Blood:口服MDM2蛋白拮抗剂Idasanutlin用于真性红细胞增多症的疗效评估

2019-06-06 QQ MedSci原创

治疗真性红细胞增多症(PV)和原发性血小板增多症(ET)的药物数量有限。John Mascarenhas等研究人员尝试寻找可靶向恶性造血干细胞/祖细胞 (HSC/HPC)的替代药物。已有研究表明MDM2蛋白在PV/ET CD34+细胞中的表达水平上调,暴露于MDM2拮抗剂nutlin中,可诱导激活TP53信号通路,选择性耗竭PV HPC/HSCs。这种抗克隆活性由p53上调介导,并可通过添加干扰素

中心点:

MDM2在PV患者中的表达水平升高,为MDM2拮抗剂药物干预的治疗靶点。

MDM2拮抗剂idasanutlin,用于PV患者耐受性良好,表现出靶向p53激活和临床活性。

摘要:

治疗真性红细胞增多症(PV)和原发性血小板增多症(ET)的药物数量有限。John Mascarenhas等研究人员尝试寻找可靶向恶性造血干细胞/祖细胞 (HSC/HPC)的替代药物。

已有研究表明MDM2蛋白在PV/ET CD34+细胞中的表达水平上调,暴露于MDM2拮抗剂nutlin中,可诱导激活TP53信号通路,选择性耗竭PV HPC/HSCs。这种抗克隆活性由p53上调介导,并可通过添加干扰素-α-2a而增强。

因此,John等人开展一1期试验,研究口服MDM2拮抗剂 idasanutlin用于既往治疗失败的高危型PV/ET患者的疗效和安全性。招募了13位携带JAK2V617F阳性的PV/ET患者,其中12位(11位PV患者、1位ET患者)接受idasanutlin治疗,100mg/日或150mg/日,连续服用5天,28天一疗程。

Idasanutlin的安全性良好,试验期间未观察到剂量限制性毒性,但常见低级别的肠毒性。idasanutlin单药治疗6个疗程后,总体缓解率为58%(7/12),与其他药物联合治疗的总体缓解率为50%(2/4)。缓解持续的中位时间位16.8个月(3.5-26.7)。患者血液学、症状、病理性和分子缓解均有获得。

综上所述,本研究表明idasanutlin是一种有望用于PV的新药物,目前关于idasanutlin的全球2期试验正在进行中。


原始出处:

John Mascarenhas, et al. Oral Idasanutlin in Patients with Polycythemia Vera. Blood 2019 :blood.2018893545; doi: https://doi.org/10.1182/blood.2018893545

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    2020-02-18 wangyang7970
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    2019-07-28 lvygwyt2781
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    2019-06-06 内科新手

    谢谢梅斯提供这么好的信息,学到很多

    0