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Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl...
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针对毛细血管静脉形的向治疗.

Lola Zerbib1,2, Sophia Ladraa1,2, Antoine Fraissenon2,3,4,5

  • 1Université Paris Cité, Paris, France.

Signal transduction and targeted therapy
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概括

阿尔佩利西布通过抑制PI3Kα.有效地治疗与PIK3CA相关的毛细血管静脉形. 在小鼠模型中,这种治疗改善了病变和延长了生存时间,并且在患有PIK3CA或TEK突变的患者中显示出显著的体积减少.

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科学领域:

  • 遗传学 遗传学 是一个
  • 血管生物学 血管生物学
  • 药理学 药理学是指药理学的学科.

背景情况:

  • 零星静脉形是由PIK3CA或TEK突变引起的,在没有经批准的治疗方法的情况下引起了严重的健康问题.
  • 这些形导致疼痛,出血,血栓形成和可能危及生命的并发症.
  • 目前的手术和硬化疗法等治疗方法往往不足.

研究的目的:

  • 开发和验证与PIK3CA相关的毛细血管静脉形小鼠模型.
  • 评估PI3Kα抑制剂,特别是alpelisib在治疗这些发育不良的疗效.
  • 评估alpelisib在人类耐火性静脉形患者中的安全性和有效性.

主要方法:

  • 创建了一个基因小鼠模型,模仿人类PIK3CA相关的毛细血管静脉形.
  • 在小鼠模型中比较了alpelisib (PI3Kα抑制剂) 与其他药物,如拉巴素和米兰塞蒂布.
  • 进行了一项临床试验,使用alpelisib治疗25名患有PIK3CA或TEK突变的患者 (包括儿童),并通过MRI评估结果.

主要成果:

  • 在小鼠模型中,阿尔佩利西布在预防,改善和延长生存方面表现出有效性.
  • 所有25名用alpelisib治疗的患者在6个月内都出现了改善,血管形体积减少 (33.4%用于PIK3CA,27.8%用于TEK).
  • 临床症状减弱,以前难以治疗的形对阿尔佩利西布治疗有了反应.

结论:

  • 用alpelisib抑制PI3Kα是PIK3CA或TEK相关的毛细血管静脉形的一个有前途的治疗策略.
  • 阿尔佩利西布为患有严重或耐火性静脉形的患者 (包括儿童) 提供了可行的治疗选择.
  • 这项研究验证了针对血管形中的PI3Kα途径的治疗潜力.