Targeting the Hedgehog pathway in cancer.
Targeting the Hedgehog pathway in cancer.
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DOI：
10.1177/1758834010366430
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发表时间：
2010-07-01
影响因子：
4.9
通讯作者：
Lorusso, Patricia
中科院分区：
文献类型：
--
作者：
Gupta, Sachin;Takebe, Naoko;Lorusso, Patricia
Hedgehog （Hh）通路是脊椎动物胚胎发育中许多基本过程的主要调控因子，包括干细胞维持、细胞分化、组织极性和细胞增殖。在基底细胞癌和成神经管细胞瘤中可以看到Hh通路导致肿瘤发生的组成性激活。多种其他人类癌症，包括脑癌、胃肠道癌、肺癌、乳腺癌和前列腺癌，也显示出这种途径的不适当激活。从肿瘤到周围基质的旁分泌Hh信号最近被证明可以促进肿瘤的发生。这一途径也被证明可以调节癌症干细胞的增殖并增加肿瘤的侵袭性。靶向抑制Hh信号可能有效地治疗和预防许多类型的人类癌症。特异性Hh通路抑制剂的发现和合成在新型癌症治疗中具有重要的临床意义。目前已有几种合成Hh拮抗剂，其中几种正在进行临床评估。口服药物GDC-0449目前处于临床开发阶段。基底细胞癌和髓母细胞瘤患者的初步临床试验显示出良好的疗效和安全性。我们回顾了Hh信号的分子基础，目前对不同类型人类癌症中通路激活的理解，并讨论了Hh通路抑制剂在人类癌症治疗中的临床进展。
The Hedgehog (Hh) pathway is a major regulator of many fundamental processes in vertebrate embryonic development including stem cell maintenance, cell differentiation, tissue polarity and cell proliferation. Constitutive activation of the Hh pathway leading to tumorigenesis is seen in basal cell carcinomas and medulloblastoma. A variety of other human cancers, including brain, gastrointestinal, lung, breast and prostate cancers, also demonstrate inappropriate activation of this pathway. Paracrine Hh signaling from the tumor to the surrounding stroma was recently shown to promote tumorigenesis. This pathway has also been shown to regulate proliferation of cancer stem cells and to increase tumor invasiveness. Targeted inhibition of Hh signaling may be effective in the treatment and prevention of many types of human cancers. The discovery and synthesis of specific Hh pathway inhibitors have significant clinical implications in novel cancer therapeutics. Several synthetic Hh antagonists are now available, several of which are undergoing clinical evaluation. The orally available compound, GDC-0449, is the farthest along in clinical development. Initial clinical trials in basal cell carcinoma and treatment of select patients with medulloblastoma have shown good efficacy and safety. We review the molecular basis of Hh signaling, the current understanding of pathway activation in different types of human cancers and we discuss the clinical development of Hh pathway inhibitors in human cancer therapy.