Osteosarcoma (OS) is one of the most common types of bone cancer in humans. It affects mostly children and adolescents, although it can occur at any age. It is also the most common bone cancer in dogs. The prognosis of osteosarcoma depends heavily on whether or not the cancer has undergone spread (metastasis) at the time of diagnosis, with the 5-year survival rate dropping from ~70% to ~20%, once the cancer has spread to the lungs. Associate Professor Nicholas Saunders and Dr Liliana Endo-Munoz at The University of Queensland’s Diamantina Institute (UQDI) have taken on the challenges of discovering the precise genetic and molecular triggers that drive the spread of osteosarcoma from the bone to the lungs, and of finding ways to block it.
By linking transcriptomic and proteomic discovery platforms available through Australian Genome Research Facility (AGRF) and Dr Michelle Hill’s Proteomics Facility at UQDI, Dr Endo-Munoz and her PhD student, Ms Eleni Topkas, identified 2 novel genes which were highly upregulated in metastatic OS tumours from patients. One gene was called Thioredoxin Reductase 2 (TXNRD2) and the other gene was called Urokinase Plasminogen Activator (uPA). The team went on to show that both these genes caused metastasis to occur. Most significantly, the team also showed that inhibition of the activity of TXNRD2 or uPA reduced metastases in vivo (1,2). Of considerable interest to the team was the discovery that TXNRD2 could be specifically inhibited by auranofin, an existing drug used to treat some forms of rheumatoid arthritis.
Identifying a new indication for an existing drug is often referred to as “repurposing”, and has the advantage that it greatly expedites the translational path from bench to clinic. Based on the promising data from the experimental models the team was faced with the challenge of how one trials a new drug in a rare paediatric cancer and how one addresses issues related to the safety of combining auranofin with existing chemotherapies. After much discussion with clinical and veterinary oncology colleagues, the team decided to conduct a Phase II efficacy trial in canine osteosarcoma patients. Osteosarcoma is a common cancer in large breeds of dogs and frequently metastasises to the lung. Moreover, clinical management of dogs with osteosarcoma is very similar to that of humans, and thus they represent an excellent model to quickly assess the clinical potential of combining auranofin with existing osteosarcoma treatments. Dr Rod Straw (Director of the Brisbane Veterinary Specialist Centre; UQ adjunct academic) and Dr Tristram Bennett are specialist Veterinary Oncologists, assisted in putting together a nationwide team of veterinary oncologists to run the clinical trial. Whilst the trial is still ongoing, the early indications are that the novel combination shows evidence of a survival benefit in dogs treated with auranofin.
Further information about the project can be accessed HERE.
Key words: Osteosarcoma, bone cancer, metastasis, genetic variation, TXNRD2, uPA.
1. Endo-Munoz L, Cai N, Cumming A, Macklin R, Merida de Long L. Topkas E, Mukhopadhyay P, Hill M, Saunders NA (2015). Progression of osteosarcoma from a nonmetastatic to a metastatic phenotype is causally associated with activation of an autocrine and paracrine uPA axis. PLoS ONE 10(8):e0133592.
2. Topkas, E, Cai, N, Cumming A, Saunders NA, Endo-Munoz L (2015). Auranofin is a potent suppressor of osteosarcoma metastasis. Oncotarget, doi: 10.18632/oncotarget.5704.
Dr Rod Straw (veterinary scientist, BVSC) , Dr Liliana Endo-Munoz (lead scientist, UQDI), Dr Tristram Bennett (veterinary oncologist, BVSC) and A/P Nicholas Saunders (Laboratory Head, UQDI).