Genentech Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
J Clin Oncol. 2010 Dec 20;28(36):5321-6. doi: 10.1200/JCO.2010.27.9943. Epub 2010 Nov 1.
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).
刺猬（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，但已表明 Hh 途径的不当重新激活与癌症的发展有关。许多肿瘤类型依赖于 Hh 配体的过度表达，以旁分泌的方式从肿瘤到周围基质激活该途径。或者，Hh 配体在某些造血癌（如慢性髓性白血病）中可能作用于癌症干细胞。然而，Hh 途径在肿瘤中的作用最为明确，例如基底细胞癌和髓母细胞瘤，其中该途径通过突变激活。了解 Hh 信号在这些各种肿瘤类型中的作用对于开发和临床应用靶向该途径的药物至关重要。在这里，我们回顾了 Hh 途径的临床抑制剂的活性，包括 GDC-0449，一种 Smoothened（SMO）的小分子抑制剂。
