Death Receptor-Induced Apoptosis of B-Cell Malignancies

基因畸变导致细胞无法执行DNA损伤诱导的凋亡，如p53的缺失或Bcl-2的过度表达，有助于b细胞恶性肿瘤对基因毒性抗癌药物的新生或获得性耐药性。本提案的总体目标是确定针对B细胞恶性肿瘤的治疗策略，这些策略基于B细胞存活的分子决定因素的调节。肿瘤细胞的死亡可能是由抗体介导的特异性b细胞分子[b细胞受体/表面免疫球蛋白（BCR/sIg）或CD20]或特异性死亡受体（TRAIL- r1 /R2）与TRAIL/Apo2L（肿瘤坏死因子相关的凋亡诱导配体）的结合引发的。由于死亡受体和DNA损伤诱导独立的信号通路在线粒体水平汇聚形成凋亡细胞，死亡受体转导的信号可能提供消除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被核因子κ B （NF-kB）抵消，NF-kB是B细胞肿瘤中由共刺激相互作用、病毒蛋白或遗传畸变激活的转录因子家族。要验证的中心假设是，b细胞肿瘤可以通过配体/抗体介导的死亡受体激活与抑制NF-kB的药物联合消除。具体目标是：1。明确Bcl-2过表达或p53缺陷的B细胞或B细胞肿瘤的抗ig、抗cd20 -或TRAIL/ apo2l介导的凋亡的分子机制和决定因素。2. 确定NF-kB在保护B细胞肿瘤免受死亡受体诱导的凋亡中的作用：a.确定共刺激信号（CD40/CD40L和TACI/BLyS）激活NF-kB的分子机制，并确定特异性NF-kB依赖蛋白在保护B细胞肿瘤免受死亡受体诱导的凋亡中的作用。b.研究靶向IKK复合物的药物抑制NF-kB是否能增强抗ig -、抗cd20 -或TRAIL/ apo2l诱导的b细胞恶性肿瘤的凋亡。提出的研究可以为设计死亡受体结合抗体/配体和NF-kB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。

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.