PT  - JOURNAL ARTICLE
AU  - Kelly M. Makielski
AU  - Alicia J. Donnelly
AU  - Ali Khammanivong
AU  - Milcah C. Scott
AU  - Andrea R. Ortiz
AU  - Dana C. Galvan
AU  - Hirotaka Tomiyasu
AU  - Clarissa Amaya
AU  - Kristi Ward
AU  - Alexa Montoya
AU  - John R. Garbe
AU  - Lauren J. Mills
AU  - Gary R. Cutter
AU  - Joelle M. Fenger
AU  - William C. Kisseberth
AU  - Timothy D. O’Brien
AU  - Logan G. Spector
AU  - Brad A. Bryan
AU  - Subbaya Subramanian
AU  - Jaime F. Modiano
TI  - Development of an exosomal biomarker signature to detect minimal residual disease in dogs with osteosarcoma using a novel xenograft platform and machine learning
AID  - 10.1101/2021.02.11.429432
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.02.11.429432
4099  - http://biorxiv.org/content/early/2021/02/12/2021.02.11.429432.short
4100  - http://biorxiv.org/content/early/2021/02/12/2021.02.11.429432.full
AB  - Osteosarcoma has a guarded prognosis. A major hurdle in developing more effective osteosarcoma therapies is the lack of disease-specific biomarkers to predict risk, prognosis, or therapeutic response. Exosomes are secreted extracellular microvesicles emerging as powerful diagnostic tools. However, their clinical application is precluded by challenges in identifying disease-associated cargo from the vastly larger background of normal exosome cargo. We developed a method using canine osteosarcoma in mouse xenografts to distinguish tumor-derived from host-response exosomal mRNAs. The model allows for the identification of canine osteosarcoma-specific gene signatures by RNA sequencing and a species-differentiating bioinformatics pipeline. An osteosarcoma-associated signature consisting of five gene transcripts (SKA2, NEU1, PAF1, PSMG2, and NOB1) was validated in dogs with spontaneous osteosarcoma by qRT-PCR, while a machine learning model assigned dogs into healthy or disease groups. Serum/plasma exosomes were isolated from 53 dogs in distinct clinical groups (“healthy”, “osteosarcoma”, “other bone tumor”, or “non-neoplastic disease”). Pre-treatment samples from osteosarcoma cases were used as the training set and a validation set from post-treatment samples was used for testing, classifying as “osteosarcoma–detected” or “osteosarcoma–NOT detected”. Dogs in a validation set whose post-treatment samples were classified as “osteosarcoma–NOT detected” had longer remissions, up to 15 months after treatment. In conclusion, we identified a gene signature predictive of molecular remissions with potential applications in the early detection and minimal residual disease settings. These results provide proof-of-concept for our discovery platform and its utilization in future studies to inform cancer risk, diagnosis, prognosis, and therapeutic response.Competing Interest StatementThe authors declare that patent Identifying Presence and Composition of Cell Free Nucleic Acids, related to this work and listing Milcah C. Scott, John R. Garbe, and Jaime F. Modiano as inventors has been filed by the Office of Technology Commercialization of the University of Minnesota. US Patent Application 15/783,776 filed on October 13, 2017 The authors declare that patent Biological Status Determination Using Cell-Free Nucleic Acids, related to this work and listing Kelly M. Makielski, Alicia J. Donnelly, Ali Khammanivong, Milcah C. Scott, Hiro Tomiyasu, and Jaime F. Modiano as inventors has been filed by the Office of Technology Commercialization of the University of Minnesota. US Patent Application 16/600,486 filed on October 12, 2019