文章：

刺猬的故事：开发针对癌症的策略

The Hedgehog's tale: developing strategies for targeting cancer

原文发布日期：2011-05-26

DOI: 10.1038/nrc3079

类型: Review Article

开放获取: 否

要点：

1. The Hedgehog (HH) pathway is an important regulator of embryogenesis that has also been implicated in tumour development. As all HH signalling through the canonical pathway requires Smoothened (SMO), small molecules such as GDC-0449, which inhibit SMO function, completely block all HH pathway signalling regardless of the ligand.
2. Drugs based on cyclopamine and other compounds that target SMO have been developed and are currently in Phase I and Phase II clinical trials. Drugs that target other aspects of the HH signalling pathway are also in development.
3. Initial results suggest that SMO inhibitors will prove useful in the treatment of basal cell carcinoma and in the subtype of medulloblastoma that is dependent on HH signalling.
4. It is important to understand how HH inhibitors could be used to treat other cancers, perhaps in combination with other therapies, which do not carry genetic lesions in the HH pathway, but that rely on HH signalling for disease progression. Improved understanding of cancer biology, particularly the interplay among cancer cells and stromal tissues, will help broaden the usefulness of such agents.
5. The identification of reliable biomarkers that indicate patients who are most likely to benefit from HH inhibitors, including non-invasive imaging approaches, is essential.
6. Understanding resistance mechanisms and developing methods to overcome resistance to SMO inhibitors will also be important in the future.
7. The importance of HH pathways during development and studies in mice indicate that SMO inhibitors in children with medulloblastoma will need to be used with care, so that potential effects on skeletal and brain development are avoided.
8. Given the dramatic responses reported in basal cell carcinoma and medulloblastoma in early trials, it is highly likely that SMO inhibitors will ultimately be approved as new therapeutic agents for treating cancer. This should be viewed as a success for basic, broad-based research in developmental biology, as well as cancer research, which laid a strong foundation for this translational opportunity.

要点翻译：

1. 刺猬（HH）信号通路是胚胎发生的重要调节因子，也被认为与肿瘤发展相关。由于所有经典HH信号传导均需经过平滑受体（SMO）的介导，因此诸如GDC-0449这类抑制SMO功能的小分子药物，能够完全阻断所有HH通路信号传导，且不受配体类型的影响。
2. 基于环巴胺及其他靶向SMO化合物的药物已被开发出来，目前正处于I期和II期临床试验阶段。针对HH信号通路其他环节的药物也正在研发中。
3. 初步研究结果表明，SMO抑制剂将对基底细胞癌及HH信号依赖型髓母细胞瘤亚型的治疗具有重要价值。
4. 需要重点探讨的是，如何将HH抑制剂应用于治疗其他癌症——这些癌症可能不携带HH通路基因突变，但依赖HH信号促进疾病进展，或许可考虑联合其他疗法。对癌症生物学（尤其是癌细胞与基质组织间相互作用）的深入理解，将有助于拓展此类药物的应用范围。
5. 确立可靠的生物标志物识别体系（包括无创影像学方法）至关重要，这能精准筛选出最可能从HH抑制剂治疗中获益的患者群体。
6. 理解耐药机制并制定克服SMO抑制剂耐药性的策略，也将成为未来研究的重要方向。
7. 鉴于HH通路在发育过程中的关键作用及小鼠实验研究结果，儿童髓母细胞瘤患者使用SMO抑制剂需审慎考量，以避免对骨骼和大脑发育产生潜在影响。
8. 早期临床试验中HH抑制剂在基底细胞癌和髓母细胞瘤治疗中展现的显著疗效，预示其极有可能最终获批成为新型抗癌药物。这应被视为发育生物学与癌症研究领域基础性广泛研究的成功典范——这些研究为此次转化医学机遇奠定了坚实基础。

英文摘要：

Research into basic developmental biology has frequently yielded insights into cancer biology. This is particularly true for the Hedgehog (HH) pathway. Activating mutations in the HH pathway cause a subset of sporadic and familial, skin (basal cell carcinoma) and brain (medulloblastoma) tumours. Furthermore, the growth of many human tumours is supported by HH pathway activity in stromal cells. Naturally occurring and synthetic inhibitors of HH signalling show great promise in animal models and in early clinical studies. However, it remains unclear how many cancers will ultimately benefit from these new, molecularly targeted therapies.

摘要翻译： 

对基础发育生物学的研究常常能为癌症生物学提供洞见，这对于Hedgehog（HH）信号通路尤为适用。HH通路的激活突变可导致部分散发性和家族性皮肤（基底细胞癌）及脑部（髓母细胞瘤）肿瘤。此外，许多人类肿瘤的生长也依赖于间质细胞中HH通路的活性。天然存在及人工合成的HH信号抑制剂在动物模型和早期临床研究中均展现出巨大潜力。然而，究竟有多少癌症最终会从这些新型分子靶向治疗中获益，目前仍不清楚。

原文链接：

The Hedgehog's tale: developing strategies for targeting cancer