Hideshima Teru, Chauhan Dharminder, Richardson Paul, Anderson Kenneth C
Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115, USA.
J Clin Oncol. 2005 Sep 10;23(26):6345-50. doi: 10.1200/JCO.2005.05.024.
In vitro and in vivo models have been developed that have allowed for delineation of mechanisms of multiple myeloma (MM) cell homing to bone marrow (BM); tumor cell adhesion to extracellular matrix proteins and BM stromal cells; and cytokine-mediated growth, survival, drug resistance, and migration within the BM milieu. Delineation of the signaling cascades mediating these sequelae has identified multiple novel therapeutic targets in the tumor cell and its BM microenvironment. Importantly, novel therapies targeting the tumor cell and the BM, as well as those targeting the tumor cell or BM alone, can overcome the growth, survival, conventional drug resistance, and migration of MM cells bound to BM using both in vitro and in vivo severe combined immunodeficiency mouse models of human MM. These studies have translated rapidly from the bench to the bedside in derived clinical trials, and have already led to the United States Food and Drug Administration approval of the novel proteasome inhibitor bortezomib for treatment of relapsed/refractory MM. Novel agents will need to be combined to enhance cytotoxicity, avoid development of drug resistance, and allow for use of lower doses in combination therapies. Genomics, proteomics, and cell signaling studies have helped to identify in vivo mechanisms of sensitivity versus resistance to novel therapies, as well as aiding in the rational application of combination therapies. These studies have therefore provided the framework for a new treatment paradigm targeting the MM cell in its BM milieu to overcome drug resistance and improve patient outcome in MM.
已经建立了体外和体内模型，这些模型有助于描绘多发性骨髓瘤（MM）细胞归巢至骨髓（BM）的机制；肿瘤细胞与细胞外基质蛋白和BM基质细胞的粘附；以及细胞因子介导的在BM微环境中的生长、存活、耐药性和迁移。对介导这些后果的信号级联的描绘已经在肿瘤细胞及其BM微环境中确定了多个新的治疗靶点。重要的是，使用人MM的体外和体内严重联合免疫缺陷小鼠模型，靶向肿瘤细胞和BM的新疗法，以及那些仅靶向肿瘤细胞或BM的疗法，可以克服与BM结合的MM细胞的生长、存活、传统耐药性和迁移。这些研究已经在衍生的临床试验中迅速从实验室转化到临床应用，并且已经导致美国食品药品监督管理局批准新型蛋白酶体抑制剂硼替佐米用于治疗复发/难治性MM。新的药物需要联合使用以增强细胞毒性、避免耐药性的产生，并允许在联合治疗中使用更低的剂量。基因组学、蛋白质组学和细胞信号研究有助于确定对新疗法敏感与耐药的体内机制，以及有助于联合疗法的合理应用。因此，这些研究为一种新的治疗模式提供了框架，该模式靶向处于其BM微环境中的MM细胞，以克服耐药性并改善MM患者的预后。
