Zoni, Eugenio; Astrologo, Letizia; Ng, Kiu Yan Charlotte; Piscuoglio, Salvatore; Melsen, Janine; Grosjean, Joël; Klima, Irena; Chen, Lanpeng; Snaar-Jagalska, Ewa B; Flanagan, Kenneth; van der Pluijm, Gabri; Kloen, Peter; Cecchini, Marco G; Kruithof-de Julio, Marianna; Thalmann, George (2019). Therapeutic targeting of CD146/MCAM reduces bone metastasis in prostate cancer. Molecular cancer research, 17(5), pp. 1049-1062. American Association for Cancer Research AACR 10.1158/1541-7786.MCR-18-1220
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Tha_therapeutic targeting of cd146MCAM reduces bone metastasis in prostate cancer_25022019.pdf - Accepted Version Available under License Publisher holds Copyright. Download (5MB) | Preview |
Prostate Cancer (PCa) is the most common cancer and the second leading cause of cancer-related death in males. When PCa acquires castration resistance, incurable metastases, primarily in the bone, occur. The aim of this study is to test the applicability of targeting MCAM (CD146) with a monoclonal antibody for the treatment of lytic PCa bone metastasis. We evaluated the effect of targeting MCAM using in vivo preclinical bone metastasis models and an in vitro bone niche co-culture system. We utilized FACS, cell proliferation assays, and gene expression profiling to study the phenotype and function of MCAM knockdown in vitro and in vivo. To demonstrate the impact of MCAM targeting and therapeutic applicability, we employed an anti-MCAM monoclonal antibody in vivo. MCAM is elevated in PCa metastases resistant to androgen-ablation. Treatment with Dihydrotestosterone showed MCAM upregulation upon castration. We investigated the function of MCAM in a direct co-culture model of human PCa cells with human osteoblasts and found that there is reduced influence of human osteoblasts on human PCa cells in which MCAM has been knocked down. Furthermore, we observed strongly reduced formation of osteolytic lesions upon bone-inoculation of MCAM-depleted human PCa cells in animal model of PCa bone metastasis. This phenotype is supported by RNA Sequencing analysis. Importantly, in vivo administration of an anti-MCAM human monoclonal antibody reduced tumor growth and lytic lesions. These results highlight the functional role for MCAM in the development of lytic-bone metastasis and suggest that MCAM is a potential therapeutic target in PCa bone metastasis. Implications: This study highlights the functional application of an anti-MCAM monoclonal antibody to target prostate cancer bone metastasis.
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