Gan Gregory N, Jimeno Antonio
a Section of Radiation Oncology, Department of Internal Medicine , University of New Mexico School of Medicine , Albuquerque , NM , USA.
b Division of Medical Oncology, Department of Medicine , University of Colorado School of Medicine , Aurora , CO , USA.
Expert Opin Investig Drugs. 2016 Oct;25(10):1153-66. doi: 10.1080/13543784.2016.1216973. Epub 2016 Aug 5.
Cancer treatment is moving away from conventional cytotoxic drugs and towards agents that target specific proteins and mechanisms important to cancer development or survival. The Hedgehog Pathway (HhP) is a signal transduction pathway and its constitutive activation is tumorigenic in basal cell carcinoma (BCC). The HhP enables phenotypic flexibility, and channels tumor-stroma interactions. As a result, it is over-expressed in numerous cancers as well as in the tumor microenvironment and may represent a promising therapeutic target.
In this article, we review the rationale for targeting HhP and its role as an oncogenic driver, in tumor epithelial-to-mesenchymal transition (EMT), and in the tumor microenvironment and describe the results of preclinical and clinical studies involving HhP inhibitors.
HhP activation plays an important role in both the tumor microenvironment and tumor EMT which can lead to treatment resistance for a number of different malignancies. In addition to standard use in BCC, several HhP inhibitors are in preclinical, early, and mid-stage clinical development for other solid and hematologic malignancies.
癌症治疗正从传统的细胞毒性药物转向针对对癌症发展或生存至关重要的特定蛋白质和机制的药物。刺猬信号通路（HhP）是一种信号转导通路，其组成性激活在基底细胞癌（BCC）中具有致瘤性。HhP能够实现表型灵活性，并引导肿瘤-基质相互作用。因此，它在多种癌症以及肿瘤微环境中过度表达，可能是一个有前景的治疗靶点。
在本文中，我们综述了靶向HhP的理论依据及其作为致癌驱动因素在肿瘤上皮-间质转化（EMT）以及肿瘤微环境中的作用，并描述了涉及HhP抑制剂的临床前和临床研究结果。
HhP激活在肿瘤微环境和肿瘤EMT中均起重要作用，这可能导致多种不同恶性肿瘤产生治疗抗性。除了在BCC中的标准应用外，几种HhP抑制剂正处于针对其他实体和血液系统恶性肿瘤的临床前、早期和中期临床开发阶段。
