Targeting ALK in neuroblastoma--preclinical and clinical advancements.
Targeting ALK in neuroblastoma--preclinical and clinical advancements.
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DOI：
10.1038/nrclinonc.2012.72
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发表时间：
2012-05-15
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尽管在过去的50年中癌症治疗有所改进，但神经母细胞瘤仍然是一个毁灭性的临床问题，也是儿童癌症死亡的主要原因。直到最近，高危神经母细胞瘤儿童治疗的进展还包括在剂量密集型方案中加入细胞毒性治疗。在这个靶向治疗的时代，已经做出了大量努力来确定不同类型癌症的最佳靶点。致癌基因ALK中遗传性和体细胞激活突变的发现现在已经将神经母细胞瘤置于其他癌症中，如黑色素瘤和非小细胞肺癌（NSCLC），这些癌症受益于致癌基因特异性小分子酪氨酸激酶抑制剂的治疗。克唑替尼是一种ALK的小分子抑制剂，已经改变了治疗携带ALK易位的NSCLC的前景，并在ALK驱动的神经母细胞瘤的临床前模型中显示出活性。然而，与易位的ALK相比，突变的ALK的抑制是复杂的，并且仍然是治疗挑战。本综述讨论了ALK在神经母细胞瘤发展中的生物学，使用ALK抑制剂和免疫治疗的临床前和临床进展，与此类治疗耐药相关的挑战以及为克服其中一些障碍而采取的步骤。
Despite improvements in cancer therapies in the past 50 years, neuroblastoma remains a devastating clinical problem and a leading cause of childhood cancer deaths. Advances in treatments for children with high-risk neuroblastoma have, until recently, involved addition of cytotoxic therapy to dose-intensive regimens. In this era of targeted therapies, substantial efforts have been made to identify optimal targets for different types of cancer. The discovery of hereditary and somatic activating mutations in the oncogene ALK has now placed neuroblastoma among other cancers, such as melanoma and non-small-cell lung cancer (NSCLC), which benefit from therapies with oncogene-specific small-molecule tyrosine kinase inhibitors. Crizotinib, a small-molecule inhibitor of ALK, has transformed the landscape for the treatment of NSCLC harbouring ALK translocations and has demonstrated activity in preclinical models of ALK-driven neuroblastomas. However, inhibition of mutated ALK is complex when compared with translocated ALK and remains a therapeutic challenge. This Review discusses the biology of ALK in the development of neuroblastoma, preclinical and clinical progress with the use of ALK inhibitors and immunotherapy, challenges associated with resistance to such therapies and the steps being taken to overcome some of these hurdles.
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影响因子：
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作者：
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