Hedgehog pathway as a drug target: Smoothened inhibitors in development.
Hedgehog pathway as a drug target: Smoothened inhibitors in development.
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DOI：
10.2147/ott.s21957
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发表时间：
2012
影响因子：
4
通讯作者：
Matsui W
中科院分区：
文献类型：
--
作者：
Lin TL;Matsui W
新出现的实验室和临床研究表明，Hedgehog信号(HH)是多种人类癌症的新治疗靶点。这种保守的信号通路精确地调节胚胎发育中的自我更新和末端分化，但在成年组织中通常是沉默的，通常只有在组织修复时才会重新激活。HH信号通路的异常与越来越多的实体和血液系统恶性肿瘤的发病机制、自我更新和化疗耐药有关。HH途径的主要组成部分包括HH配体(Sonic、Desert和Indian)、跨膜受体Patted、信号转导蛋白Smoothens(Smo)和调节HH靶基因转录的转录因子Gli1-3。HH通路基因的突变、肿瘤间质中HH信号的增加以及自我更新细胞(肿瘤干细胞)中HH的过度表达已被描述，这些不同的HH信号模式对HH通路抑制剂的设计及其与常规治疗方案的整合具有重要意义。一种自然产生的Smo抑制剂--环多巴胺的发现，以及HH途径突变和在癌细胞中过度表达的鉴定，促使了几种环多巴胺衍生物的开发。令人鼓舞的实验室和体内数据导致了Smo抑制剂的I期和II期临床试验。在这篇综述中，我们将讨论HH信号通路在恶性肿瘤中的研究现状以及Smo拮抗剂的研究进展。最近关于这些药物的数据表明，它们耐受性很好，可能对部分患者有效。在适当的患者选择以及将这些靶向疗法的最佳组合和顺序纳入当前的治疗范例方面仍然存在挑战。
Emerging laboratory and clinical investigations demonstrate that Hedgehog signaling (Hh) represents a novel therapeutic target in various human cancers. This conserved signaling pathway precisely regulates self-renewal and terminal differentiation in embryonic development, but is typically silenced in adult tissues, with reactivation usually only during tissue repair. Aberrant Hh pathway signaling has been implicated in the pathogenesis, self-renewal, and chemotherapy resistance of a growing number of solid and hematologic malignancies. Major components of the Hh pathway include the Hh ligands (Sonic, Desert, and Indian), the transmembrane receptor Patched, the signal transducer Smoothened (Smo), and transcription factors Gli1–3 which regulate the transcription of Hh target genes. Mutations in Hh pathway genes, increased Hh signaling in tumor stroma, and Hh overexpression in self-renewing cells (cancer stem cells) have been described, and these different modes of Hh signaling have implications for the design of Hh pathway inhibitors and their integration into conventional treatment regimens. Discovery of a naturally-occurring Smo inhibitor, cyclopamine, and the identification of Hh pathway mutations and over expression in cancer cells prompted the development of several cyclopamine derivatives. Encouraging laboratory and in vivo data has resulted in Phase I and II clinical trials of Smo inhibitors. In this review, we will discuss the current understanding of Hh pathway signaling in malignancy and Smo antagonists in development. Recent data with these agents shows that they are well-tolerated and may be effective for subsets of patients. Challenges remain for appropriate patient selection and the optimal combination and sequence of these targeted therapies into current treatment paradigms.