Notch as a New Therapeutic Target in Hematological Malignancies

Notch作为血液系统恶性肿瘤的新治疗靶点

• 批准号: 7684263
• 负责人: Yulia Nefedova
• 金额: $ 27.14万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7684263
• 关键词: Apoptosis; Bone Marrow; Cell Death; Cells; Clinical; Cytoprotection; Cytotoxic agent; Data; Development; Drug resistance; Family; Family member; Germ Cells; Goals; Growth; Hematologic Neoplasms; Hypoxia; Integrins; Ligands; Mediating; Molecular; Multiple Myeloma; Patients; Pharmaceutical Preparations; Play; Publishing; Receptor Activation; Relapse; Residual Neoplasm; Resistance; Role; Signal Transduction; Stromal Cells; Therapeutic; Work; base; cancer cell; cancer type; chemotherapy; improved; inhibitor/antagonist; jagged1 protein; neoplastic cell; new therapeutic target; notch protein; novel therapeutic intervention; public health relevance; receptor; response; tumor

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.

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。过去十年积累的证据表明，微环境在肿瘤细胞的存活和生长中发挥着重要作用。针对多发性骨髓瘤，我们最近证明微环境，特别是骨髓基质细胞，对肿瘤细胞对化疗的反应具有显着影响。骨髓基质保护骨髓瘤细胞免受细胞毒性药物的初始治疗。骨髓基质允许肿瘤细胞亚群存活，因此可能有助于微小残留病的发展并最终导致临床复发。我们之前的工作表明，这种骨髓基质介导的耐药机制之一是MM细胞中受体/转录调节因子Notch的激活。该应用的总体假设是肿瘤微环境激活 MM 细胞中的 Notch 信号传导，使它们能够逃避药物诱导的细胞死亡。 Notch 的药理学抑制可逆转这种效应，因此可能对 MM 患者有治疗益处。在本提案中，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以及克服它的可能方法。该提案的总体目标是开发一种基于抑制 Notch 信号传导的新治疗方法。项目具体目标： 目的1.研究不同Notch家族成员和配体在MM细胞耐药中的参与；目标 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Notch信号传导及耐药性的影响；目标 4. 评估 Notch 抑制剂与 Bcl-2/Bcl-xL 抑制剂 ABT-737 联合治疗 MM 的治疗潜力。耐药性是治疗包括多发性骨髓瘤在内的不同类型癌症患者的主要障碍之一。公共健康相关性：拟议的研究将确定 Notch 信号传导在骨髓瘤细胞耐药性中的作用，并评估 Notch 药理靶向的治疗潜力。如果成功，这可能会显着改善多发性骨髓瘤患者的治疗效果。