The Role of RANK-Ligand Inhibition in Cancer: The Story of Denosumab

The bone is a very common site of metastasis in patients with advanced cancer. Skeletal metastases are most common in breast and prostate cancer, but virtually any advanced cancer may disseminate to the bone. On the basis of recent advances in the understanding of bone remodeling processes, denosumab, a fully human monoclonal antibody against RANK-L, has been developed. Phase III clinical trials have demonstrated that denosumab is well tolerated and effective in the treatment of bone loss and prevention of skeletal-related events in patients with bone metastases

The effect of osteoprotegerin administration on the intra-tibial growth of the osteoblastic LuCaP 23.1 prostate cancer xenograft

Osteoprotegerin (OPG) plays a central role in controlling bone resorption. Exogenous administration of OPG has been shown to be effective in preventing osteolysis and limiting the growth of osteolytic metastasis. The objective of this study was to investigate the effects of OPG on osteoblastic prostate cancer (CaP) metastases in an animal model. LuCaP 23.1 cells were injected intra-tibially and Fc-OPG (6.0 mg/kg) was administered subcutaneously three times a week starting either 24 hours prior to cell injection (prevention regimen) or at 4 weeks post-injection (treatment regimen). Changes in bone mineral density at the tumor site were determined by dual x-ray absorptiometry. Tumor growth was monitored by evaluating serum prostate specific antigen (PSA). Fc-OPG did not inhibit establishment of osteoblastic bone lesions of LuCaP 23.1, but it decreased growth of the tumor cells, as determined by decreases in serum PSA levels of 73.0 ± 44.3% ( P < 0.001) and 78.3 ± 25.3% ( P < 0.001) under the treatment and prevention regimens, respectively, compared to the untreated tumor-bearing animals. Administration of Fc-OPG decreased the proliferative index by 35.0% ( P = 0.1838) in the treatment group, and 75.2% ( P = 0.0358) in the prevention group. The results of this study suggest a potential role for OPG in the treatment of established osteoblastic CaP bone metastases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42587/1/10585_2004_Article_2869.pd

Humanised xenograft models of bone metastasis revisited: novel insights into species-specific mechanisms of cancer cell osteotropism

The determinants and key mechanisms of cancer cell osteotropism have not been identified, mainly due to the lack of reproducible animal models representing the biological, genetic and clinical features seen in humans. An ideal model should be capable of recapitulating as many steps of the metastatic cascade as possible, thus facilitating the development of prognostic markers and novel therapeutic strategies. Most animal models of bone metastasis still have to be derived experimentally as most syngeneic and transgeneic approaches do not provide a robust skeletal phenotype and do not recapitulate the biological processes seen in humans. The xenotransplantation of human cancer cells or tumour tissue into immunocompromised murine hosts provides the possibility to simulate early and late stages of the human disease. Human bone or tissue-engineered human bone constructs can be implanted into the animal to recapitulate more subtle, species-specific aspects of the mutual interaction between human cancer cells and the human bone microenvironment. Moreover, the replication of the entire "organ" bone makes it possible to analyse the interaction between cancer cells and the haematopoietic niche and to confer at least a partial human immunity to the murine host. This process of humanisation is facilitated by novel immunocompromised mouse strains that allow a high engraftment rate of human cells or tissue. These humanised xenograft models provide an important research tool to study human biological processes of bone metastasis