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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）：拟议研究的长期目标是确定治疗复发性或难治性B细胞非霍奇金淋巴瘤（B-NHL）的新型有效治疗方法。尽管最近在B-NHL治疗设计方面取得了进展（即纳入利妥昔单抗），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。拟议研究的具体目的是寻求了解硼替佐米（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了前景。硼替佐米的确切作用机制在很大程度上尚未确定，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B-NHL细胞系，以及患者淋巴瘤标本。有趣的是，硼替佐米证明了参与几种分子途径以促进细胞死亡的能力。在第一个具体目标中，将研究细胞凋亡和Bcl-2蛋白家族在调节硼替佐米介导的治疗抗性B-NHL的细胞死亡中的作用。在第二个目标中，将探索细胞死亡的另外两种模式（自噬和坏死）的潜在作用。从这一目标获得的结果预计将特别感兴趣，因为靶向细胞死亡的非凋亡机制才刚刚开始被认为是治疗。最后，在目标3中，我们将应用从实验室研究中获得的知识，进一步描述硼替佐米的治疗效果，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微阵列进行分类（合作者：L.施陶德德，NIH）鉴定为具有活化的B细胞（ABC）、生发中心B细胞（GCB）或其它基因型。这将允许直接比较具有不良预后（ABC）的DLBCL与具有一般较好结果（GCB）的DLBCL之间的每种独特蛋白酶体的活性，包括离体和（用硼替佐米）临床。最近完成的NCI Velcade-EPOCH II期临床试验的初步数据（PI：W。Wilson，NCI;合作研究者：M. Czuczman，RPCI）在复发性/难治性B细胞NHL患者中的研究表明，硼替佐米主要在“预后不良”ABC亚组中增加EPOCH的抗肿瘤活性，其次是其下调NF：B活性并导致淋巴瘤细胞中促凋亡潜力增加的能力。总体而言，拟定研究旨在揭示硼替佐米在克服耐药性B-NHL背景下的详细作用机制，同时为复发性/难治性DLBCL患者开发有效、毒性较小的新型免疫化疗挽救方案（即VDR）。为了加强我们最初的提交，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。我们的研究结果将被用于未来B细胞淋巴瘤的循证蛋白酶体相关疗法的开发。

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

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

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