Cancer drug discovery is an inefficient process, with more than 90% of newly-19 discovered therapies failing to gain regulatory approval. Patient-derived models of cancer offer a 20promising new approach to identifying personalized treatments; however, for rare cancers, such 21 as sarcomas, access to patient samples can be extremely limited, which precludes development 22of patient-derived models. To address the limited access to patient samples, we have turned to 23 pet dogs with naturally-occurring sarcomas. Although sarcomas make up less than 1% of all 24 cancers in humans, sarcomas represent at least 15% of all cancers in dogs. Dogs with naturally-25 occurring sarcomas also have intact immune systems, an accelerated pace of cancer progression, 26and share the same environment as humans, making them ideal models that bridge key gaps 27 between mouse models and human sarcomas. 28Here, we develop a framework for a personalized medicine pipeline that integrates drug 29 screening, validation, and genomics to identify new therapies. We tested this paradigm through 30the study of a pet dog, Teddy, who presented with six synchronous leiomyosarcomas. By 31integrating patient-derived cancer models, in vitro drug screens, and in vivo validation we 32 identified proteasome inhibitors as a potential therapy for Teddy. After showing an initial 33 response to the proteasome inhibitor, bortezomib, Teddy developed rapid resistance, and tumor 34 growth resumed. Whole exome sequencing revealed substantial genetic heterogeneity across 35Teddy's multiple recurrent tumors and metastases, suggesting that intra-patient heterogeneity 36was responsible for the heterogeneous clinical response. Ubiquitin proteomics coupled with 37 exome sequencing revealed multiple candidate driver mutations in proteins related to the 38 proteasome pathway. Together, our results demonstrate how the comparative study of canine 39 sarcomas can offer rapid insights into the process of developing personalized medicine 40 approaches that can lead to new treatments for sarcomas in both humans and canines. 41