Targeting the proteasome to overcome therapy resistance in B-NHL

靶向蛋白酶体克服 B-NHL 的治疗耐药性

• 批准号: 8193045
• 负责人: MYRON S CZUCZMAN
• 金额: $ 35.46万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-08 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193045
• 关键词: Apoptosis; Apoptotic; Autophagocytosis; B lymphoid malignancy; B-Cell Lymphomas; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Biopsy; Bortezomib; Caspase; Caspase Inhibitor; Cell Death; Cell Death Induction; Cell Line; Cells; Cessation of life; Chemicals; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Collaborations; DNA Microarray Chip; Data; Development; Dimethyl Sulfoxide; Disease Resistance; Doxorubicin; Doxorubicin Hydrochloride Liposome; Event; Experimental Designs; FDA approved; Family; Future; Gene Expression Profiling; Generations; Genes; Genotype; Goals; Health; Knowledge; Laboratories; Laboratory Study; Lead; Letters; Liposomal Doxorubicin; Lymphoma; Mediating; Modeling; Molecular; Morbidity - disease rate; Necrosis; Neoplasms; Noxae; Outcome; Pathway interactions; Patients; Personal Communication; Phase; Phase II Clinical Trials; Primary Neoplasm; Proteasome Inhibition; Proteasome Inhibitor; Protein Family; Recurrence; Refractory; Refractory Disease; Regimen; Relapse; Research; Research Design; Research Personnel; Resistance; Role; Sampling; Secondary to; Signal Transduction; Specimen; Structure of germinal center of lymph node; Subgroup; Testing; Therapeutic; Time; Treatment Efficacy; Treatment Protocols; United States National Institutes of Health; Velcade; base; cancer therapy; cancer type; cell killing; chemotherapy; conventional therapy; cytotoxic; design; evidence base; in vivo; inhibitor/antagonist; interest; killings; large cell Diffuse non-Hodgkin' s lymphoma; mortality; multicatalytic endopeptidase complex; neoplastic; next generation; novel; outcome forecast; prognostic; protein profiling; rituximab; small molecule; therapy design; therapy development; therapy resistant; tumor

DESCRIPTION (provided by applicant): A long-range goal of the proposed research is to identify novel and effective therapeutic approaches for the treatment of relapsed or refractory B cell non-Hodgkin's lymphoma (B-NHL). Despite recent advances (i.e. incorporation of rituximab) in the design of treatment for B-NHL, greater than half of previously treated patients subsequently demonstrate therapy-resistant disease at the time of relapse. The specific aims of the proposed research seek to understand the mechanism(s)-of-action of bortezomib (Velcade"), a proteasome inhibitor that has shown recent promise in the treatment of therapy-resistant B cell malignancies. The precise mechanism(s)-of-action of bortezomib remains largely undefined, but in many cases likely involves the induction of cell death via apoptosis. Preliminary data indicate that bortezomib is effective at killing several chemotherapy-resistant aggressive B-NHL cell lines, as well as in patient lymphoma specimens. Interestingly, bortezomib demonstrates the capacity to engage several molecular pathways to promote cell death. In the first specific aim, a role for apoptosis and the Bcl-2 family of proteins in regulating bortezomib-mediated cell death of therapy resistant B-NHL will be investigated. In the second aim, a potential role for two additional modes of cell death, autophagy and necrosis, will be explored. The results obtained from this aim are expected to be of particular interest, as targeting non-apoptotic mechanisms of cell death are just beginning to be considered therapeutically. Finally, in aim 3, we will apply the knowledge gained from the laboratory studies to further delineate bortezomib's therapeutic efficacy and validate its mechanism(s)-of-action in primary lymphoma samples. Each refractory/resistant lymphoma will be categorized by DNA microarray (Collaborator: L. Staudt, NIH) as having an activated B cell (ABC), a germinal center B cell (GCB), or other genotype. This will allow direct comparison of each unique proteasome's activity, both ex vivo and (with bortezomib) clinically, between DLBCLs with poor prognosis (ABC) versus those with generally better outcomes (GCB). Preliminary data from a recently completed Phase II NCI Velcade-EPOCH clinical trial (PI: W. Wilson, NCI; Co-investigator: M. Czuczman, RPCI) in patients with relapsed/refractory B-cell NHL indicates that bortezomib increased EPOCH's anti-tumor activity primarily in the "poor prognosis" ABC subgroup secondary to its ability to down- modulate NF:B activity and lead to an increased pro-apoptotic potential in lymphoma cells. Collectively, the proposed studies are designed to reveal detailed mechanism(s)-of-action of bortezomib in the context of overcoming therapy-resistant B-NHL, and concurrently developing an effective, less toxic, novel immunochemotherapeutic salvage regimen (i.e. VDR) for patients with relapsed/refractory DLBCL. To strengthen our original submission, we have identified three next-generation proteasome inhibitors with unique mechanisms-of-action which we will include into our experimental design. Our research findings will be utilized in the development of future evidence-based proteasome inhibitor-associated therapies for B-cell lymphomas. PUBLIC HEALTH RELEVANCE: Despite remarkable advances in the treatment of cancer, therapy-refractory disease and development of therapy resistance remains a major clinical problem and cause of mortality. This is true for many types of cancer, including B-cell non-Hodgkin lymphoma (B-NHL). The proposed research is directly relevant to this problem, as the goals of the study are to identify novel ways to treat therapy-refractory B-cell lymphoma, and to precisely define how these agents kill B-NHL that are resistant to conventional therapies.

