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Extracellular DNA in regulation of multiple myeloma

细胞外DNA调控多发性骨髓瘤

基本信息

批准号：
9982212
负责人：
Yulia Nefedova
金额：
$ 42.8万
依托单位：
WISTAR INSTITUTE
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：
2016-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9982212
关键词：
Address Binding Bone Marrow Bone Marrow Cells Cancer Model Cancer Patient Cell Communication Cells Clinical DNA Data Dendritic Cells Disease Disease Management Extracellular Structure Goals Growth Hematologic Neoplasms Hematopoietic Neoplasms Human In Vitro Link Malignant Neoplasms Mediating Molecular Multiple Myeloma Myelogenous Myeloid Cells Nature Nuclear Outcome Pathway interactions Patients Plasma Cells Play Population Pre-Clinical Model Proteins Publications Regulation Resistance Role Serum Signal Transduction Testing Therapeutic XBP1 gene antitumor effect base cancer cell cancer transplantation cell free DNA chemotherapy clinically relevant extracellular improved improved outcome in vivo macrophage mouse model neoplastic cell neutrophil novel novel therapeutics pathogen peripheral blood public health relevance release factor response sensor therapeutic target therapy resistant transcription factor tumor growth tumor microenvironment tumor progression uptake

项目摘要

Abstract Multiple myeloma (MM) is a devastating bone marrow (BM) cancer that remains uniformly fatal despite the emergence of novel therapeutics. The tumor microenvironment promotes tumor growth and resistance to chemotherapy through poorly understood interactions between tumor cells and the surrounding BM cells. Our preliminary data demonstrates that a population of BM mature and immature neutrophils is involved in the regulation of MM chemoresistance. In response to MM-derived soluble factors, neutrophils can release DNA. This extracellular cell-free DNA induces the chemoresistance of MM cells, possibly through activation of IRE1/XBP1 pathway of the unfolded protein response (UPR). The goal of this proposal is to determine the molecular mechanism responsible for cell-free DNA mediated chemoresistance in MM cells and to develop an approach to target it. By targeting of this novel chemoresistance mechanism we hope to improve chemotherapy responses and thereby improve MM outcomes. The following specific aims will be addressed: Specific Aim 1. Identify the mechanisms and clinical relevance of DNA release by neutrophils in MM. Specific Aim 2. Determine the mechanisms of cell-free DNA effect on MM cells. Specific Aim 3. Determine the role of the UPR in cell-free DNA mediated MM chemoresistance.

摘要多发性骨髓瘤（MM）是一种毁灭性的骨髓（BM）癌症，仍然是一致致命的尽管出现了新的治疗方法。肿瘤微环境促进肿瘤肿瘤生长和对化疗的抗性通过肿瘤之间的相互作用知之甚少细胞和周围的骨髓细胞。我们的初步数据表明，一个群体的BM 成熟和未成熟的中性粒细胞参与MM化学抗性的调节。在在对MM衍生的可溶性因子的应答中，中性粒细胞可以释放DNA。这种细胞外的无细胞 DNA可能通过激活IRE 1/XBP 1诱导MM细胞的化疗耐药性未折叠蛋白反应（Unfolded protein response，UPR）本提案的目的是确定负责MM细胞中游离DNA介导的化学抗性的分子机制，开发一种靶向它的方法。通过靶向这种新的化学抗性机制，我们希望改善化疗反应，从而改善MM结局。以下具体将致力于：具体目标1.确定中性粒细胞释放DNA的机制和临床意义毫米具体目标2。确定游离DNA对MM细胞的作用机制。具体目标3。确定UPR在无细胞DNA介导的MM化疗耐药性中的作用。