Robert H. Lurie Comprehensive Cancer Center and Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Curr Opin Oncol. 2011 Nov;23(6):601-8. doi: 10.1097/CCO.0b013e32834b8943.
Chronic lymphocytic leukemia (CLL) therapy has evolved over the past few decades as modern chemo-immunotherapy significantly improved the response and survival of CLL patients. However, treatment toxicity of the intensive chemo-immunotherapy often limits its use in the mostly elderly population of patients. Further, the disease eventually relapses and additional therapy options are required. Of particular interest are molecular targeted therapies that interfere with critical signal transduction pathways controlling cell growth and survival. This review will provide an update on the most recent preclinical and clinical development of signal transduction targeted therapy in CLL.
Small molecular kinase inhibitors have been developed to target the proximal B-cell receptor signaling pathway (e.g. spleen tyrosine kinase inhibitors and Bruton's tyrosine kinase inhibitors) or the downstream phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin pathway. These agents showed unique in-vitro activities by inducing apoptosis and blocking interaction of CLL cells and the protective microenvironment. They have also shown promising clinical activity in early-phase clinical studies and appear to alter lymphocyte trafficking. Inhibitors of the B-cell CLL/lymphoma 2 (BCL-2) family of antiapoptotic proteins and Cdk inhibitors are in active clinical development. Strategies modulating the CLL interaction with the microenvironment niche are emerging. Further understanding of novel signaling pathways helps to identify additional potential therapeutic targets.
Signal transduction inhibitors are promising new strategy for targeted CLL treatment. Identification of novel molecular targets and therapeutic agents will further expand our therapeutic options.
慢性淋巴细胞白血病（CLL）的治疗在过去几十年中发生了演变，现代化疗免疫疗法显著提高了 CLL 患者的反应和生存率。然而，强化化疗免疫疗法的治疗毒性常常限制了其在大多数老年患者中的应用。此外，该疾病最终会复发，需要额外的治疗选择。特别感兴趣的是分子靶向疗法，这些疗法可以干扰控制细胞生长和存活的关键信号转导途径。这篇综述将提供最新的 CLL 信号转导靶向治疗的临床前和临床发展的最新信息。
已经开发出小分子激酶抑制剂来靶向 B 细胞受体信号转导途径的近端（例如，脾酪氨酸激酶抑制剂和布鲁顿酪氨酸激酶抑制剂）或下游的磷脂酰肌醇 3 激酶/Akt/哺乳动物雷帕霉素靶蛋白途径。这些药物通过诱导细胞凋亡和阻断 CLL 细胞与保护性微环境的相互作用，具有独特的体外活性。它们在早期临床试验中也表现出有希望的临床活性，并且似乎改变了淋巴细胞的迁移。BCL-2 家族抗凋亡蛋白和 Cdk 抑制剂的 B 细胞 CLL/淋巴瘤 2（BCL-2）抑制剂正在积极进行临床开发。调节 CLL 与微环境龛相互作用的策略正在出现。对新信号通路的进一步了解有助于确定其他潜在的治疗靶点。
信号转导抑制剂是针对 CLL 治疗的有前途的新策略。鉴定新的分子靶点和治疗剂将进一步扩大我们的治疗选择。
