Pharmacodynamic study of radium-223 in men with bone metastatic castration resistant prostate cancer
Pharmacodynamic study of radium-223 in men with bone metastatic castration resistant prostate cancer
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DOI：
10.1371/journal.pone.0216934
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发表时间：
2019-05-28
期刊：
影响因子：
3.7
通讯作者：
George, Daniel J.
中科院分区：
文献类型：
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作者：
Armstrong, Andrew J.;Gupta, Santosh;George, Daniel J.
镭-223是一种靶向α粒子治疗，可提高转移性去势抵抗性前列腺癌（mCRPC）患者的生存率，特别是血清骨碱性磷酸酶（B-ALP）水平升高的患者。我们假设，骨拟态，上皮可塑性的一种形式，导致成骨细胞表型，可能有助于intralesional沉积的镭-223和随后的照射的肿瘤microenvironment.MethodsWe进行了药效学研究（NCT 02204943）的镭-223在男性骨mCRPC。在镭-223治疗开始之前和之后的三个月和六个月，我们收集CTC和转移性活检用于表型表征和CTC基因组分析。主要目的是描述镭-223对CTC B-ALP患病率随时间的影响。我们在治疗过程中测量了肿瘤和周围正常骨中的镭-223衰变产物。我们验证了一个单独的独立研究的男性骨转移性mCRPC（n = 45）和公开访问的数据转移性CRPC tissues.ResultsWe招募了20名男性有症状的骨为主的mCRPC和治疗镭-223的基因组结果。我们观察到更大的镭-223放射性水平，转移性骨肿瘤活检包含与相邻的正常骨。我们发现，尽管血清B-ALP正常化，但在镭-223治疗期间，随着时间的推移，大多数男性中持续存在Cellsearch CTC和B-ALP（+）CTC的证据。我们鉴定了成骨细胞拟态基因的基因组获得，包括ALPL、骨桥蛋白、骨桥蛋白、OB-钙粘蛋白的获得和RUNX 2的丢失，并在一个独立的45例骨转移CRPC患者和150例mCRPC患者的转移活检标本中验证了基因组改变或DNA和RNA水平表达增加。223，从而可以增强这种骨靶向放射疗法的治疗益处。
BackgroundRadium-223 is a targeted alpha-particle therapy that improves survival in men with metastatic castration resistant prostate cancer (mCRPC), particularly in men with elevated serum levels of bone alkaline phosphatase (B-ALP). We hypothesized that osteomimicry, a form of epithelial plasticity leading to an osteoblastic phenotype, may contribute to intralesional deposition of radium-223 and subsequent irradiation of the tumor microenvironment.MethodsWe conducted a pharmacodynamic study (NCT02204943) of radium-223 in men with bone mCRPC. Prior to and three and six months after radium-223 treatment initiation, we collected CTCs and metastatic biopsies for phenotypic characterization and CTC genomic analysis. The primary objective was to describe the impact of radium-223 on the prevalence of CTC B-ALP over time. We measured radium-223 decay products in tumor and surrounding normal bone during treatment. We validated genomic findings in a separate independent study of men with bone metastatic mCRPC (n = 45) and publicly accessible data of metastatic CRPC tissues.ResultsWe enrolled 20 men with symptomatic bone predominant mCRPC and treated with radium-223. We observed greater radium-223 radioactivity levels in metastatic bone tumor containing biopsies compared with adjacent normal bone. We found evidence of persistent Cellsearch CTCs and B-ALP (+) CTCs in the majority of men over time during radium-223 therapy despite serum B-ALP normalization. We identified genomic gains in osteoblast mimicry genes including gains of ALPL, osteopontin, SPARC, OB-cadherin and loss of RUNX2, and validated genomic alterations or increased expression at the DNA and RNA level in an independent cohort of 45 men with bone-metastatic CRPC and in 150 metastatic biopsies from men with mCRPC.ConclusionsOsteomimicry may contribute in part to the uptake of radium-223 within bone metastases and may thereby enhance the therapeutic benefit of this bone targeting radiotherapy.