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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. !

摘要