Molecular pathways: novel approaches for improved therapeutic targeting of Hedgehog signaling in cancer stem cells.
Molecular pathways: novel approaches for improved therapeutic targeting of Hedgehog signaling in cancer stem cells.
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DOI：
10.1158/1078-0432.ccr-14-0507
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发表时间：
2015-02-01
期刊：
影响因子：
--
通讯作者：
Fields AP
中科院分区：
文献类型：
--
作者：
Justilien V;Fields AP
Hedgehog （Hh）信号通路对胚胎发育至关重要。在成人组织中，除了在组织维护和修复中的作用外，Hh信号相对静止。Hh信号的异常激活涉及转化的多个方面，包括癌症干细胞（CSC）表型的维持。临床前研究表明，许多肿瘤类型的CSCs对Hh通路抑制敏感，Hh靶向治疗阻断了CSCs的许多方面的转化，包括耐药、复发和转移。然而，迄今为止，Hh抑制剂，特别是靶向Smoothened的Hh抑制剂（如Vismodegib、BMS-833923、Saridegib （IPI-926）、Sonidegib/Erismodegib （LDE225）、sf -04449913、LY2940680、LEQ 506和ak -441）在基底细胞癌和成神经管细胞瘤患者中显示出良好的单药治疗效果，但在其他肿瘤类型中显示出有限的活性。这种缺乏成功可能是由于许多因素造成的，包括早期试验中缺乏患者分层，Hh和其他可调节治疗反应的致癌信号通路之间的串扰，以及大多数肿瘤类型的CSCs中Hh通路激活机制的有限知识。在这里，我们讨论了Hh信号传导机制在人类癌症的背景下，特别是在CSC表型的维持，并考虑了新的治疗策略，这有可能大大扩大Hh指导的抗癌治疗的范围和治疗效果。
The Hedgehog (Hh) signaling pathway is critical for embryonic development. In adult tissues, Hh signaling is relatively quiescent with the exception of roles in tissue maintenance and repair. Aberrant activation of Hh signaling is implicated in multiple aspects of transformation including the maintenance of the cancer stem cell (CSC) phenotype. Pre-clinical studies indicate that CSCs from many tumor types are sensitive to Hh pathway inhibition and that Hh-targeted therapeutics block many aspects of transformation attributed to CSCs including, drug resistance, relapse and metastasis. However, to date, Hh inhibitors, specifically those targeting Smoothened (such as Vismodegib, BMS-833923, Saridegib (IPI-926), Sonidegib/Erismodegib (LDE225), PF-04449913, LY2940680, LEQ 506 and TAK-441) have demonstrated good efficacy as monotherapy in patients with basal cell carcinoma and medulloblastoma, but have shown limited activity in other tumor types. This lack of success is likely due to many factors including a lack of patient stratification in early trials, crosstalk between Hh and other oncogenic signaling pathways that can modulate therapeutic response, and a limited knowledge of Hh pathway activation mechanisms in CSCs from most tumor types. Here we discuss Hh signaling mechanisms in the context of human cancer, particularly in the maintenance of the CSC phenotype, and consider new therapeutic strategies that hold the potential to expand considerably the scope and therapeutic efficacy of Hh-directed anti-cancer therapy.