New Multi-Drug Resistance Mechanism in Multiple Myeloma

多发性骨髓瘤多重耐药新机制

基本信息

批准号：
10029257
负责人：
SHIGEKI MIYAMOTO
金额：
$ 37.85万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-09 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10029257
关键词：
Bioinformatics Biological Assay Bone Marrow Bortezomib Cell Survival Cells Cessation of life Clinical Disease Disease Progression Disease Resistance Drug resistance Extracellular Matrix Extracellular Matrix Proteins Future Generations Genes Goals Hematologic Neoplasms Hematopoietic Neoplasms Hyaluronan Hyaluronic Acid Immunomodulators In Vitro Length Mediating Modeling Monoclonal Antibodies Multi-Drug Resistance Multiple Myeloma Mus Newly Diagnosed Oncogenic Pathogenicity Pathologic Patients Pharmaceutical Preparations Plasma Progressive Disease Proteasome Inhibitor Proteoglycan Proteolysis Reagent Refractory Relapse Resistance Resistance development Role Signal Pathway Signal Transduction Structure Testing Therapeutic Xenograft procedure activating transcription factor base cancer type cell type drug development efficacy testing in vivo individual patient innovation link protein mesenchymal stromal cell multicatalytic endopeptidase complex neutralizing antibody new therapeutic target novel novel marker novel therapeutics prevent receptor resistance factors resistance mechanism response targeted treatment transcriptome sequencing transcriptomics tumor microenvironment

Bioinformatics Biological Assay Bone Marrow Bortezomib Cell Survival Cells Cessation of life Clinical Disease Disease Progression Disease Resistance Drug resistance Extracellular Matrix Extracellular Matrix Proteins Future Generations Genes Goals Hematologic Neoplasms Hematopoietic Neoplasms Hyaluronan Hyaluronic Acid Immunomodulators In Vitro Length Mediating Modeling Monoclonal Antibodies Multi-Drug Resistance Multiple Myeloma Mus Newly Diagnosed Oncogenic Pathogenicity Pathologic Patients Pharmaceutical Preparations Plasma Progressive Disease Proteasome Inhibitor Proteoglycan Proteolysis Reagent Refractory Relapse Resistance Resistance development Role Signal Pathway Signal Transduction Structure Testing Therapeutic Xenograft procedure activating transcription factor base cancer type cell type drug development efficacy testing in vivo individual patient innovation link protein mesenchymal stromal cell multicatalytic endopeptidase complex neutralizing antibody new therapeutic target novel novel marker novel therapeutics prevent receptor resistance factors resistance mechanism response targeted treatment transcriptome sequencing transcriptomics tumor microenvironment

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项目摘要

Multiple myeloma (MM) is the second most common hematologic malignancies and is currently considered incurable with a 5-7 year median survival. Newer drugs, such as the proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies in combination with more traditional drugs enable better clinical responses. However, development of resistance to these drugs is still the major cause of patient demise. There is also a significant fraction of newly diagnosed MM patients who are refractory even to these newer drugs and thus have not benefited from the recent therapeutic advancements. We previously found that many MM patient-derived bone marrow mesenchymal stromal cells (BMSCs), a key MM tumor microenvironment cell type, secrete factor(s) capable of activating transcription factor NF-κB and causing proteasome inhibitor resistance in MM cells. We now identified HAPLN1 (hyaluronan and proteoglycan link protein 1) as a responsible BMSC secreted factor that also causes such drug resistance in MM cells in vitro and in vivo. RNA-seq and bioinformatic analyses revealed that HAPLN1 induces large-scale transcriptomic changes, including induction of a host of antiapoptotic genes. Accordingly, HAPLN1 also causes resistance to multiple other drugs in MM cells in vitro. HAPLN1 expression is higher in MM BMSCs relative to normal BMSCs, and proteolytic forms of HAPLN1 are often detected in bone marrow plasma from highly therapy refractory MM patients. Thus, we hypothesize that HAPLN1 is a new oncogenic factor and multi-drug resistance inducer in MM disease. This hypothesis will be tested by determining the pathologic role of HAPLN1 in primary MM patient cells and in vivo (Aim 1), elucidating the mechanism of HAPLN1-mediated drug resistance in MM (Aim 2), and immuno-targeting HAPLN1-mediated drug resistance in MM (Aim 3). Overall, the proposed study may identify soluble HAPLN1 as a novel marker for therapy resistance in MM, as well as a new therapeutic target to prevent or reduce the multi-drug resistance problem in MM.

多发性骨髓瘤（MM）是第二常见的血液系统恶性肿瘤，目前被认为无法治愈的中位生存期5 - 7年。较新的药物，例如蛋白酶体抑制剂，免疫调节性药物和单克隆抗体与更传统的药物结合使用，可以更好地临床反应。但是，对这些药物的抵抗力的发展仍然是患者灭亡的主要原因。还有一个新诊断的MM患者的大部分很大一部分，即使对这些新药物也是难治性的，因此最近的治疗进步没有受益。我们以前发现许多MM衍生的MM 骨髓间充质基质细胞（BMSCS），一种关键的MM肿瘤微环境细胞类型，秘密能够激活转录因子NF-κB并在MM中引起蛋白酶体抑制剂的因子细胞。现在，我们将HAPLN1（透明质酸和蛋白聚糖链接蛋白1）确定为负责的BMSC分泌在体外和体内也会引起MM细胞中这种耐药性的因素。 RNA-seq和生物信息学分析揭示了HAPLN1引起了大规模的转录组变化，包括引入大量抗凋亡基因。根据，HAPLN1在体外还会引起对MM细胞中多种其他药物的耐药性。 Hapln1 相对于正常BMSC，MM BMSC的表达较高，而HAPLN1的蛋白水解形式通常是在高度治疗难治性MM患者的骨髓血浆中检测到。那我们假设该hapln1 是一种新的致癌因子和在MM疾病中诱导的多药抗性。该假设将通过确定HAPLN1在原代MM患者细胞和体内的病理作用（AIM 1），阐明 MM中HAPLN1介导的耐药性的机理（AIM 2）和免疫靶向HAPLN1介导的药物毫米的抗性（AIM 3）。总体而言，拟议的研究可以将固体Hapln1识别为新的标记 MM的治疗耐药性以及一种新的治疗靶标，以防止或降低多药耐药性 MM的问题。