Targeted therapy of multiple myeloma based upon tumor-microenvironmental interactions
Targeted therapy of multiple myeloma based upon tumor-microenvironmental interactions
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DOI：
10.1016/j.exphem.2007.01.024
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发表时间：
2007-04-01
影响因子：
2.6
通讯作者：
Anderson, Kenneth C.
中科院分区：
文献类型：
--
作者：
Anderson, Kenneth C.
多发性骨髓瘤（MM）仍然无法治愈，但基因组学和蛋白质组学的最新进展使我们对疾病发病机制的理解取得了进展，确定了新的治疗靶点，允许分子分类，并为联合靶向治疗提供了科学依据，以增加肿瘤细胞的细胞毒性并消除耐药性。除了这些进展之外，认识到骨髓（BM）环境在实验室和动物模型中赋予MM细胞生长、存活和耐药性的作用，已经允许建立靶向肿瘤细胞及其微环境的新治疗范例，以克服耐药性并改善MM中的患者结果。和来那度胺都克服了传统的耐药性，不仅通过直接诱导肿瘤细胞的细胞毒性，而且通过抑制MM细胞与BM的粘附。这消除了组成型和MM结合诱导的细胞因子转录和分泌，抑制血管生成，并增强宿主抗MM免疫力。这三种药物已迅速从实验室转移到床边和MM的治疗方案中，首先用于复发性难治性疾病患者，然后单独或联合用于新诊断患者。有前途的新型靶向药物包括新型蛋白酶体抑制剂NPI-0052和热休克蛋白抑制剂科斯-953。重要的是，基因阵列、蛋白质组学和细胞信号传导研究不仅有助于确定体内作用机制和对新药物的耐药性，而且有助于设计有前途的联合治疗方案。(c)2007年国际实验血液学学会。爱思唯尔公司出版
Multiple myeloma (MM) remains incurable, but recent advances in genomics and proteomics have allowed for advances in our understanding of disease pathogenesis, identified novel therapeutic targets, allowed for molecular classification, and provided the scientific rationale for combining targeted therapies to increase tumor cell cytotoxicity and abrogate drug resistance. Besides these advances, recognition of the role of the bone marrow (BM) milieu in conferring growth, survival, and drug resistance in MM cells, both in laboratory and animal models, has allowed for the establishment of a new treatment paradigm targeting the tumor cell and its microenvironment to overcome drug resistance and improve patient outcomes in MM. In particular, thalidomide, bortezomib, and lenalidamide all overcome conventional drug resistance, not only by directly inducing tumor cell cytotoxicity, but by inhibiting adhesion of MM cells to BM. This abrogates constitutive and MM-binding-induced transcription and secretion of cytokines, inhibits angiogenesis, and augments host anti-MM immunity. These three drugs have rapidly translated from bench to bedside and in treatment protocols of MM, first in patients with relapsed refractory disease, and then alone and in combination in newly diagnosed patients. Promising novel targeted agents include the novel proteasome inhibitor NPI-0052 and the heat shock protein inhibitor KOS-953. Importantly, gene-array, proteomic, and cell-signaling studies have not only helped to identify in vivo mechanisms of action and drug resistance to novel agents, but also aided in the design of promising combination-therapy protocols. (c) 2007 International Society for Experimental Hematology. Published by Elsevier Inc.