Canine Osteosarcoma: A Naturally Occurring Disease to Inform Pediatric Oncology

Abstract

Osteosarcoma (OSA) is the most common form of malignant bone cancer in children and dogs, although the disease occurs in dogs approximately 10 times more frequently than in people. Multidrug chemotherapy and aggressive surgical techniques have improved survival; however, new therapies for OSA are critical, as little improvement in survival times has been achieved in either dogs or people over the past 15 years, even with significant efforts directed at the incorporation of novel therapeutic approaches. Both clinical and molecular evidence suggests that human and canine OSA share many key features, including tumor location, presence of microscopic metastatic disease at diagnosis, development of chemotherapy-resistant metastases, and altered expression/activation of several proteins (e.g. Met, ezrin, phosphatase and tensin homolog, signal transducer and activator of transcription 3), and p53 mutations, among others. Additionally, canine and pediatric OSA exhibit overlapping transcriptional profiles and shared DNA copy number aberrations, supporting the notion that these diseases are similar at the molecular level. This review will discuss the similarities between pediatric and canine OSA with regard to histology, biologic behavior, and molecular genetic alterations that indicate canine OSA is a relevant, spontaneous, large animal model of the pediatric disease and outline how the study of naturally occurring OSA in dogs will offer additional insights into the biology and future treatment of this disease in both children and dogs.

The animal-dependent risk factors in canine osteosarcomas

“…Genetic analysis revealed specific recurrent cytogenetic aberrations in pure-breed dogs, including Rottweilers, such as loss of WT1, TP53, CDKN2A, PTEN, RB1 (Thomas et al 2009). The first two abnormalities occurred exclusively or more frequently in Rottweilers than in other breeds, and as many as 48% and 24% of Rottweilers with osteosarcoma had deletion of WT1 gene or TP53 gene, respectively (Dobson 2013, Fenger et al 2014. Moreover, germline mutation in the receptor tyrosine kinase MET involved in pathogenesis of canine OSA was identified mainly in Rottweilers (Liao et al 2006).…”

“…However, it has also been postulated that large size of adult animals and tall shoulder height is a more reliable predictive factor for the development of OSA than dog's breed (Rosenberg et al 2007, Eberle et al 2010, Kruse et al 2012, Rehbun et al 2016. In most studies male dogs are slightly more often affected with OSA than females (Spodnick et al 1992, Romano et al 2016, although there are publications which contradict this statement (Eberle et al 2010, Anfinsen et al 2011, Coyle et al 2013, Fenger et al 2014, Nagamine et al 2015. It was also suggested that in Rottweilers, Saint Bernards and Great Danes females suffer more commonly than males (Morello et al 2011).…”

Phase I Clinical Pharmacology Study of F14512, a New Polyamine-Vectorized Anticancer Drug, in Naturally Occurring Canine Lymphoma

“…As part of the broader field of comparative oncology, translational drug development studies in dogs with spontaneous cancers have been used to define doses and schedules for therapeutic agents through rigorous PK-PD endpoints, often involving serial biopsies of tumor tissue and the collection of biologic materials before and after exposure to novel therapeutics (34,35). Comparative oncology has been focusing on the study of homologies, differences, and translational relevance of various cancers, including lymphomas (36), osteosarcomas (37,38), soft tissue sarcomas (39), urinary bladder cancer (40), mammary cancers (41), and others.…”

Comparative oncology: what dogs and other species can teach us about humans with cancer

“…Breeds considered at high risk of developing canine osteosarcoma tend to be some of larger and giant breeds, including the Rottweiler, Great Pyrenees, mastiff, Dobermann pinscher, Irish wolfhound, Scottish deerhound. Given its frequency in canines, the dog model of naturally occurring osteosarcoma has offered an unparalleled opportunity to understand the genomic origins of osteosarcoma, to learn about the role of metastasis in disease and to pilot new investigational drugs in trials that would otherwise take too long to accrue in humans [12,69]. Several years ago, Scott et al [70] took advantage of the genetic homogeneity in dogs to identify molecular subtypes of osteosarcoma based on genome-wide gene expression profiling in a cohort of high-risk breeds of dogs with osteosarcoma (N ¼ 79).…”