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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：
10439626
负责人：
SHIGEKI MIYAMOTO
金额：
$ 38.67万
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/10439626
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 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

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