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Targeting notch signaling pathway in cancer: clinical development advances and challenges.
Pharmacology & Therapeutics ( IF 12.0 ) Pub Date : 2013-10-01 , DOI: 10.1016/j.pharmthera.2013.09.005
Naoko Takebe 1 , Dat Nguyen 2 , Sherry X Yang 2
Affiliation  

Notch signaling plays an important role in development and cell fate determination, and it is deregulated in human hematologic malignancies and solid tumors. This review includes a brief introduction of the relevant pathophysiology of Notch signaling pathway and primarily focuses on the clinical development of promising agents that either obstruct Notch receptor cleavages such as γ-secretase inhibitors (GSIs) or interfere with the Notch ligand-receptor interaction by monoclonal antibodies (mAbs). Antitumor activity by GSIs and mAbs administered as single agent in early phases of clinical trials has been observed in advanced or metastatic thyroid cancer, non-small cell lung cancer, intracranial tumors, sarcoma or desmoid tumors, colorectal cancer with neuroendocrine features, melanoma and ovarian cancer. A number of mechanism-based adverse events particularly gastrointestinal toxicities emerged and mitigation strategies are developed after testing multiple GSIs and Notch targeting mAbs. We also discuss pharmacodynamic biomarkers in conjunction with methods of assessment of the molecular target inhibition validation. Biomarkers of efficacy or benefit may be of importance for a successful development of this class of drugs.

中文翻译:

靶向癌症中的缺口信号通路:临床开发进展和挑战。

Notch 信号在发育和细胞命运决定中起着重要作用,它在人类血液系统恶性肿瘤和实体瘤中被解除管制。这篇综述简要介绍了 Notch 信号通路的相关病理生理学,主要关注阻碍 Notch 受体裂解的药物的临床开发,如γ-分泌酶抑制剂 (GSI) 或通过单克隆抗体干扰 Notch 配体-受体相互作用。抗体(mAb)。已经在晚期或转移性甲状腺癌、非小细胞肺癌、颅内肿瘤、肉瘤或硬纤维瘤、具有神经内分泌特征的结直肠癌、黑色素瘤和卵巢癌中观察到 GSI 和 mAb 在临床试验早期作为单药给药的抗肿瘤活性癌症。在测试多种 GSI 和 Notch 靶向 mAb 后,出现了许多基于机制的不良事件,尤其是胃肠道毒性,并制定了缓解策略。我们还讨论了药效生物标志物以及分子靶标抑制验证的评估方法。功效或益处的生物标志物对于此类药物的成功开发可能很重要。
更新日期:2013-09-27
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