Image-guided EMT inhibition for treating metastatic breast cancer

图像引导 EMT 抑制治疗转移性乳腺癌

• 批准号: 9301500
• 负责人: ZHENG-RONG LU
• 金额: $ 47.39万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9301500
• 关键词: Accounting; Actin-Binding Protein; Adverse effects; Biological; Blood Vessels; Breast Cancer Cell; Breast cancer metastasis; Carcinoma; Cells; Cessation of life; Combined Modality Therapy; Contrast Media; Data; Development; Diagnosis; Disease; Down-Regulation; Effectiveness; Epithelial; Epithelial Cells; Event; Family; Fibronectins; Goals; Image; Imaging technology; In Vitro; Injection of therapeutic agent; Integrin beta3; Lead; Life; Lipids; Magnetic Resonance Imaging; Mesenchymal; Metastatic breast cancer; Micrometastasis; Modeling; Molecular; Molecular Target; Monitor; Morphology; Multi-Drug Resistance; Mus; Neoplasm Metastasis; Outcome; Patients; Phenotype; Primary Neoplasm; Property; Proteins; RNA Interference; Recurrent disease; Regimen; Regulation; Regulator Genes; Resistance; SOX4 gene; Small Interfering RNA; System; Therapeutic; Time; Treatment Efficacy; Treatment Protocols; Tumor Tissue; United States; Woman; cancer cell; cancer imaging; cancer subtypes; chemotherapy; clinical development; contrast enhanced; effective therapy; image guided; improved; in vivo; innovation; malignant breast neoplasm; member; molecular imaging; nanoparticle; non-invasive imaging; novel therapeutics; preclinical development; premature; prevent; public health relevance; response; stem; targeted delivery; targeted imaging; targeted treatment; therapeutic siRNA; therapeutic target; therapy outcome; triple-negative invasive breast carcinoma; tumor

 DESCRIPTION (provided by applicant): The goal of this project is to develop innovative image-guided EMT inhibition by targeting the proteins in the key biological event associated with metastasis using RNAi to effectively treat metastatic BC. Metastatic breast cancer is the leading cause of the premature deaths of women diagnosed with the disease in the United States. Currently, there are limited treatment options for the patients whose breast cancer becomes multidrug resistance and relapsed disease. Epithelial-mesenchymal transition (EMT) is a key biological event associated with breast cancer metastasis and multidrug resistance. We have identified several markers of breast cancer EMT for imaging metastatic breast cancer and for effective treatment of metastatic breast cancer by inhibiting cancer cell EMT and resensitizing the cells to chemotherapy under imaging guidance. In this project, we will develop molecular MRI and DCE-MRI to direct the inhibition of BC EMT using targeted lipid siRNA nanoparticles in treating metastatic BC. We will develop targeted multifunctional lipid siRNA delivery systems to down-regulate the expression of key proteins that promote cancer cell EMT for effective inhibition of BC EMT and treatment of metastatic BC alone and in combination with chemotherapy under imaging guidance. Non-invasive and timely assessment of therapeutic efficacy of the new therapeutic regimens using the imaging technologies will guide the optimization of the delivery systems and treatment protocols to achieve the best possible outcomes and to cure the disease. The specific aims of this project are 1) to first establish molecular imaging technologies for non-invasive image-guided inhibition of EMT with targeted multifunctional siRNA delivery systems in treating metastatic breast cancer; 2) to evaluate and optimize image-guided silence of EMT-regulatory genes and inhibition of BC EMT and metastasis using targeted multifunctional siRNA delivery systems; 3) to evaluate and optimize image-guided combination therapy of the multifunctional siRNA delivery systems and chemotherapeutics in treating TNBC. Substantial preliminary data have been obtained to demonstrate the effectiveness of the proposed image-guided therapeutic regimens in treating metastatic breast cancer. Our long-term goal is to develop an image-guided therapeutic approach to effectively treat life-threatening metastatic BC.

 描述（由申请人提供）：该项目的目标是通过使用 RNAi 靶向与转移相关的关键生物事件中的蛋白质来开发创新的图像引导 EMT 抑制，以有效治疗转移性乳腺癌。目前，对于乳腺癌多药耐药性和复发性疾病（EMT）的患者来说，治疗选择有限。在这个项目中，我们已经确定了几种乳腺癌 EMT 标志物，用于对转移性乳腺癌进行成像，并通过抑制癌细胞 EMT 并使细胞在成像指导下对化疗重新敏感来有效治疗转移性乳腺癌。我们将开发分子 MRI 和 DCE-MRI 来指导使用靶向脂质 siRNA 纳米颗粒抑制 BC EMT 治疗转移性 BC。我们将开发靶向多功能脂质 siRNA 递送系统来下调表达。促进癌细胞EMT的关键蛋白的研究，以有效抑制BC EMT，并在影像学指导下单独或联合化疗治疗转移性BC。利用影像技术对新治疗方案的疗效进行非侵入性及时评估将指导癌症的治疗。优化递送系统和治疗方案，以实现最佳结果并治愈疾病。该项目的具体目标是 1) 首先建立分子成像技术，通过靶向多功能 siRNA 递送来非侵入性图像引导抑制 EMT。治疗转移性乳腺的系统癌症；2) 使用多功能 siRNA 递送系统评估和优化 EMT 调节基因的图像引导沉默以及 BC EMT 和转移的抑制；3) 评估和优化多功能 siRNA 递送系统和化疗药物的靶向图像引导联合治疗已获得大量初步数据来证明所提出的图像引导治疗方案在治疗转移性乳腺癌方面的有效性。有效治疗危及生命的转移性乳腺癌的方法。