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

基本信息

批准号：
8495747
负责人：
MYRON S CZUCZMAN
金额：
$ 34.22万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
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/8495747
关键词：
Apoptosis Apoptotic Autophagocytosis B lymphoid malignancy B-Cell Lymphomas B-Cell NonHodgkins Lymphoma B-Lymphocytes BCL2 gene 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&apos 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

项目摘要

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.

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。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Regulation of CD20 in rituximab-resistant cell lines and B-cell non-Hodgkin lymphoma.

DOI：
10.1158/1078-0432.ccr-11-1429
发表时间：
2012-02-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Tsai PC;Hernandez-Ilizaliturri FJ;Bangia N;Olejniczak SH;Czuczman MS
通讯作者：
Czuczman MS

Entinostat, a novel histone deacetylase inhibitor is active in B-cell lymphoma and enhances the anti-tumour activity of rituximab and chemotherapy agents.

DOI：
10.1111/bjh.13318
发表时间：
2015-05
期刊：
British journal of haematology
影响因子：
6.5
作者：
Frys S;Simons Z;Hu Q;Barth MJ;Gu JJ;Mavis C;Skitzki J;Song L;Czuczman MS;Hernandez-Ilizaliturri FJ
通讯作者：
Hernandez-Ilizaliturri FJ

Pevonedistat, a NEDD8-Activating Enzyme Inhibitor, Induces Apoptosis and Augments Efficacy of Chemotherapy and Small Molecule Inhibitors in Pre-clinical Models of Diffuse Large B-cell Lymphoma.

Pevonedistat 是一种 NEDD8 激活酶抑制剂，可在弥漫性大 B 细胞淋巴瘤的临床前模型中诱导细胞凋亡并增强化疗和小分子抑制剂的疗效。

DOI：
10.1002/jha2.2
发表时间：
2020-07
期刊：
EJHaem
影响因子：
0
作者：
Torka P;Mavis C;Kothari S;Belliotti S;Gu J;Sundaram S;Barth M;Hernandez-Ilizaliturri FJ
通讯作者：
Hernandez-Ilizaliturri FJ

Mitotic catastrophe and cell cycle arrest are alternative cell death pathways executed by bortezomib in rituximab resistant B-cell lymphoma cells.

DOI：
10.18632/oncotarget.14405
发表时间：
2017-02-21
期刊：
Oncotarget
影响因子：
0
作者：
Gu JJ;Kaufman GP;Mavis C;Czuczman MS;Hernandez-Ilizaliturri FJ
通讯作者：
Hernandez-Ilizaliturri FJ

The novel proteasome inhibitor carfilzomib induces cell cycle arrest, apoptosis and potentiates the anti-tumour activity of chemotherapy in rituximab-resistant lymphoma.

DOI：
10.1111/bjh.12452
发表时间：
2013-09
期刊：
British journal of haematology
影响因子：
6.5
作者：
Gu JJ;Hernandez-Ilizaliturri FJ;Kaufman GP;Czuczman NM;Mavis C;Skitzki JJ;Czuczman MS
通讯作者：
Czuczman MS