RT Journal Article
SR Electronic
T1 From the clinic to the bench and back again in one dog year: identifying new treatments for sarcoma using a cross-species personalized medicine pipeline
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 517086
DO 10.1101/517086
A1 Sneha Rao
A1 Jason A. Somarelli
A1 Erdem Altunel
A1 Laura E. Selmic
A1 Mark Byrum
A1 Maya U. Sheth
A1 Serene Cheng
A1 Kathryn E. Ware
A1 So Young Kim
A1 Joseph A. Prinz
A1 Nicolas Devos
A1 David L. Corcoran
A1 Arthur Moseley
A1 Erik Soderblom
A1 S. David Hsu
A1 William C. Eward
YR 2019
UL http://biorxiv.org/content/early/2019/01/10/517086.abstract
AB Cancer drug discovery is an inefficient process, with more than 90% of newly-discovered therapies failing to gain regulatory approval. Patient-derived models of cancer offer a promising new approach to identifying personalized treatments; however, for rare cancers, such as sarcomas, access to patient samples can be extremely limited, which precludes development of patient-derived models. To address the limited access to patient samples, we have turned to pet dogs with naturally-occurring sarcomas. Although sarcomas make up less than 1% of all cancers in humans, sarcomas represent at least 15% of all cancers in dogs. Dogs with naturally-occurring sarcomas also have intact immune systems, an accelerated pace of cancer progression, and share the same environment as humans, making them ideal models that bridge key gaps between mouse models and human sarcomas.Here, we develop a framework for a personalized medicine pipeline that integrates drug screening, validation, and genomics to identify new therapies. We tested this paradigm through the study of a pet dog, Teddy, who presented with six synchronous leiomyosarcomas. By integrating patient-derived cancer models, in vitro drug screens, and in vivo validation we identified proteasome inhibitors as a potential therapy for Teddy. After showing an initial response to the proteasome inhibitor, bortezomib, Teddy developed rapid resistance, and tumor growth resumed. Whole exome sequencing revealed substantial genetic heterogeneity across Teddy’s multiple recurrent tumors and metastases, suggesting that intra-patient heterogeneity was responsible for the heterogeneous clinical response. Ubiquitin proteomics coupled with exome sequencing revealed multiple candidate driver mutations in proteins related to the proteasome pathway. Together, our results demonstrate how the comparative study of canine sarcomas can offer rapid insights into the process of developing personalized medicine approaches that can lead to new treatments for sarcomas in both humans and canines.