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

• 批准号: 9609071
• 负责人: Elias Oluwatobi Utseoritselaju Eteshola
• 金额: $ 3.59万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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/9609071
• 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; pathogen; programs; receptor; sensor; targeted cancer therapy; targeted treatment; tool; transcriptome sequencing; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; tumorigenesis; validation studies

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 乳腺癌(BC)仍然是全世界女性中最致命的恶性肿瘤，位居第二。 美国癌症相关死亡的原因。亚型异质性和侵袭性转移潜能为 被认为是这些结果的主要贡献者。尽管标准的靶向治疗显示 对经典的过度表达的BC受体(即雌激素/孕激素受体，ER+/PR+)的一些疗效 和人表皮生长因子受体2，HER2+)，BC缺乏这三种受体(三阴性， TNBC)是出了名的侵略性、难治性和转移性。目前TNBC的治疗方案包括 新辅助化疗和手术在晚期转移性疾病中的作用有限。最近 对肿瘤相关炎症在转移进展中的作用的兴趣激增导致了这一观察 炎症驱动的肿瘤形成的程度往往与游离DNA水平的增加相关 (CfDNA)在癌症患者血清中。这些观察结果促使我们的实验室探索核酸的用途 清道夫(NASS)作为一种手段来阻断由这些cfDNA先天引发的促炎信号 免疫传感器，如TLRs。在这项建议中，我的目标是(1)定义NAS治疗对先天的影响 使用体外和体外模型研究BC中的免疫系统信号，(2)阐明这些信号传导的机制 NAS使用实验室开发的新分子工具在BC环境中工作，以及(3)评估这些工具如何 在具有免疫活性的体内模型中，分子限制转移。因此，我提议用机械论的研究来定义 NAS如何改善异常免疫细胞激活，以及体内验证研究以更好地了解 这些分子在临床相关疾病模型中的作用。成功完成本建议书 将加强对转移进展及其与免疫系统的相互作用的基本了解，以及 揭示可能有助于开发抗转移疗法以改善TNBC患者的原则 结果。 好了！