ABSTRACT

Hedgehog (HH) signaling, a critical developmental pathway, has been implicated in cancer initiation and progression. With vismodegib and sonidegib having been approved for clinical use, increasing numbers of HH inhibitors alone and in combination with chemotherapies are in clinical trials. Here we highlight the clinical research on HH antagonists and the genetics of response to these compounds in human cancers. Selectivity of HH inhibitors, determined by decreased pathway transcriptional activity, has been demonstrated in many clinical trials. Patients with advanced/metastatic basal cell carcinoma have benefited the most, whereas HH antagonists did little to improve survival rates in other cancers. Correlation between clinical response and HH gene expression vary among different cancer types. Predicting response and resistance to HH inhibitors presents a challenge and continues to remain an important area of research. New approaches combine standard of care chemotherapies and molecularly targeted therapies to increase the clinical utility of HH inhibitors.

摘要

Hedgehog (HH) 信号传导是一种关键的发育途径，与癌症的发生和进展有关。随着 vismodegib 和 Sonidegib 已被批准用于临床，越来越多的 HH 抑制剂单独和与化学疗法联合进行临床试验。在这里，我们重点介绍了 HH 拮抗剂的临床研究以及人类癌症中对这些化合物的反应的遗传学。HH 抑制剂的选择性由通路转录活性降低决定，已在许多临床试验中得到证实。晚期/转移性基底细胞癌患者受益最大，而 HH 拮抗剂对提高其他癌症的存活率几乎没有作用。临床反应和 HH 基因表达之间的相关性在不同的癌症类型中有所不同。预测对 HH 抑制剂的反应和抗性是一项挑战，并且仍然是一个重要的研究领域。新方法将标准护理化学疗法和分子靶向疗法相结合，以提高 HH 抑制剂的临床效用。