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Abstract

Purpose:

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.

Experimental Design: 

Mice bearing intratibial LNCaP or LuCaP 58 tumors were randomized into groups (n = 12-17) based on lesion grade and/or serum PSA level and administered 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.

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 after treatment, providing further evidence of the antitumor effects.

Conclusions: Taken together, radium-223 therapy exhibits a dual targeting mode-of-action that induces tumor cell death and suppresses tumor-induced pathologic bone formation in tumor microenvironment of osseous CRPC growth in mice.

Author information​

Suominen MI1, Fagerlund KM1, Rissanen JP1, Konkol YM1, Morko JP1, Peng Z1, Alhoniemi EJ2, Laine SK3, Corey E4, Mumberg D5, Ziegelbauer K5, Käkönen SM3,6, Halleen JM1, Vessella RL4, Scholz A7.

1 Pharmatest Services Ltd., Turku, Finland.

2 Avoltus Oy, Turku, Finland.

3 Aurexel Life Sciences Ltd., Askainen, Finland.

4 Department of Urology, University of Washington, Seattle, Washington.

5 Bayer AG, Pharmaceuticals Division, Drug Discovery, Therapeutic Research Groups Oncology, Berlin, Germany.

6 Department of Cell Biology and Anatomy, University of Turku, Turku, Finland.

7 Bayer AG, Pharmaceuticals Division, Drug Discovery, Therapeutic Research Groups Oncology, Berlin, Germany. arne.scholz@bayer.com.