Oral tumors account for approximately 6% of all neoplasms in dogs. Oral squamous cell carcinoma (OSCC) is by far the most common oral malignant tumor of epithelial origin in dogs representing approximately 17-25% of all oral neoplasms. It is a locally aggressive tumor with up to 20% of patients showing regional or distant metastasis at the time of diagnosis. The treatment of choice depends on stage of progression and may include wide surgical excision (i.e., mandibulectomy or maxillectomy), chemotherapy, radiation therapy or any combination thereof. Although long-term remission is possible, treatments are associated with significant morbidity and can negatively impact functionality and quality of life. Novel targeted therapies are expected to complement or replace current treatment modalities and help minimize complications and side effects while improving outcomes. Recent molecular discoveries [indicate up-regulation of the RAS-RAF-MAPK signaling axis, the epithelial-tomesenchymal- transition pathway, and other key pathways which suggest interesting targets for pharmacological intervention in OSCC.] Although these biologic mechanisms represent potential targets for small molecule inhibition, no experimental in vivo or in vitro models of canine OSCC have been developed and thus no novel interventions have been tested for potential translation to the clinic. Our group has made significant progress establishing model systems of canine OSCC including successful engraftment of [two different] patient-derived tumors in immunosuppressed mice as well as in vitro growth of a derived cell line, but [OSCC is a heterogeneous disease, and additional model systems will be needed to robustly test any given therapeutic approach]. Thus, the overall objective of this 1-year project is to expand our preliminary work, [with the twin goals of expanding our basic understanding of the disease and securing future funding that will lead to clinical applications]. Specifically, we intend to 1) achieve engraftment and passage of tumor tissues derived from 3 [or more] client-owned dogs diagnosed with OSCC in NOD scid gamma mice; 2) establish stably proliferating tumor cell lines from engrafted tissues, and 3) subject [our model systems] to inhibition assays using small molecules chemotherapeutics, [both those] currently in use for similar tumors and novel targeted agents which may have fewer toxic effects. Given the relevance of OSCC in dogs and the remarkable clinical and molecular similarities with its analogue tumor in people, this project is of high veterinary, comparative, and translational value.