Proteasome Assembly Chaperones in Sensitivity and Resistance to Proteasome Inhibitors

蛋白酶体组装伴侣对蛋白酶体抑制剂的敏感性和耐药性

基本信息

批准号：
9030014
负责人：
ROBERT ZYGMUNT ORLOWSKI
金额：
$ 37.49万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9030014
关键词：
Apoptotic Biological Assay Biological Markers Bortezomib Cell Line Cells Cellular Stress Chemosensitization Cleaved cell Clinic Clinical Clinical Research Clinical Sensitivity Clinical Trials Complex Development Diagnosis Disease remission Drug resistance Equilibrium Genes Genetic Genomics HGF gene Hematologic Neoplasms Immunoglobulins In Vitro Interruption KRAS2 gene Knowledge Link MAP Kinase Gene MET gene Mediating Minority Modeling Molecular Molecular Chaperones Mucins Multiple Myeloma Oligopeptides Outcome Pathway interactions Patient-Focused Outcomes Patients Peptide Hydrolases Pharmaceutical Preparations Plasma Cells Plasmablast Production Proteasome Inhibition Proteasome Inhibitor Protein Inhibition Proteins Proteolysis Refractory Refractory Disease Relapse Reporter Research Resistance Retreatment Role Sampling Signal Pathway Signal Transduction Pathway Therapeutic Therapeutic Agents Time Translating Ubiquitin base cell growth chromatin immunoprecipitation design drug sensitivity gel mobility shift assay genetic signature improved in vivo in vivo Model inhibitor/antagonist interest mouse model multicatalytic endopeptidase complex mutant novel nuclear factor-erythroid 2 overexpression plasma cell differentiation potential biomarker pre-clinical promoter prospective protein degradation public health relevance resistance mechanism response transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): Regulated intracellular proteolysis occurs through the ubiquitin-proteasome pathway, and proteasome inhibitors (PIs) have been validated as key therapeutic agents in multiple myeloma by studies from our group and others. Plasma cell capacity for protein turnover is reduced during their development, while they are at the same time faced with a high load of misfolded immunoglobulins, creating an imbalance and cellular stress which are further exacerbated by PIs, which may explain their unique sensitivity to this class of drugs. However, only a minority of patients in the relapsed/refractory setting achieve complete remissions with single agent therapy, while the vast majority eventually develop drug resistance. Our group has made the novel observation that chaperones responsible for new proteasome assembly, and their associated signaling pathways, are activated in the setting of PI resistance. Moreover, interruption of these pathways can both sensitize to PIs in the drug-naïve setting, and overcome PI resistance in vitro and in vivo. These findings support our central hypothesis, which proposes that primary and secondary PI resistance is mediated by proteasome assembly chaperones which promote cellular expansion of proteasome capacity, and that these chaperones and their associated pathways are rational biomarkers of PI sensitivity, as well as potential targets for approaches to enhance the efficacy of PIs. To evaluate these possibilities, additional studies are proposed to further dissect the molecular pathways involved in proteasome assembly and PI resistance. In addition, genomic studies will be performed in association with prospective cooperative group trials of bortezomib and carfilzomib to validate the possibility that expression of one of our genes of interest, MUC20, and associated activation signatures of HGF/c-MET and p44/42 MAPK, may help to identify patients who are most likely to benefit from PI-based therapy. Finally, approaches to suppress the activity of these pathways, or possibly of enhancing MUC20 expression, will be evaluated for their ability to induce chemosensitization, and overcome chemoresistance in cell lines, primary samples, and physiologically relevant in vivo murine models.

描述（由申请人提供）：调节的细胞内蛋白水解通过泛素-蛋白酶体途径发生，并且蛋白酶体抑制剂（PI）已被我们小组和其他人的研究证实为多发性骨髓瘤的关键治疗剂。浆细胞蛋白质周转能力降低。在它们的发育过程中，它们同时面临着大量错误折叠的免疫球蛋白，造成不平衡和细胞应激，PIs进一步加剧了这种应激，这可能解释了他们对此类药物的独特敏感性。然而，只有少数复发/难治性患者通过单药治疗获得完全缓解，而绝大多数患者最终出现耐药性。负责新蛋白酶体组装的分子伴侣及其相关信号通路在 PI 耐药的情况下被激活，此外，中断这些通路既可以在未接触药物的情况下对 PI 敏感，又可以在体外克服 PI 耐药。这些发现支持了我们的中心假设，即初级和次级 PI 抗性是由蛋白酶体组装伴侣介导的，促进细胞蛋白酶体能力的扩展，并且这些伴侣及其相关途径也是 PI 敏感性的合理生物标志物。作为增强 PI 功效的方法的潜在目标，为了评估这些可能性，建议进行额外的研究来进一步剖析涉及蛋白酶体组装和 PI 抗性的分子途径。与硼替佐米和卡非佐米的前瞻性合作小组试验相关，以验证我们感兴趣的基因之一 MUC20 的表达以及 HGF/c-MET 和 p44/42 MAPK 的相关激活特征可能有助于识别患有以下疾病的患者：最后，将评估抑制这些途径活性或可能增强 MUC20 表达的方法诱导化疗增敏和克服这些途径的能力。细胞系、初级样品和生理相关的体内小鼠模型中的化学耐药性。