Hagemann Urs B, Schatz Christoph A, Suominen Mari I, Schlicker Andreas, Knuuttila Matias, Wilson Timothy, Alhoniemi Esa, Käkönen Sanna-Maria, Haendler Bernard, Scholz Arne
Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany.
Pharmatest Services Ltd., 20520 Turku, Finland.
Int J Mol Sci. 2024 Dec 21;25(24):13672. doi: 10.3390/ijms252413672.
Despite treatment, prostate cancer commonly progresses into castration-resistant prostate cancer (CRPC), which remains largely incurable, requiring the development of new interventions. Darolutamide is an orally administered second-generation androgen receptor inhibitor indicated for patients with non-metastatic CRPC or metastatic hormone-sensitive prostate cancer. Here, we evaluated the effect of androgen receptor (AR) inhibition by darolutamide in combination with DNA double-strand-break-inducing targeted radium-223 alpha therapy in vitro and in an intratibial LNCaP xenograft model mimicking prostate cancer metastasized to bone. The results highlight the synergistic antitumor efficacy of darolutamide in combination with radium-223 both in vitro and in vivo. This effect was most likely driven by the downregulation of genes involved in DDR signaling, which was demonstrated in vitro by a gene set enrichment analysis. The combination treatment also reduced pathological tumor-induced effects in bone by decreasing the number of osteoblasts and osteoclasts and reducing abnormal bone formation in tumor-bearing bone. Additionally, it was shown that darolutamide does not affect the uptake of radium-223 into bone tissue. These results support the investigation of darolutamide in combination with radium-223 for the treatment of patients with CRPC metastasized to bone.
尽管进行了治疗，但前列腺癌通常会进展为去势抵抗性前列腺癌（CRPC），而这种癌症在很大程度上仍然无法治愈，因此需要开发新的干预措施。达洛鲁胺是一种口服的第二代雄激素受体抑制剂，适用于非转移性CRPC或转移性激素敏感性前列腺癌患者。在此，我们在体外以及在模拟前列腺癌骨转移的胫骨内LNCaP异种移植模型中，评估了达洛鲁胺抑制雄激素受体（AR）并联合诱导DNA双链断裂的靶向镭-223α疗法的效果。结果突出了达洛鲁胺与镭-223联合在体外和体内的协同抗肿瘤疗效。这种效应很可能是由参与DNA损伤修复（DDR）信号传导的基因下调所驱动，这在体外通过基因集富集分析得到了证实。联合治疗还通过减少成骨细胞和破骨细胞的数量以及减少荷瘤骨中的异常骨形成，降低了病理性肿瘤对骨骼的影响。此外，研究表明达洛鲁胺不会影响镭-223在骨组织中的摄取。这些结果支持对达洛鲁胺与镭-223联合用于治疗骨转移CRPC患者的研究。