描述（由申请人提供）：拟议研究的长期目标是确定治疗复发或难治性 B 细胞非霍奇金淋巴瘤 (B-NHL) 的新颖且有效的治疗方法。尽管最近在 B-NHL 治疗设计方面取得了进展（即加入利妥昔单抗），但超过一半的既往治疗患者随后在复发时表现出治疗耐药性疾病。拟议研究的具体目标是了解硼替佐米 (Velcade) 的作用机制，硼替佐米是一种蛋白酶体抑制剂，最近在治疗耐药性 B 细胞恶性肿瘤方面显示出前景。确切的机制硼替佐米的作用在很大程度上仍不清楚，但在许多情况下可能涉及通过细胞凋亡诱导细胞死亡，初步数据表明硼替佐米可有效杀死几种化疗耐药的侵袭性细胞。有趣的是，硼替佐米在 B-NHL 细胞系以及患者淋巴瘤标本中表现出参与多种分子途径促进细胞死亡的能力，其第一个具体目标是细胞凋亡和 Bcl-2 蛋白家族在调节中的作用。在第二个目标中，将研究硼替佐米介导的治疗耐药性 B-NHL 的细胞死亡，即自噬和坏死这两种其他细胞死亡模式的潜在作用。预计会引起特别关注，因为针对细胞死亡的非凋亡机制才刚刚开始在治疗上被考虑。最后，在目标 3 中，我们将应用从实验室研究中获得的知识来进一步描述硼替佐米的治疗功效并验证其在原发性淋巴瘤样本中的作用机制。每种难治性/耐药性淋巴瘤将通过 DNA 微阵列（合作者：L. Staudt，NIH）分类为具有激活的 B 细胞 (ABC)、生发中心 B 细胞 (GCB) 或其他基因型。这将允许直接比较预后不良 (ABC) 与一般预后较好 (GCB) 的 DLBCL 之间的每种独特蛋白酶体的离体活性和临床活性（使用硼替佐米）。最近完成的一项针对复发/难治性 B 细胞 NHL 患者的 II 期 NCI Velcade-EPOCH 临床试验（PI：W. Wilson，NCI；联合研究者：M. Czuczman，RPCI）的初步数据表明，硼替佐米可增加 EPOCH 的抗-肿瘤活性主要出现在“预后不良”的 ABC 亚组中，继发于其下调 NF:B 活性并导致 NF:B 活性增加的能力。淋巴瘤细胞的促凋亡潜力。总的来说，拟议的研究旨在揭示硼替佐米在克服治疗耐药的 B-NHL 方面的详细作用机制，同时开发一种有效的、毒性较小的新型免疫化疗挽救方案（即 VDR）复发/难治性 DLBCL 患者。为了加强我们最初提交的材料，我们已经确定了三种具有独特作用机制的下一代蛋白酶体抑制剂，我们将其纳入我们的实验设计中。我们的研究结果将用于开发未来基于证据的蛋白酶体抑制剂相关 B 细胞淋巴瘤疗法。公共卫生相关性：尽管癌症治疗取得了显着进展，但难治性疾病和治疗耐药性的发展仍然是主要的临床问题和死亡原因。对于许多类型的癌症来说都是如此，包括 B 细胞非霍奇金淋巴瘤 (B-NHL)。拟议的研究与这个问题直接相关，因为该研究的目标是确定治疗难治性 B 细胞淋巴瘤的新方法，并精确定义这些药物如何杀死对常规疗法耐药的 B-NHL。