Clinical Experience With Hedgehog Pathway Inhibitors
Clinical Experience With Hedgehog Pathway Inhibitors
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DOI：
10.1200/jco.2010.27.9943
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发表时间：
2010-12-20
影响因子：
45.3
通讯作者：
de Sauvage, Frederic J.
中科院分区：
文献类型：
--
作者：
Low, Jennifer A.;de Sauvage, Frederic J.
Hedgehog (Hh) 信号通路对于胚胎发生和早期发育过程中的细胞生长和分化至关重要。虽然它在成人中大多处于静止状态，但 Hh 通路的不适当重新激活已被证明与癌症的发展有关。许多肿瘤类型依赖于 Hh 配体的过度表达，以旁分泌方式激活从肿瘤到周围基质的通路。或者，Hh 配体可能作用于某些造血系统癌症（例如慢性粒细胞白血病）中的癌症干细胞。然而，Hh 通路的作用在基底细胞癌和髓母细胞瘤等肿瘤中得到了最好的证实，在这些肿瘤中，该通路是通过突变激活的。了解 Hh 信号传导在这些不同肿瘤类型中的贡献对于在临床中开发和使用针对该通路的药物至关重要。我们在此回顾 Hh 通路临床抑制剂的活性，包括 GDC-0449，一种 Smoothened (SMO) 的小分子抑制剂。
The Hedgehog (Hh) signaling pathway is critical for cell growth and differentiation during embryogenesis and early development. While it is mostly quiescent in adults, inappropriate reactivation of the Hh pathway has been shown to be involved in the development of cancer. A number of tumor types rely on overexpression of Hh ligands to activate the pathway in a paracrine manner from the tumor to the surrounding stroma. Alternatively, Hh ligands may act on cancer stem cells in some hematopoietic cancers, such as chronic myelogenous leukemia. However, the role of the Hh pathway is best established in tumors, such as basal cell carcinoma and medulloblastoma, where the pathway is activated via mutations. Understanding the contribution of Hh signaling in these various tumor types will be critical to the development and use of agents targeting this pathway in the clinic. We review here the activity of clinical inhibitors of the Hh pathway, including GDC-0449, a small molecule inhibitor of Smoothened (SMO).