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：
9204811
负责人：
ROBERT ZYGMUNT ORLOWSKI
金额：
$ 35.99万
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/9204811
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 Pharmaceutical Preparations Pharmacology Physiological Plasma Cells Plasmablast Production Proteasome Inhibition Proteasome Inhibitor Protein Inhibition Protein Overexpression 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 clinical predictors 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（由适用提供）：细胞内蛋白水解通过泛素 - 蛋白酶体途径发生，蛋白酶体抑制剂（PI）已通过我们的研究和其他研究的多发性骨髓瘤中的关键治疗剂验证为关键治疗剂。血浆细胞在发育过程中的蛋白质更新能力降低，而它们同时面临着高折叠式免疫球蛋白的高负载，产生了免疫球蛋白和细胞应激，PIS进一步加剧了PIS，这可能解释了它们对这类药物的独特敏感性。但是，在接力/难治性的环境中，只有少数患者可以通过单药治疗完全缓解，而绝大多数的患者最终会产生耐药性。我们的小组已经进行了新的观察，即负责新蛋白酶体组装的链酮及其相关的信号通路在PI电阻的情况下被激活。此外，这些途径的中断既可以在没有药物的环境中对PI敏感，又可以在体外和体内克服PI耐药性。这些发现支持了我们的中心假设，该假设提出了蛋白酶体组装链酮介导的原发性PI耐药性，这些蛋白酶体链酮促进了蛋白酶体能力的细胞膨胀，并且这些链酮及其相关途径是PI敏感性的有理生物标志物，以及用于提高PIS效率的方法的潜在靶标。为了评估这些可能性，提出了其他研究，以进一步剖析与蛋白酶体组装和PI耐药性有关的分子途径。此外，基因组研究将与Bortezomib和Carfilzomib的前瞻性合作小组试验有关，以验证我们感兴趣的基因之一，MUC20，相关的HGF/C-MET和P44/42 MAPK的激活特征的表达可能有助于鉴定最有可能受益于PI受益于PI的患者。最后，将评估抑制这些途径的活性或增强MUC20表达的活性的方法，以诱导化学敏化的能力，并在细胞系，主要样本中克服化学敏感性，并在体内鼠模型中具有物理相关性。