Sagopilone Inhibits Breast Cancer Bone Metastasis and Bone Destruction Due to Simultaneous Inhibition of Both Tumor Growth and Bone Resorption

• Published in: Clinical cancer research Vol. 15; no. 11; pp. 3751 - 3759
• Main Authors: STRUBE, Anne, HOFFMANN, Jens, STEPINA, Elizaveta, HAUFF, Peter, KLAR, Ulrich, KÄKÖNEN, Sanna-Maria
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.06.2009
• Subjects: Acid Phosphatase - blood; Acid Phosphatase - metabolism; Animals; Antineoplastic agents; Antineoplastic Agents, Phytogenic - pharmacology; Benzothiazoles - pharmacology; Biological and medical sciences; Bone and Bones - drug effects; Bone and Bones - metabolism; Bone and Bones - pathology; bone metastasis; Bone Neoplasms - prevention & control; Bone Neoplasms - secondary; bone resorption; Bone Resorption - blood; Bone Resorption - pathology; Bone Resorption - prevention & control; breast cancer; Cachexia - etiology; Cachexia - prevention & control; Cell Line, Tumor; Diseases of the osteoarticular system; Dose-Response Relationship, Drug; Epothilones - pharmacology; Female; Gynecology. Andrology. Obstetrics; Humans; Isoenzymes - blood; Isoenzymes - metabolism; Mammary gland diseases; Mammary Neoplasms, Experimental - complications; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - pathology; MDA-MB-231(SA); Medical sciences; Mice; Mice, Nude; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteoclasts - pathology; Osteolysis - etiology; Osteolysis - prevention & control; Paclitaxel - pharmacology; Pharmacology. Drug treatments; sagopilone; Tartrate-Resistant Acid Phosphatase; Tumor Burden - drug effects; Tumors; Tumors of striated muscle and skeleton; Xenograft Model Antitumor Assays; Antineoplastic agent; Breast disease; Diseases of the osteoarticular system; Resorption; Breast cancer; Sagopilone; Malignant tumor; Osteoarticular system; Mammary gland diseases; Bone metastasis; Bone cancer; Tumor growth; Breast metastasis; Inhibitor; Inhibition; Bone; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-3123

Purpose: Bone metastases have a considerable impact on quality of life in patients with breast and other cancers. Tumors produce osteoclast-activating factors, whereas bone resorption promotes the growth of tumor cells, thus leading to a “vicious cycle” of bone metastasis. Sagopilone, a novel, fully synthetic epothilone, inhibits the growth of breast cancer cells in vitro and in vivo , and here we report its activity in the MDA-MB-231(SA) breast cancer bone metastasis mouse model. Experimental Design: The potency of sagopilone was determined in treatment models simulating the adjuvant (preventive) and metastatic (therapeutic) settings in the clinic. Results: We showed that sagopilone inhibited tumor burden and bone destruction, in addition to reducing tumor-induced cachexia and paraplegia. The reduction in osteolytic lesions, tumor growth in bone, and weight loss was statistically significant in the preventive model compared with the vehicle group. In the therapeutic model, sagopilone treatment significantly lowered the number of activated osteoclasts and significantly reduced the osteolytic lesion area, bone volume loss, and bone resorption compared with vehicle treatment while simultaneously inhibiting tumor burden. An in vitro assay confirmed that sagopilone inhibited osteoclast activation without cytotoxic effects, whereas paclitaxel resulted in lower inhibition and high levels of cytotoxicity. Conclusions: Sagopilone seems to inhibit the vicious cycle at both the tumor growth and bone resorption stages, suggesting the possibility for substantial benefit in the treatment of patients with breast cancer at risk from bone metastases or with bone lesions already present. Phase II clinical trials with sagopilone in patients with breast cancer are ongoing.