Auranofin improves overall survival when combined with standard of care in a pilot study involving dogs with osteosarcoma

Abstract

Osteosarcoma is the most common paediatric primary bone malignancy. The major cause of death in osteosarcoma is drug-resistant pulmonary metastasis. Previous studies have shown that thioredoxin reductase 2 is a driver of metastasis in osteosarcoma and can be inhibited by auranofin (AF). Moreover, studies have shown that AF significantly reduces pulmonary metastases in xenotransplant models. Here, we describe a phase I/II study of AF in canine osteosarcoma, a well-recognized spontaneous model of human osteosarcoma. We performed a single-arm multicentre pilot study of AF in combination with standard of care (SOC) (amputation + carboplatin).We recruited 40 dogs to the trial and used a historical SOC-only control group (n = 26). Dogs >15 kg received 9 mg AF q3d PO and dogs <15 kg received 6 mg q3d. Follow-up occurred over at least a 3-year period. Auranofin plus SOC improved overall survival (OS) (P = .036) in all dogs treated. The improved outcome was attributable entirely to improved OS in male dogs (P = .009). At the time of writing, 10 dogs (25%) survive without measurable disease in the treatment group with survival times Liliana Endo-Munoz and Tristram C. Bennett contributed equally to the work.

Toxicity of zoledronic acid after intravenous administration: A retrospective study of 95 dogs

“…The dogs with a confirmed diagnosis of osteosarcoma that received ZA had substantially shorter survival times with the median survival time of 131 days (range, 24‐614) when compared to dogs receiving standard of care treatment (amputation or partial amputation with adjunctive platinum‐based chemotherapy) for osteosarcoma, which was reported to be 277 days (range, 203‐355). 17 , 18 In the authors' opinion, this is likely because of a selection bias for cases with late‐stage disease, many of which had amputation declined by the owners. A prospective study investigating dogs receiving ZA as part of a palliative medical treatment protocol where owners have elected against amputation and chemotherapy for appendicular bone cancer is recommended.…”

Biological behaviour of primary osteosarcoma of the digits, metacarpal and metatarsal bones in dogs

“…The signalment of patients in this study does not differ from the signalment of patients affected by OSA in other locations. 6,21,28 Distribution of the tumour was 10 occurrences (66%) in a thoracic limb and 5 occurrences (34%) in a pelvic limb. This distribution is similar to the one reported for other appendicular OSAs, where the front limb location is more frequent.…”

“…A study on the efficacy of auranofin for treating appendicular OSA in dogs 21 looked at the ST of historical cases treated with surgery and chemotherapy published between 1988 and 2016. 11,[21][22][23][24][25][26][27][28][29][30][31] The average median ST from those studies was 304 days (range 207-423 days). This is shorter compared with the overall median ST (687 days) in the current study.…”

MACC1 Contributes to the Development of Osteosarcoma Through Regulation of the HGF/c-Met Pathway and Microtubule Stability

“…Importantly, the incidence of OS is increasing annually, and the overall five-year survival rate is still low owing to the high heterogeneity and metastasis of advanced OS, as well as the lack of effective treatment (Anderson, 2016). In recent years, targeted therapy has led to a significant improvement in the prognosis of OS patients (Endo-Munoz et al, 2019). For highly metastatic tumors, while liposomal drug delivery system has achieved good results (Yang et al, 2020), targeted therapy for protein targets is more common.…”