Hedgehog Signaling Pathway and Cancer Therapeutics: Progress to Date
Hedgehog Signaling Pathway and Cancer Therapeutics: Progress to Date
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DOI：
10.1007/s40265-013-0045-z
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发表时间：
2013-05-01
期刊：
影响因子：
11.5
通讯作者：
Kim, Edward J.
中科院分区：
文献类型：
--
作者：
Ruch, Joshua M.;Kim, Edward J.
Hedgehog (Hh) 通路是一种发育信号通路，参与许多发育过程，包括细胞命运、模式、增殖、存活和分化的决定。虽然该通路在大多数成人组织中处于沉默状态，但在多种恶性肿瘤中已记录到其异常激活。在基底细胞癌 (BCC) 等癌症中，配体独立机制通过通路组件（包括 patched-1 (PTCH1) 或 smoothened (SMO)）的突变导致组成型 Hh 通路激活。相反，许多其他实体瘤和血液肿瘤已显示出通过自分泌或旁分泌机制对 Hh 途径进行配体依赖性激活。鉴于在许多恶性肿瘤中都发现了异常的 Hh 通路信号传导，该通路已成为药物开发的一个有吸引力的目标。虽然最具特色的方法是靶向 SMO 受体，但抑制 Hh 途径的其他合理方法包括抑制下游成分或直接结合 Hh 配体。 2012年1月，SMO拮抗剂vismodegib在治疗BCC的I期和II期试验中显示出显着的活性，成为第一个获得美国食品和药物管理局（FDA）批准的针对Hh通路的药物。尽管 Hh 通路抑制剂在其他恶性肿瘤中的临床前研究有希望，表明这些药物具有潜在作用，但将这种潜力转化为临床益处的尝试却令人失望。未来的努力将需要进一步仔细的解释和分析，以确定功效的潜在决定因素和预测因素。目前，评估 Hh 抑制剂在各种肿瘤环境中的几项 I 期和 II 期试验正在进行中。
The Hedgehog (Hh) pathway is a developmental signaling pathway involved in numerous developmental processes, including determination of cell fate, patterning, proliferation, survival, and differentiation. While this pathway is silenced in most adult tissues, aberrant activation of it has been documented in a variety of malignancies. In cancers such as basal cell carcinoma (BCC), ligand-independent mechanisms lead to constitutive Hh pathway activation through mutations in components of the pathway, including patched-1 (PTCH1) or smoothened (SMO). On the contrary, numerous other solid and hematologic tumors have been shown to harbor ligand-dependent activation of the Hh pathway by autocrine or paracrine mechanisms. Given that aberrant Hh pathway signaling has been seen in a number of malignancies, this pathway has been an attractive target for drug development. While the best-characterized approach is to target the SMO receptor, other rational approaches for inhibiting the Hh pathway include inhibiting downstream components or directly binding Hh ligands. In January of 2012, vismodegib, a SMO antagonist, became the first agent to target the Hh pathway to receive approval by the United States Food and Drug Administration (FDA) after this agent showed remarkable activity in phase I and II trials for the treatment of BCC. Despite promising preclinical studies with Hh pathway inhibitors in other malignancies that have suggested a potential role for these agents, attempts to translate this potential to clinical benefit has been disappointing. Future efforts will require further careful interpretation and analysis to determine the potential determinants and predictors of efficacy. Currently, several phase I and II trials evaluating Hh inhibitors in a variety of tumor settings are underway.