Efficacy of a Cathepsin K Inhibitor in a Preclinical Model for Prevention and Treatment of Breast Cancer Bone Metastasis
Menée in vivo, cette étude suggère l'intérêt d'un inhibiteur de la cathepsine K, appelé L-235, pour la prévention et le traitement des métastases osseuses d'un cancer du sein
Cathepsin K (CatK) is essential for osteoclast mediated bone resorption. CatK expression is also detected in breast cancer (BrCa) cells that metastasize to bone. Here, the CatK inhibitor L-235 dosed in prevention (10, 30 and 100mg/kg, p.o., b.i.d.) or treatment regimen (30mg/kg) was compared to the bisphosphonate zoledronic acid (ZOL, 7.5microg/kg/wk, s.c.) in the intratibial injection model of MDA-MB-231 breast carcinoma in nude rats. Progression of osteolysis, skeletal tumor burden and local metastasis were evaluated by radiography through 42 days and ex vivo microCT and histology. Immunohistochemistry and RT-PCR confirmed the increases in CatK protein and mRNA levels in human BrCa primary and metastatic tumors. In the experimental model of BrCa bone metastasis, L-235 dosed in preventive mode resulted in a dose-related reduction of osteolysis of 72, 75, and 87% respectively, compared to ZOL by 86% vs. intact. Similarly, L-235 significantly reduced intratibial tumor volume by 29, 40 and 63% respectively, compared to 56% by ZOL vs. vehicle. Efficacy of L-235 and ZOL on reduction of osteolytic lesions and tumor burden were comparable in treatment vs. preventive regimens. All L-235 doses inhibited cortical disruption and extraskeletal tumor growth to a level comparable with ZOL. Assessment of local metastasis demonstrated that treatment with the CatKi was more effective than ZOL in reducing BrCa invasion. These data support the role of CatK in BrCa skeletal growth and metastasis and CatK inhibitors may represent a novel oral therapy for treatment of metastatic breast cancer.
http://mct.aacrjournals.org/content/early/2014/09/23/1535-7163.MCT-14-0253.abstract