Canine histiocytic sarcoma (HS) is a highly aggressive cancer that affects Bernese Mountain Dogs (BMD), with a particularly high prevalence rate that ranges from 15 to 25% of the population. The current treatment options for HS are based on the administration of conventional chemotherapeutic drugs, to which dogs respond poorly and only for a short period of time. This study will evaluate a novel modality of treatment for HS using small molecule inhibitors of key cancer pathways. Three inhibitors, which have shown promising results in cell culture studies, will be evaluated in a mouse model. A focus on the gene expression associated with response to treatment will allow the investigators to better understand the events leading to the development of HS in BMD, and therefore, develop better therapeutic strategies. These inhibitors are expected to be effective without any significant drug-related toxic effects, so further safety and clinical efficacy studies can be pursued in dogs. The treatment of dogs with HS remains challenging, and additional therapeutic options are needed. The study of novel small molecule inhibitors for this malignancy may contribute to improvement of quality of life and survival time of dogs with HS. Funding for the research is provided through the efforts and generosity of the Bernese Mountain Dog Club of America. The AKC Canine Health Foundation supports this effort and will oversee administration of funds and scientific progress reporting.