Death Receptor-Induced Apoptosis of B-Cell Malignancies

导致细胞不能执行DNA损伤诱导的细胞凋亡的基因异常，如P53丢失或Bcl2过表达，导致B细胞恶性肿瘤对遗传毒性抗癌药物的从头或获得性耐药。这项建议的总体目标是确定针对B细胞恶性肿瘤的治疗策略，这些策略基于对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]的结合或特异性死亡受体(TRAIL-R1/R2)与TRAIL/Apo2L(肿瘤坏死因子相关的凋亡诱导配体)的连接而触发的。由于死亡受体和DNA损伤诱导独立的信号通路汇聚在线粒体水平形成凋亡体，死亡受体转导的信号可能为消除P53缺陷或Bcl2过表达的B细胞肿瘤提供了一种潜在的机制。然而，死亡受体诱导的信号可能被核因子-kB(NF-kB)所抵消，核因子-kB是一类转录因子，由共刺激相互作用、病毒蛋白或B细胞肿瘤中的遗传异常激活。有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激活与抑制核因子-kB的药物相结合而被消除。1.明确抗Ig、抗CD20或TRAIL/Apo2L介导的Bcl2过表达或P53缺陷B细胞或B细胞肿瘤细胞凋亡的分子机制和决定因素。2.明确核因子-kB在抗死亡受体诱导的B细胞肿瘤中的作用：a.明确共刺激信号(CD_(40)/CD_(40)L和TacI/BlyS)激活核因子-k_B的分子机制(S)，明确特定的核因子-k_B依赖蛋白在抗死亡受体诱导的B细胞肿瘤中的作用。B.研究靶向Ikappa B激酶(IKK)复合体的药物抑制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。本研究为设计死亡受体结合抗体/配体和核因子-kB抑制剂联合治疗耐受常规化疗或放疗的B细胞恶性肿瘤提供了潜在的协同联合方案的基础。

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.