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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：
10626002
负责人：
SHIGEKI MIYAMOTO
金额：
$ 39.28万
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/10626002
关键词：
Apoptotic Bioinformatics Biological Assay Bone Marrow Bortezomib Cell Separation Cell Survival Cell secretion 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 In Vitro Length Mediating Modeling Monoclonal Antibodies Multi-Drug Resistance Multidrug Resistance Induction Multiple Myeloma Mus Newly Diagnosed Oncogenic Pathogenicity Pathologic Patient Selection Patients Pharmaceutical Preparations Plasma Progressive Disease Proteasome Inhibitor Proteoglycan Proteolysis Reagent Refractory Relapse Resistance Resistance development Role Signal Induction Signal Pathway Signal Transduction Testing Therapeutic Xenograft procedure activating transcription factor cancer type cell type drug resistance development efficacy testing immune modulating agents 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

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）是第二常见的血液恶性肿瘤，目前被认为是中位生存期为5-7年。较新的药物，如蛋白酶体抑制剂，免疫调节剂，药物和单克隆抗体与更传统的药物组合能够实现更好的临床反应。然而，对这些药物产生耐药性仍然是患者死亡的主要原因。还有一个很大一部分新诊断的MM患者甚至对这些新药也难治，因此没有从最近的治疗进展中受益。我们以前发现，许多MM患者源性骨髓间充质基质细胞（BMSCs）是MM肿瘤微环境的关键细胞类型，能够激活转录因子NF-κB并导致MM中蛋白酶体抑制剂耐药的因子细胞我们现在确定HAPLN 1（透明质酸和蛋白聚糖连接蛋白1）是负责BMSC分泌的在体外和体内MM细胞中也引起这种耐药性的因子。RNA-seq和生物信息学分析揭示了HAPLN 1诱导大规模的转录组学变化，包括诱导宿主的抗凋亡基因，基因.因此，HAPLN 1还在体外引起MM细胞对多种其他药物的抗性。HAPLN1 相对于正常的BMSC，在MM BMSC中的表达更高，并且HAPLN 1的蛋白水解形式通常是在来自高度治疗难治性MM患者的骨髓血浆中检测到。因此，我们假设HAPLN 1 是MM疾病中一种新的致癌因子和多药耐药诱导剂。这一假设将由以下人员进行检验：确定HAPLN 1在原代MM患者细胞中和体内的病理作用（目的1），阐明HAPLN 1在原发性MM患者细胞中的病理作用。 MM中HAPLN 1介导的耐药机制（目的2），以及免疫靶向HAPLN 1介导的药物 MM中的耐药性（目标3）。总的来说，拟议的研究可能会将可溶性HAPLN 1作为一种新的标志物， MM的治疗耐药性，以及预防或减少多药耐药性的新治疗靶点 MM的问题。