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.

Objective

From our series of 570 Dynesys flexible stabilisation procedures, we studied two prospective series of patients with a minimum one-year follow-up comparing uncoated and hydroxyapatite-coated (HA) screws.

We have studied two matching cohorts of patients treated by Dynesys flexible stabilisation with and without hydroxyapatite (HA) coating of the pedicle screws.

From our series of 570 Dynesys procedures, we studied patients with HA coated screws with a minimum one year follow-up.

Patients were entered prospectively and followed up at 6 weeks, 3, 6, and 12 months and annually thereafter. Plain radiographs were obtained annually. 58 patients (26 males, 32 females, mean age 55 years at surgery) underwent Dynesys stabilisation with HA coated screws. The data was compared with 69 patients who underwent Dynesys stabilisation with non-coated pedicle screws between 2004 and 2006 (26 male, 53 female, mean age 54 years). Outcome measures were screw loosening, breakage, implant removal or revision.

A total of 320 HA coated pedicle screws were inserted. 12 patients were lost to follow-up. 2 patients underwent subsequent level extension, and 2 had their implants removed. There were four screw breakages in three patients, all affecting S1 screws. There was no evidence of screw loosening in any patient. In the non-HA coated group 354 pedicle screws were inserted. 5 patients required revision or subsequent surgery. 12 patients had screw loosening and required implant removal. There was a significant improvement of anchorage of the HA coated screws.

Change to HA coating was investigated because of high loosening in plain screws. The improvement has been highly significant. Flexible stabilisation is a better model than fusion because the implant remains under constant load.

Disclosure: The authors did not receive any outside funding in support of preparation of this work.