Utilizing Nucleic-Acid Scavengers to Ameliorate Inflammation-driven Metastatic Progression in Breast Cancer

利用核酸清除剂改善炎症驱动的乳腺癌转移进展

基本信息

批准号：
9795354
负责人：
Elias Oluwatobi Utseoritselaju Eteshola
金额：
$ 3.67万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2021-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9795354
关键词：
4T1 Abate Aggressive behavior Back Behavior Biodistribution Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Cancer Biology Cancer Etiology Cancer Patient Cations Cells Cellular Assay Clinical Combined Modality Therapy DNA Development Disease Disease model ERBB2 gene Epidermal Growth Factor Receptor Estrogens Excision Feedback Fluorochrome Genetic Transcription Goals Growth Factor Receptors Heterogeneity Hormone Receptor Human Immune Immune Cell Activation Immune system Immunoblot Analysis Immunocompetent In Vitro Infection Inflammation Inflammatory Innate Immune System Intervention Investigation Lead Link Lupus Malignant Neoplasms Malignant neoplasm of pancreas Mediating Metastatic breast cancer Methods Migration Assay Mission Modeling Molecular Molecular Target Nature Neoadjuvant Therapy Neoplasm Metastasis Nucleic Acid Binding Nucleic Acids Nucleosomes Operative Surgical Procedures Outcome Patient-Focused Outcomes Patients Pattern Pattern recognition receptor Pharmacology Plasma Polymers Primary Neoplasm Progesterone Receptors Property Proteins Proteomics Receptor Activation Receptor Signaling Refractory Reporter Research Role Signal Transduction Testing Therapeutic Toll-like receptors Treatment Efficacy Tumor Cell Invasion Woman Work base body system cancer cell cancer immunotherapy cancer subtypes cancer therapy cell free DNA chemotherapy clinically relevant exosome experimental study improved in vitro Model in vivo in vivo Model inflammatory breast cancer innovation interest malignant breast neoplasm mortality mouse model novel outcome forecast overexpression pancreatic cancer patients pathogen programs receptor sensor targeted cancer therapy targeted treatment tool transcriptome sequencing triple-negative invasive breast carcinoma tumor tumor microenvironment tumorigenesis validation studies

项目摘要

Abstract Breast cancers (BC) remain the most lethal malignancies amongst women worldwide and the second leading cause of cancer-related mortality in the US. Subtype heterogeneity and aggressive metastatic potential are believed to be the major contributors of these outcomes. Although the standard targeted therapies have shown some efficacy against classically overexpressed BC receptors (i.e. estrogen/progesterone receptors, ER+/PR+ and human epidermal growth factor receptor 2, HER2+), BC lacking all three of these receptors (triple-negative, TNBC) are notoriously aggressive, difficult-to-treat, and metastatic. Current treatment options for TNBC include neoadjuvant chemotherapy and surgery which can have limited utility in advanced metastatic disease. A recent surge of interest on the role of tumor-associated inflammation on metastatic progression lead to the observation that the degree of inflammation-driven tumorigenesis tends to correlate with increased levels of cell-free DNA (cfDNA) in cancer patient sera. Such observations prompted our lab to explore the use of nucleic-acid scavengers (NASs) as a means of blocking the pro-inflammatory signals elicited by these cfDNA to innate immune sensors such as TLRs. In this proposal, I aim to (1) define the effects of NAS treatment on innate immune system signaling in BC using in vitro and ex vivo models, (2) elucidate the mechanism by which these NAS work in the BC setting using novel molecular tools developed in the lab, and (3) evaluate how these molecules limit metastases in an immune-competent in vivo model. Thus, I propose mechanistic studies to define how NAS ameliorate aberrant immune cell activation, and in vivo validation studies to gain a better understanding of how these molecules behave in a clinically relevant disease model. Successful completion of this proposal will enhance basic understanding of metastatic progression and its interplay with the immune system, and uncover principles that may aid in the development efforts of anti-metastatic therapies to improve TNBC patient outcomes. !

抽象的乳腺癌（BC）仍然是全球妇女中最致命的恶性肿瘤，是第二名美国与癌症有关的死亡率的原因。亚型异质性和攻击性转移潜力是被认为是这些结果的主要贡献者。尽管标准靶向疗法已显示对经典过表达的BC受体（即雌激素/孕酮受体，ER+/PR+）的一些功效和人类表皮生长因子受体2，HER2+），卑诗省缺乏所有这三个受体（三阴性，众所周知，TNBC是积极进取的，难以治疗和转移性的。当前的TNBC治疗选择包括新辅助化学疗法和手术可能在晚期转移性疾病中效用有限。最近肿瘤相关炎症对转移性进展的作用的兴趣激增导致观察炎症造成的肿瘤发生程度往往与无细胞DNA水平升高相关（CFDNA）在癌症患者血清中。这种观察促使我们的实验室探索核酸的使用清道夫（NASS）是阻止这些CFDNA先天引起的促炎信号的一种手段免疫传感器，例如TLR。在此提案中，我的目标是（1）定义NAS治疗对先天性的影响使用体外和离体模型在BC中的免疫系统信号传导，（2）阐明这些机制 NAS使用实验室中开发的新分子工具在卑诗省设置中工作，（3）评估这些工具分子在体内模型中限制了能竞争性的转移。因此，我建议机械研究来定义 NAS如何改善异常免疫细胞激活和体内验证研究以获得更好的理解这些分子在临床相关疾病模型中的行为方式。成功完成此建议将增强对转移性进展及其与免疫系统相互作用的基本理解，以及发现可能有助于改善TNBC患者的抗转移疗法的开发工作的原则结果。呢