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）：拟议的研究的一个远距离目标是确定新颖有效的治疗方法，用于治疗复发或难治性B细胞非霍奇金淋巴瘤（B-NHL）。尽管最近进步（即利妥昔单抗掺入B-NHL），但先前治疗的患者中，超过一半的患者随后在复发时表现出耐药性疾病。 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表明硼替佐比有效地杀死了多个化学疗法的攻击性B-NHL细胞系，以及在患者淋巴瘤的样本中，bortezomib表现出几种分子途径的能力。在第二个目标中进行了研究，将探索两个细胞死亡，自噬和坏死的潜在作用。最后，在AIM 3中，我们将应用实验室研究所获得的知识，以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品中的机制。 DNA微阵列（合作者：L。Staudt，NIH）将每个难治性/抗性淋巴瘤分类为具有活化的B细胞（ABC），生发中心B细胞（GCB）或其他基因型。这将允许在临床上直接比较每个独特的蛋白酶体活动，无论是在bortezomib和硼替佐米的活性，即预后不良（ABC）与总体上更好的结果（GCB）之间的DLBCL之间的直接比较。来自最近完成的II期NCI Velcade-Epoch临床试验的初步数据（PI：W。Wilson，NCI；共同投资者：M。Czuczman，RPCI）患有复发/反应B-cell NHL的患者bortezomib表明bortezomib的次要次数均可表明其抗抑郁症的次数不足，其次数不足以证明其次要的措施。 NF：B活性并导致淋巴瘤细胞中促凋亡的潜力增加。总的来说，拟议的研究旨在揭示在克服治疗耐药的B-NHL的背景下硼替佐米的详细机制，并同时为患有重质/反射/反应/反应/重质量dlbcl的患者的患者共同开发有效，有毒，新型的新型免疫治疗方法（即VDR）。为了加强我们的原始提交，我们已经确定了具有独特作用机制的三种下一代蛋白酶体抑制剂，我们将在实验设计中包括在内。我们的研究发现将用于开发对B细胞淋巴瘤的未来循证蛋白酶体抑制剂相关疗法。公共卫生相关性：尽管治疗癌症，治疗 - 难治性疾病和耐药性的发展取得了显着进步仍然是一个主要的临床问题和死亡率。对于许多类型的癌症，包括B细胞非霍奇金淋巴瘤（B-NHL）都是如此。拟议的研究与该问题直接相关，因为该研究的目标是确定治疗治疗 - 耐受性B细胞淋巴瘤的新方法，并精确地定义了这些药物如何杀死对常规疗法抗性的B-NHL。