Notch as a New Therapeutic Target in Hematological Malignancies

描述(申请人提供)：耐药性仍然是包括多发性骨髓瘤(MM)在内的各种癌症患者治疗的主要障碍之一。过去十年积累的证据表明，微环境在肿瘤细胞的生存和生长中发挥着突出的作用。聚焦于多发性骨髓瘤，我们最近证明了微环境，特别是骨髓基质细胞，对肿瘤细胞对化疗的反应有显著的影响。骨髓基质保护骨髓瘤细胞免受细胞毒药物的初步治疗。因此，允许存活的肿瘤细胞亚群，骨髓基质可能有助于微小残留病的发展，并最终导致临床复发。我们以前的工作表明，骨髓基质介导的耐药机制之一是激活MM细胞中的受体/转录调节因子Notch。这一应用的总体假设是，肿瘤微环境激活了MM细胞中的Notch信号，使它们能够逃脱药物诱导的细胞死亡。药物抑制Notch逆转了这一效应，因此可能对MM患者有治疗上的好处。在这项建议中，我们将研究Notch介导的MM细胞保护免受化疗药物诱导的细胞凋亡的分子机制及其可能的克服方法。该提案的总体目标是开发一种基于抑制Notch信号的新的治疗方法。目的：1.探讨不同的Notch家族成员和配体在MM细胞耐药中的作用；2.研究Notch信号在整合素介导的MM细胞耐药中的作用；3.研究缺氧对MM细胞中Notch信号和耐药的影响；以及4.评价Notch抑制剂联合Bcl2/Bclxl抑制剂ABT-737治疗MM的可能性。耐药是包括多发性骨髓瘤在内的不同类型肿瘤治疗的主要障碍之一。公共卫生相关性：拟议的研究将确定Notch信号在骨髓瘤细胞耐药中的作用，并评估Notch的药理学靶向治疗潜力。如果成功，这可能会极大地改善多发性骨髓瘤患者的治疗效果。

DESCRIPTION (provided by applicant): Drug resistance remains one of the major obstacles in treatment of patients with various types of cancer, including multiple myeloma (MM). Evidence accumulated for the past decade has indicated a prominent role of microenvironment in survival and growth of tumor cells. Focusing on MM we have recently demonstrated that microenvironment, particularly bone marrow stromal cells, has a significant impact on the response of tumor cells to the chemotherapy. Bone marrow stroma protected myeloma cells from initial treatment with cytotoxic drugs. Allowing surviving a subpopulation of tumor cells, bone marrow stroma thus may contribute to the development of minimal residual disease and eventually clinical relapse. Our previous work has indicated that one of the mechanisms of this bone marrow stroma mediated drug-resistance is activation of receptor/transcriptional regulator Notch in MM cells. The overall hypothesis of this application is that tumor microenvironment activates Notch signaling in MM cells allowing them to escape drug-induced cell death. Pharmacological inhibition of Notch reverses this effect and therefore may be therapeutically beneficial for patients with MM. In this proposal, we will investigate the molecular mechanisms of Notch mediated MM cell protection from apoptosis induced by chemotherapeutic drugs and possible approaches to overcome it. The overall goal of the proposal is to develop a new therapeutic approach based on inhibition of Notch signaling. Specific aims of the project: Aim 1. Investigate the involvement of different Notch family members and ligands in MM cell drug resistance; Aim 2. Examine the contribution of Notch signaling to integrin mediated drug resistance in MM cells; Aim 3. Study the effect of hypoxia on Notch signaling and drug resistance in MM cells; and Aim 4. Evaluate the therapeutic potential of Notch inhibitor in combination with Bcl-2/Bcl-xL inhibitor ABT-737 in treatment of MM. Drug resistance is one of the major obstacles in treatment of patients with different types of cancer, including multiple myeloma. PUBLIC HEALTH RELEVANCE: Proposed study will determine the role of Notch signaling in myeloma cell drug resistance and evaluate therapeutic potential of pharmacological targeting of Notch. If successful, this may dramatically improve the effect of therapy in patients with multiple myeloma.