骨髓纤维化的新型疗法
Novel Therapies for Myelofibrosis.
作者信息
Pettit Kristen, Odenike Olatoyosi
机构信息
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, 5841 S. Maryland Ave, MC2115, Chicago, IL, 60637, USA.
出版信息
Curr Hematol Malig Rep. 2017 Dec;12(6):611-624. doi: 10.1007/s11899-017-0403-0.
PURPOSE OF REVIEW
The purpose of the review was to provide a contemporary update of novel agents and targets under investigation in myelofibrosis in the Janus kinase (JAK) inhibitor era.
RECENT FINDINGS
Myelofibrosis (MF) is a clonal stem cell disease characterized by marrow fibrosis and a heterogeneous disease phenotype with a variable degree of splenomegaly, cytopenias, and constitutional symptoms that significantly impact quality of life and survival. Overactive JAK/STAT signaling is a hallmark of MF. The only approved therapy for MF, JAK1/2 inhibitor ruxolitinib, can ameliorate splenomegaly, improve symptoms, and prolong survival in some patients. Therapeutic challenges remain, however. Myelosuppression limits the use of ruxolitinib in some patients, eventual drug resistance is common, and the underlying malignant clone persists despite therapy. A deeper understanding of the pathogenesis of MF has informed the development of additional agents. Promising targets under investigation include JAK1 and JAK2 and downstream intermediates in related signaling pathways, epigenetic modifiers, pro-inflammatory cytokines, and immune regulators.
综述目的
本综述旨在对在Janus激酶（JAK）抑制剂时代骨髓纤维化中正在研究的新型药物和靶点进行当代更新。
最新发现
骨髓纤维化（MF）是一种克隆性干细胞疾病，其特征为骨髓纤维化和异质性疾病表型，伴有不同程度的脾肿大、血细胞减少和全身症状，这些症状会显著影响生活质量和生存期。JAK/STAT信号过度激活是MF的一个标志。MF唯一获批的治疗药物JAK1/2抑制剂芦可替尼，可改善部分患者的脾肿大、缓解症状并延长生存期。然而，治疗挑战依然存在。骨髓抑制限制了芦可替尼在部分患者中的使用，最终耐药很常见，且尽管进行了治疗，潜在的恶性克隆仍持续存在。对MF发病机制的更深入理解推动了其他药物的研发。正在研究的有前景的靶点包括JAK1和JAK2以及相关信号通路中的下游中间体、表观遗传修饰因子、促炎细胞因子和免疫调节剂。
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