Death Receptor-Induced Apoptosis of B-Cell Malignancies

死亡受体诱导的 B 细胞恶性肿瘤细胞凋亡

• 批准号: 6640125
• 负责人: ATUL BEDI
• 金额: $ 32.74万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6640125
• 关键词: B cell lymphoma; B cell receptor; BCL2 gene /protein; CD40 molecule; DNA damage; JUN kinase; antibody; apoptosis; biological signal transduction; clinical research; cysteine endopeptidases; cytoprotection; enzyme activity; gel mobility shift assay; genetically modified animals; human subject; laboratory mouse; molecular pathology; neoplasm /cancer genetics; nuclear factor kappa beta; p53 gene /protein; phosphorylation; protein protein interaction; protein structure function; proteolysis; receptor binding

Genetic aberrations that render cells incapable of executing DNA damage-induced apoptosis, such as loss of p53 or overexpression of Bcl-2, contribute to the de novo or acquired resistance of B-cell malignancies to genotoxic anticancer agents. The overall objective of this proposal is to identify therapeutic strategies against B-cell malignancies that are based on modulation of the molecular determinants of B cell survival. Tumor cell death may be triggered by antibody-mediated engagement of specific B-cell molecules [B-cell receptor/surface immunoglobulin (BCR/sIg) or CD20] or ligation of specific death receptors (TRAIL-R1/R2) with TRAIL/Apo2L (tumor necrosis factor- related apoptosis-inducing ligand). Since death receptors and DNA damage induce independent signaling pathways that converge at the level of the mitochondria to form the apoptosome, death- receptor-transduced signals may offer a potential mechanism of eliminating p53-deficient or Bcl-2-overexpressing B-cell tumors. However, death receptor-induced signals may be counteracted by nuclear factor-kappa B (NF-kB), a family of transcription factors that is activated by costimulatory interactions, viral proteins, or genetic aberrations in B-cell tumors. The central hypothesis to be tested is that B-cell tumors can be eliminated via ligand/antibody-mediated activation of death receptors in combination with agents that inhibit NF-kB. The specific aims are: 1. Define the molecular mechanisms and determinants of anti-Ig, anti-CD20-, or TRAIL/Apo2L-mediated apoptosis of Bcl-2- overexpressing or p53-deficient B cells or B-cell tumors. 2. Define the role of NF-kB in protection of B-cell tumors from death receptor-induced apoptosis: a. Identify the molecular mechanism(s) by which costimulatory signals (CD40/CD40L and TACI/BLyS) activate NF-kB and define the role of specific NF-kB-dependent proteins in protection of B cell tumors from death receptor-induced apoptosis. b. Investigate whether inhibition of NF-kB with agents that target the Ikappa B kinase (IKK) complex can augment anti-Ig-, anti-CD20-, or TRAIL/Apo2L-induced apoptosis of B-cell malignancies. The proposed studies could provide a foundation for the design of potentially synergistic combinatorial regimens of death receptor- binding antibodies/ligands and NF-kB inhibitors for treatment of B-cell malignancies that resist conventional chemotherapy or irradiation.

使细胞不能执行DNA损伤诱导的细胞凋亡的遗传畸变，例如p53的缺失或Bcl-2的过表达，导致B细胞恶性肿瘤对遗传毒性抗癌剂的新生或获得性抗性。该提案的总体目标是确定基于B细胞存活的分子决定因素的调节的针对B细胞恶性肿瘤的治疗策略。肿瘤细胞死亡可通过抗体介导的特异性B细胞分子[B细胞受体/表面免疫球蛋白（BCR/sIg）或CD 20]的结合或特异性死亡受体（TRAIL-R1/R2）与TRAIL/Apo 2L（肿瘤坏死因子相关凋亡诱导配体）的连接来触发。 由于死亡受体和DNA损伤诱导独立的信号传导途径，这些信号传导途径在线粒体水平会聚以形成线粒体，因此死亡受体转导的信号可以提供消除p53缺陷或Bcl-2过表达的B细胞肿瘤的潜在机制。然而，死亡受体诱导的信号可能会被核因子-κ B（NF-κ B）抵消，NF-κ B是一个转录因子家族，可被B细胞肿瘤中的共刺激相互作用、病毒蛋白或遗传畸变激活。 待检验的中心假设是B细胞肿瘤可以通过配体/抗体介导的死亡受体活化与抑制NF-κ B的药物组合来消除。 具体目标是：1.定义抗Ig、抗CD 20或TRAIL/Apo 2L介导的Bcl-2过表达或p53缺陷B细胞或B细胞肿瘤凋亡的分子机制和决定因素。2.定义NF-κ B在保护B细胞肿瘤免于死亡受体诱导的细胞凋亡中的作用：确定共刺激信号（CD 40/CD 40 L和TACI/BLyS）激活NF-κ B的分子机制，并确定特异性NF-κ B依赖性蛋白在保护B细胞肿瘤免受死亡受体诱导的细胞凋亡中的作用。B.研究用靶向Ikappa B激酶（IKK）复合物的药物抑制NF-κ B是否可以增加抗Ig、抗CD 20或TRAIL/Apo 2 L诱导的B细胞恶性肿瘤细胞凋亡。提出的研究可以为设计死亡受体结合抗体/配体和NF-κ B抑制剂的潜在协同组合方案提供基础，用于治疗抵抗常规化疗或放疗的B细胞恶性肿瘤。