinical investigation of novel therapeutics

Abstract

Abstract Spontaneous cancers occur commonly in the pet dog population. Indeed, an estimated 60% of dogs that live to 10 years of age will develop some form of neoplasia. These naturally occurring tumors in dogs exhibit several clinical and molecular similarities to human cancers that are challenging to replicate in experimental systems. As such, they represent a unique opportunity to answer critical questions in the development of new cancer diagnostics and therapeutics that are difficult to evaluate in conventional preclinical models or in human clinical trials (reviewed in [1, 2]) In support of this effort, the National Cancer Institute has initiated the Comparative Oncology Program (http://ccr.nci.nih.gov/resources/cop/) within the Center for Cancer Research, which is designed to promote and include companion species with spontaneous cancer in 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 develop a biospecimen repository that can be utilized for future molecular and genetic studies of canine cancers. 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. Dogs are an outbred population and as such, their tumors recapitulate the heterogeneity and tumor-stromal interactions found in human tumors. Unlike most rodent models, cancer in dogs reliably exhibits spontaneous metastases and resistance to standard therapeutics. Furthermore, similar druggable targets, angiogenic pathways, and mechanisms of apoptosis are present in dog cancers (3-6). Dogs possess an intact immune system permitting a reliable assessment of immunotherapeutic approaches. Given their larger size, diagnostic imaging and treatment modalities typically used in humans (e.g., radiation therapy), can be routinely employed. Additionally, their size provides an opportunity for repeated tissue and fluid sampling over time with more abundant tissue for analysis than that available in rodent models. One of the challenges of human cancer clinical trials is the fact that many patients have undergone several prior therapeutic regimens, and as such are often heavily pretreated prior to study entry. 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. As toxicity studies are initially performed in normal laboratory dogs, subsequent studies in pet dogs with cancer can be initiated at doses close to the predicted maximum tolerated dose, permitting rapid toxicity to activity assessments. 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 concept of utilizing cancer in dogs to inform the human drug development path is not new. For example, dogs with lymphoma were used to develop protocols for autologous bone marrow transplantation 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-Hodgkin's 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, establish pharmacokinetic/pharmacodynamic relationships, and 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. Such an approach has the potential not only to serve as an important bridge from rodent systems to humans, but to assist in the optimization of subsequent human clinical trials.