From the Clinic to the Bench and Back Again in One Dog Year: How a Cross-Species Pipeline to Identify New Treatments for Sarcoma Illuminates the Path Forward in Precision Medicine

Abstract

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 identify new treatments; however, for rare cancers, such as sarcomas, access to patient samples is 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 <1% of all human cancers, sarcomas represent 15% of cancers in dogs. Because dogs have similar immune systems, an accelerated pace of cancer progression, and a shared environment with humans, studying pet dogs with cancer is ideal for bridging gaps between mouse models and human cancers. Here, we present our cross-species personalized medicine pipeline to identify new therapies for sarcomas. We explore this process through the focused study of a pet dog, Teddy, who presented with six synchronous leiomyosarcomas. Using our pipeline we identified proteasome inhibitors as a potential therapy for Teddy. Teddy was treated with bortezomib and showed a varied response across tumors. Whole exome sequencing revealed substantial genetic heterogeneity across Teddy's recurrent tumors and metastases, suggesting that intra-patient heterogeneity and tumoral adaptation were 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 offers important insights into the development of personalized medicine approaches that can lead to new treatments for sarcomas in both humans and canines.

The tree that hides the forest: identification of common predisposing loci in several hematopoietic cancers and several dog breeds

“…Over the past decade, the Dog has arisen as a relevant and under used spontaneous model for the analysis of cancer predisposition and progression, as well as development and trials of more efficient therapies for a number of human cancers [1][2][3][4][5][6][7][8][9][10] . With over 4.2 million dogs diagnosed with cancer annually in USA 8 , canine cancers represent a unique source of spontaneous tumors.…”

A cross-species drug discovery pipeline to identify and validate new treatments for osteosarcoma

“…While the in vivo studies are a critical validation step in the pipeline, these studies are costly and time consuming. Future iterations of the pipeline that exploit continued improvement in patient-derived models, such as patient-derived organoids [16,35,36], are sure to improve the speed and cost-effectiveness of the pipeline and will further enable rapid translation of lead candidates into clinical practice [37]. Fifth, and perhaps most critically, the ability to test these candidates in veterinary clinical trials "closes the loop" of drug .…”

“…(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint this version posted October 21, 2020. ; https://doi.org/10.1101/2020.10.19.346387 doi: bioRxiv preprint previously [37,38]. Briefly, compounds were first stamped in triplicate into well plates for a final concentration of μM using an Echo Acoustic Dispenser (Labcyte).…”

“…All patients provided written informed consent to participate in the study. PDX models of the human and canine sarcoma were generated as described previously[37] and all in vivo mouse experiments were performed in accordance with the animal guidelines and with Duke University IACUC approval. To develop PDXs, human and canine tumor tissuesamples were washed in phosphate buffered saline (PBS), dissected into small pieces (<2 mm), and injected into the flanks of 8-10-week-old JAX NOD.CB17-PrkdcSCID-J mice obtained from the Duke University Rodent Genetic and Breeding Core.…”

Comparative Oncology: New Insights into an Ancient Disease

“…When an animal is diagnosed with cancer, veterinarians collaborate with veterinary oncologists to develop a treatment plan. Similar to human patients, researchers are beginning to sequence DNA from non-human tumors to understand what alterations are shared, as well as unique, in tumor genomes between species ( Gardner et al., 2019 ; Rao et al., 2020 ). Understanding tumor driver mutations will help veterinary oncologists tailor treatments to the individual animal, similar to targeted therapies used to treat humans with cancer.…”