ECTS Abstracts (2015) 1 P139

Radium-223 dichloride exhibits dual mode-of-action inhibiting both tumour and tumour-induced bone growth in two osteoblastic prostate cancer models

Mari I. Suominen1, Katja M. Fagerlund1, Jukka Rissanen1, Yvonne Konkol1, Jukka Morko1, Zhiqi Peng1, Esa Alhoniemi2, Dominik Mumberg3, Karl Ziegelbauer3, Sanna-Maria Käkönen4, Jussi M Halleen1, Robert L Vessella5 & Arne Scholz3

1Pharmatest Services Ltd., Turku, Finland; 2Avoltus Oy, Turku, Finland; 3Bayer Healthcare, Glodal Drug Discovery, TRG-Onc/GT, Berlin, Germany; 4University of Turku, Turku, Finland, 5University of Washington, Seattle, WA, USA.

Radium-223 dichloride, an alpha particle-emitting calcium-mimetic, improves overall survival in prostate cancer patients with symptomatic bone metastases. Here, we define radium-223 mode-of-action and efficacy in two clinically relevant prostate cancer xenograft models. Human LNCaP or patient-derived LuCaP 58 prostate cancer cells were inoculated intratibially and mice were stratified into treatment groups based on lesion grade and/or serum PSA levels. Radium-223 (300 kBq/kg) or vehicle was administered twice at 4-week intervals. X-rays and serum samples were obtained biweekly. Bone samples were collected for γ-counter measurements, micro-CT, autoradiography and histology. Radium-223 inhibited tumour-induced osteoblastic reaction as indicated by reduced bone volume and surface area in both prostate cancer models. Additionally, radium-223 suppressed metabolic activity in bone as evidenced by decreased osteoblast and osteoclast numbers and reduced PINP levels. Radium-223 treatment also resulted in lower PSA levels as early as two weeks post first dosing, indicating constrained tumour growth. This phenomenon was further supported by reduced tumour area in tibia in both models and an overall increase in necrotic tumour area in the LuCaP 58 model. Moreover, DNA double-strand breaks were increased in cancer cells 24 hours post radium-223 administration in the LuCaP 58 model providing further evidence of anti-tumour effects. Autoradiography confirmed radium-223 deposition in the intratumoural bone matrix in conjunction with osteoblasts. We demonstrate that radium-223 dichloride is successfully incorporated into the intratumoural bone matrix and inhibits tumour growth in both cell line- and patient-derived osteoblastic prostate cancer models. Importantly, given the α-particle range of 50-80 μm, potent radiation effects on the immediate tumour microenvironment are expected with minimal or no effects on the more distant bone marrow. Taken together, radium-223 therapy exhibits a dual mode-of-action that impacts on tumour growth and tumour-induced bone reaction, both important players in the destructive vicious cycle of osteoblastic bone metastasis in prostate cancer.

Disclosure: MIS, JPR, and JMH are stockholders of Pharmatest Services; EA and SK are consultants of Pharmatest Services; DM, KZ and AS are stockholders of Bayer Pharma AG.