Image-guided EMT inhibition for treating metastatic breast cancer

 描述(申请人提供)：该项目的目标是开发创新的图像引导的EMT抑制，通过使用RNAi靶向与转移相关的关键生物学事件中的蛋白质来有效治疗转移的BC。转移性乳腺癌是美国被诊断患有乳腺癌的妇女过早死亡的主要原因。目前，对于乳腺癌变得多药耐药和复发的患者，治疗选择有限。上皮-间充质转化(EMT)是乳腺癌转移和多药耐药相关的重要生物学事件。我们已经确定了乳腺癌EMT的几个标志物，用于成像转移性乳腺癌和有效治疗转移性乳腺癌，方法是在影像指导下抑制癌细胞EMT并使其对化疗重新敏感。在这个项目中，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，下调促进癌细胞EMT的关键蛋白的表达，以有效抑制BC EMT，并在影像引导下单独和联合化疗治疗转移性BC。使用成像技术对新治疗方案的治疗效果进行无创性和及时的评估将指导优化给药系统和治疗方案，以实现尽可能好的结果和治愈疾病。本项目的具体目标是1)首先建立图像引导下无创抑制EMT的分子成像技术，靶向多功能siRNA递送系统用于治疗转移性乳腺癌；2)评估和优化图像引导下EMT调节基因的沉默，以及使用靶向多功能siRNA递送系统抑制乳腺癌的EMT和转移；3)评估和优化多功能siRNA递送系统和化疗药物在治疗TNBC中的联合治疗。已经获得了大量的初步数据来证明所建议的图像引导治疗方案在治疗转移性乳腺癌方面的有效性。我们的长期目标是开发一种影像引导的治疗方法，以有效地治疗危及生命的转移性BC。

 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.