Increased serum insulin-like growth factor-1 levels are associated with prolonged response to dasatinib-based regimens in metastatic prostate cancer
Increased serum insulin-like growth factor-1 levels are associated with prolonged response to dasatinib-based regimens in metastatic prostate cancer
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DOI：
10.1002/pros.22645
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发表时间：
2013-06-01
期刊：
影响因子：
2.8
通讯作者：
Gallick, Gary E.
中科院分区：
文献类型：
--
作者：
Dayyani, Farshid;Varkaris, Andreas;Gallick, Gary E.
背景达沙替尼，一种Src家族激酶抑制剂，与多西他赛联合治疗去势抵抗性前列腺癌（CRPC）男性，在转移性CRPC的I/II期临床试验中影响骨转换标志物。只有一部分男性从这种疗法中受益，并且缺乏预测标记物。我们假设胰岛素样生长因子-1（IGF-1）作为一种预测标志物，因为IGF-1在前列腺癌进展和骨发育中都很重要。因此，我们确定了IGF-1表达与治疗反应的关系，以及这种表达是否由肿瘤细胞、微环境或它们的相互作用引起。方法我们检测了达沙替尼联合多西他赛治疗的CRPC男性患者血清IGF-1水平。为了研究IGF-1的来源，我们利用了两种不同的携带人前列腺癌细胞的小鼠模型，并使用了物种特异性IGF-1 ELISA试剂盒（小鼠与人）。结果：在CRPC男性患者中，达沙替尼和多西他赛治疗一个周期后IGF-1水平升高与更高的缓解率和更长的治疗持续时间相关。皮下和胫骨内注射前列腺癌细胞的异种移植实验表明，前列腺癌细胞与骨微环境的直接相互作用是IGF-1诱导所必需的，完全是宿主来源的，并且仅发生在对基于达沙替尼的治疗有反应的小鼠中。结论我们的研究结果支持血清IGF-1作为CRPC患者从基于达沙替尼的联合治疗中获益的潜在生物标志物的作用。前列腺73：979985，2013年。(c)2013 Wiley Periodicals，Inc.
BACKGROUND Dasatinib, an inhibitor of Src-family kinases, combined with docetaxel in men with castrate-resistant prostate cancer (CRPC), affects bone turnover markers in a phase I/II clinical trial in metastatic CRPC. Only a subset of men benefit from this therapy, and predictive markers are lacking. We hypothesized a role for insulin-like growth factor-1 (IGF-1) as a predictive marker, since IGF-1 is important in both prostate cancer progression and bone development. Hence, we determined the association of IGF-1 expression to treatment response, and whether this expression resulted from tumor cells, the microenvironment, or their interactions. METHODS We measured serum IGF-1 levels in men with CRPC treated with dasatinib plus docetaxel. To investigate the source of IGF-1, we utilized two different mouse models harboring human prostate cancer cells, and used species-specific IGF-1 ELISA kits (mouse vs. human). RESULTS In men with CRPC, an increase in IGF-1 levels after one cycle of treatment with dasatinib and docetaxel is associated with a higher response rate and longer duration of treatment. Xenograft experiments with subcutaneous and intratibial injection of prostate cancer cells suggest that direct interaction of prostate cancer cells with bone microenvironment is necessary for IGF-1 induction, is entirely host-derived, and occurs only in mice that respond to dasatinib-based therapy. CONCLUSION Our results support a role for serum IGF-1 as a potential biomarker for benefit from dasatinib-based combination treatments in CRPC. Prostate 73: 979985, 2013. (c) 2013 Wiley Periodicals, Inc.