Therapeutic trial of fluvastatin in a cell line xenograft model of canine mammary gland cancer

Abstract

The Hippo signalling pathway is involved in breast cancer and canine mammary tumour (CMT). This study sought to evaluate the efficacy of fluvastatin on the Hippo pathway and its main effectors, YAP and TAZ, in vivo in a murine CMT cell line xenograft model. On treatment day 1, mice were divided into four groups: vehicle, fluvastatin, doxorubicin or a combination therapy. Tumour volumes were monitored with callipers and tissues harvested on day 28th of treatment. Histopathological examination of tumour tissues and major organs was performed as well as tumour evaluation of necrosis, apoptosis, cellular proliferation, expression of YAP, TAZ and the mRNA levels of four of their target genes (CTGF, CYR61, ANKRD1 and RHAMM2). Results showed a statistically significant variation in tumour volumes only for the combination therapy and final tumour weight only for the doxorubicin group compared to control. There was no significant difference in tumour necrosis, expression of CC3, ki‐67, YAP and TAZ measured by immunohistochemistry and in the mRNA levels of the target genes. Unexpectedly, lung metastases were found in the control group (9) and not in the fluvastatin treated group (7). In addition, mass spectrometry‐based quantification of fluvastatin reveals concentrations comparable to levels reported to exert therapeutic effects. This study shows that fluvastatin tumours concentration reached therapeutic levels without having an effect on the hippo pathway or various tumour parameters. Interestingly, only the control group had lung metastases. This study is the first to explore the repurposing of statins for cancer treatment in veterinary medicine.

Expression and Clinicopathological Relevance of Fibroblast Growth Factor Receptors in Canine Mammary Gland Tumors

“…Metastasis in these tumors is high as more than 50% are diagnosed as malignant (Klopfleisch et al 2011;Zuccari et al 2011;Canadas et al 2019) and the most fatal location of metastasis is in the lungs (Klopfleisch et al 2011). Due to the low success rate of treatment using conventional drugs (Lavalle et al 2009), research is now geared towards identifying genes and proteins that are involved in tumorigenesis and tumor progression to serve as biomarkers that can accurately predict prognosis and possibly be targeted for therapy in canine and even human cancers (Selvarajah et al 2009;Queiroga et al 2011;Saijo, 2012;Lin et al 2022;Atmane et al 2023).…”