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Orthopaedic Proceedings
Vol. 103-B, Issue SUPP_3 | Pages 73 - 73
1 Mar 2021
Lazarides A Somarelli J Altunel E Rao S Hoskinson S Cheng S Eward C Hsu D Eward W
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Osteosarcoma (OSA) is a rare, but disproportionately lethal cancer that predominantly affects children. Sadly, discovery of new therapies for OSA has largely been unsuccessful in the past 30 years; there is an urgent need to identify new treatments for OSA. Pet dogs with naturally-occurring OSA represent a unique comparative “model” to discover new treatments for OSA. Unlike humans, in which fewer than 1,000 cases of OSA occur each year, there are nearly 50,000 new cases each year of OSA in dogs. In addition, dogs have an intact immune system, a shared environment with humans, and more rapid progression of disease. Together these factors make dogs an important comparative model for new therapies for OSA. The purpose of this study was: 1) to validate this mouse-dog-human pipeline for drug discovery and 2) to validate CRM1 as a novel target for ostesoarcoma treatment.

We developed patient-derived cell lines and xenografts of OSA from both dogs and humans and applied these models to identify new therapies for OSA using high-throughput drug screens in vitro followed by in vivo validation. Whole exome sequencing was performed on the patient-derived models and original tumors to identify potential driver mutations.

A high-throughput screen in both dog and human OSA identified CRM1 inhibitors as effective at killing dog and human OSA patient-derived cell lines in vitro. In vivo, CRM1 inhibition led to significant tumor growth inhibition in patient-derived xenografts from dogs and humans. Western blotting demonstrated increased levels of CRM1 protein expression across nine different dog and human OSA cell lines compared to non-transformed human osteoblasts. CRM1 upregulation in OSA cells was further verified by immunofluorescence staining. Increased CRM1 expression was prognostic for poorer metastasis-free survival and poorer overall survival.

Our cross-species personalized medicine pipeline identified CRM1 as a potential therapeutic target to treat OSA in both dogs and humans. Future studies are focused on testing CRM1 inhibitors in canine clinical trials.


Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_IV | Pages 137 - 137
1 Mar 2012
Cheng S Wallace W Buchanan D Sivardeen Z Hulse D Fairbairn K Kemp S Brooks J
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Objective

Shoulder instability is a common cause of morbidity amongst Professional Rugby Union players. This study explores whether the risk of shoulder dislocation is associated with innate shoulder laxity.

Methods

A randomised controlled study was completed in which all the Premiership Rugby Clubs in England were visited in 2006. 169 professional rugby players (mean age 25.1 years) with no history of instability in either shoulder were assessed and 46 injured players with one shoulder with a history of Bankart lesion or dislocation (mean age 27.5 years) also took part in this study. Shoulder laxity was measured by dynamic ultrasound. Anterior, posterior and inferior translations were measured in both shoulders for healthy players and the uninjured shoulder only for injured players.