Notch as a New Therapeutic Target in Hematological Malignancies

描述（由申请人提供）：耐药性仍然是治疗各种类型癌症（包括多发性骨髓瘤（MM））患者的主要障碍之一。过去十年来积累的证据表明，微环境在肿瘤细胞的生存和生长中起着重要作用。我们最近研究了MM的微环境，特别是骨髓基质细胞，对肿瘤细胞对化疗的反应有显著影响。骨髓基质保护骨髓瘤细胞免受细胞毒性药物的初始治疗。允许存活的肿瘤细胞亚群，骨髓基质因此可能有助于微小残留疾病的发展，并最终临床复发。我们以前的工作表明，这种骨髓基质介导的耐药性的机制之一是激活MM细胞中的受体/转录调节因子Notch。本申请的总体假设是，肿瘤微环境激活MM细胞中的Notch信号传导，使其能够逃避药物诱导的细胞死亡。药理学抑制Notch逆转这种作用，因此可能是治疗MM患者有益的。在这项提案中，我们将调查Notch介导的MM细胞保护化疗药物诱导的细胞凋亡的分子机制和可能的方法来克服it. The提案的总体目标是开发一种新的治疗方法的基础上抑制Notch信号。项目的具体目标：目标1。研究Notch家族不同成员和配体在MM细胞耐药中的作用;目的2.检查Notch信号传导对MM细胞中整合素介导的耐药性的贡献;目的3.研究缺氧对MM细胞中Notch信号传导和耐药性的影响;目的4.评估Notch抑制剂联合Bcl-2/Bcl-xL抑制剂ABT-737治疗MM的治疗潜力。耐药性是治疗不同类型癌症（包括多发性骨髓瘤）患者的主要障碍之一。公共卫生相关性：拟定的研究将确定Notch信号传导在骨髓瘤细胞耐药性中的作用，并评估Notch的药理学靶向治疗潜力。如果成功，这可能会显着提高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.