Efficacy of a cathepsin K inhibitor in a preclinical model for prevention and treatment of breast cancer bone metastasis

• Published in: Molecular cancer therapeutics 2014-12, Vol.13 (12), p.2898-2909
• Main Authors: Duong, Le T, Wesolowski, Gregg A, Leung, Patrick, Oballa, Renata, Pickarski, Maureen
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Bone Neoplasms - drug therapy; Bone Neoplasms - metabolism; Bone Neoplasms - secondary; Breast Neoplasms - pathology; Cathepsin K - antagonists & inhibitors; Cathepsin K - genetics; Cathepsin K - metabolism; Cell Line, Tumor; Disease Models, Animal; Drug Evaluation, Preclinical; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - pharmacology; Female; Gene Expression; Humans; Immunohistochemistry; Neoplasm Grading; Neoplasm Metastasis; Osteolysis; Tumor Burden - drug effects; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-14-0253

Cathepsin K (CatK) is essential for osteoclast-mediated bone resorption. CatK expression is also detected in breast cancer cells that metastasize to bone. Here, the CatK inhibitor L-235 dosed in prevention (10, 30, and 100 mg/kg, p.o., b.i.d.) or treatment regimen (30 mg/kg) was compared with the bisphosphonate zoledronic acid (ZOL, 7.5 μg/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 was evaluated by radiography through 42 days and ex vivo μCT and histology. IHC and RT-PCR confirmed the increases in CatK protein and mRNA levels in human breast cancer primary and metastatic tumors. In the experimental model of breast cancer bone metastasis, L-235 dosed in preventive mode resulted in a dose-related reduction of osteolysis of 72%, 75%, and 87% respectively, compared with ZOL by 86% versus intact. Similarly, L-235 significantly reduced intratibial tumor volume by 29%, 40%, and 63%, respectively, compared with 56% by ZOL versus vehicle. Efficacy of L-235 and ZOL on reduction of osteolytic lesions and tumor burden was comparable in treatment versus 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 CatK inhibitor was more effective than ZOL in reducing breast cancer invasion. These data support the role of CatK in breast cancer skeletal growth and metastasis and CatK inhibitors may represent a novel oral therapy for treatment of metastatic breast cancer.