Abstract 2664: Alpharadin inhibits osteoclast differentiation in vitro and progression of established breast cancer bone metastases in vivo

Abstract

Abstract Alpharadin is an alpha-emitting radium isotope currently in phase III clinical study for the treatment of castration resistant prostate cancer bone metastases. As a calcium mimetic Alphapharmaceutical, radium localizes to bone, where the emitted alpha-particles provide an efficient and localized radiation treatment to the metastatic skeletal tumor lesion. While promising clinical data in predominately osteoblastic bone metastases such as prostate cancer have already been obtained (Nilsson, Lancet Oncol 2007), robust clinical evidence for the activity of Alpharadin in osteolytic bone metastases associated with other cancer entities is lacking. As previously reported (Henriksen, Cancer Res 2002), Alpharadin increases symptom-free survival in an osteolytic breast cancer bone metastasis model in nude rats. Besides this study on the therapeutic efficacy in a preclinical skeletal metastasis tumor model it is still unclear how Alpharadin affects the vicious cycle of tumor growth and osteolysis. We report here the effects of Alpharadin on differentiation and activity of human osteoclasts in vitro and on treatment of established breast cancer bone metastases in vivo. The in vitro effects of Alpharadin (50-1600 Bq/ml, n=8/group) on osteoclasts were studied using human osteoclast precursor cells cultured on bovine bone slices. Alpharadin was added in the osteoclast differentiation assay at day 0, and in the activity assay at day 7. Secreted tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) was measured at day 7 as a marker of osteoclast differentiation and secreted C-terminal cross-linked telopeptides of type I collagen (CTX) at day 10 as a marker of resorption during days 7-10. The in vivo effects were studied using a model where human MDA-MB-231SA/GFP cells were inoculated intracardially in nude mice. The animals were randomized to two groups (n=15) based on body weight and presence of osteolytic lesions at day 14. Either vehicle or Alpharadin (300 kBq/kg) were administered iv at day 15. Radiography and fluorescence imaging were performed at day 14 and at sacrifice (day 25). Alpharadin inhibited dose dependently differentiation of osteoclasts in vitro at all tested concentrations, but had no effect on resorption activity of mature osteoclasts. In vivo, Alpharadin decreased whole body tumor burden by 43% as quantified by fluorescence imaging and osteolysis by 56% compared to the vehicle control group. Furthermore, Alpharadin treatment completely prevented tumor associated cachexia observed in the control group. In summary, Alpharadin inhibits differentiation of osteoclasts and progression of established, osteolytic breast cancer bone metastases. These preclinical findings strongly support the clinical development of Alpharadin in additional cancer indications which form predominantely osteolytic bone metastasis, e.g. breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2664. doi:10.1158/1538-7445.AM2011-2664