Radium-223 dichloride (radium-223, Xofigo®), a targeted alpha therapy, is currently used for the treatment of patients with castration-resistant prostate cancer (CRPC) with bone metastases. This study examines the mode-of-action and antitumor efficacy of radium-223 in two prostate cancer xenograft models. <br /><br />Experimental Design: Mice bearing intratibial LNCaP or LuCaP 58 tumors were randomized to groups (n = 12-17) based on lesion grade and/or serum PSA level and administered with radium-223 (300 kBq/kg) or vehicle, twice at 4-week intervals. X-rays and serum samples were obtained biweekly. Soft tissue tumors were observed macroscopically at sacrifice. Tibiae were analyzed by gamma counter, micro-CT, autoradiography and histology.<br /><br />Results: Radium-223 inhibited tumor-induced osteoblastic bone growth and protected normal bone architecture leading to reduced bone volume in LNCaP and abiraterone-resistant LuCaP 58 models. Furthermore, radium-223 resulted in lower PSA values and reduced total tissue and tumor areas, indicating that treatment constrains prostate cancer growth in bone. In addition, radium-223 suppressed abnormal bone metabolic activity as evidenced by decreased number of osteoblasts and osteoclasts and reduced level of the bone formation marker PINP. Mode-of-action studies revealed that radium-223 was deposited in the intratumoral bone matrix. DNA double-strand breaks were induced in cancer cells within 24 hours after radium-223 treatment and PSA levels were significantly lower 72 hours post treatment providing further evidence of the anti-tumor effects.<br /><br />Conclusions: Taken together, radium-223 therapy exhibits a dual targeting mode-of-action that induces tumor cell death and suppresses tumor-induced pathological bone formation in tumor microenvironment in osseous CRPC growth in mice.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2017 Mar 31 [Epub ahead of print]
Mari I Suominen, Katja M Fagerlund, Jukka P Rissanen, Yvonne M Konkol, Jukka P Morko, ZhiQi Peng, Esa J Alhoniemi, Salla K Laine, Eva Corey, Dominik Mumberg, Karl Ziegelbauer, Sanna-Maria Käkönen, Jussi Halleen, Robert L Vessella, Arne Scholz
Pharmatest Services Ltd, Pharmatest Services Ltd., Pharmatest Services Ltd., Preclinapps Ltd., Avoltus Oy., Aurexel Life Sciences Ltd., Aurexel Life Sciences Ltd., Department of Urology, University of Washington., Global Drug Discovery/Oncology, Bayer Pharma AG., Bayer AG., Aurexel Life Sciences., biotechnology, Pharmatest Services Ltd., Urology, University of Washington., Pharmaceuticals Division, Drug Discovery, Therapeutic Research Groups Oncology II, Bayer AG .