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Personalized Therapeutics for Inhibiting Breast Cancer Metastasis

抑制乳腺癌转移的个性化治疗

基本信息

批准号：
9540125
负责人：
Debra Auguste
金额：
$ 47.1万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-20 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9540125
关键词：
Address African American Antibodies Aromatase Inhibitors Binding Biodistribution Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Breast Cancer cell line Breast cancer metastasis CXC Chemokines Cell surface Chemical Engineering Chemotaxis Clinical Trials Complement Coupled Diagnosis E-Cadherin Endothelial Cells Engineering Estrogen Antagonists Estrogen Receptor alpha Fibronectins Gel Growth Homing Hormones Human In Vitro Knowledge LCN2 gene Lipids Liposomes Lymphocyte Malignant Neoplasms Malignant neoplasm of lung Metastatic breast cancer Methods Molecular Monitor Nanotechnology Neoplasm Metastasis Phase Population Small Interfering RNA Surface Survival Rate Technology Therapeutic Trastuzumab Tumor Cell Migration Vimentin Woman Work antibody conjugate base beta-Chemokines cancer cell cell motility cell type chemokine chemokine receptor chromophore cytokine density design epithelial to mesenchymal transition experience global health in vivo knock-down malignant breast neoplasm materials science personalized approach personalized therapeutic receptor therapeutic target tumor tumor progression

项目摘要

Breast cancer is a major global health issue; it is the second most common form of cancer in women exceeded only by lung cancer. Current breast cancer treatments are regulated by cell surface presentation; for example, breast cancer cells that express estrogen receptor-α (ERα) and human epidermal growth receptor-2 (HER2) on their surface are treated with hormone (anti-estrogen or aromatase inhibitors) or targeted (Herceptin) therapies, respectively. In this proposal, we propose a personalized approach to treat four metastatic breast cancer populations: black, white, over 40 and under 40. These populations were chosen based on statistical differences in survival and rate of diagnoses. I will characterize the surface density and proximity of two Gprotein coupled receptors that facilitate tumor chemotaxis, CXC chemokine receptor type 4 (CXCR4) and CC chemokine receptor type 7 (CCR7). CXCR4 and CCR7 induce directional migration of tumor cells along chemokine gradients in a manner similar to lymphocyte homing. In addition, lipocalin-2 (Lcn2) has been shown to induce the epithelial to mesenchymal transition (EMT). I propose to synthesize complementary engineered liposomes (CELs) that cooperatively bind CXCR4 and CCR7 and deliver short interfering RNA (siRNA) to knockdown Lcn2. Homogeneous and biphasic CELs are designed to complement the relative surface density and organization of receptors on breast cancer cells by allowing conjugated antibodies to rearrange on the surface or clustering antibodies within gel-phase lipid domains. CEL therapies will be designed to enhance cooperative binding to each cell type and be evaluated to reduce cell migration and invasion. Mechanistic studies will complement in vitro studies; the expression of RhoA, Rac1, Erk1, PI3K, E-cadherin, vimentin, and fibronectin will assess the effect of CEL therapy on cell migration, activation, survival, and the EMT. In vivo tumor progression and metastasis will be evaluated after delivery of CEL therapies. This work will demonstrate similarities and differences between 6 different breast cancer cell lines and deliver a platform technology designed specifically to address tumor metastasis. In comparison to the antibody and the antagonist targeted towards CXCR4 in clinical trials, this method has the advantage of localizing within tumors, cooperatively binding multiple chemokine receptors, blocking chemotaxis, delivering Lcn2 siRNA to impede the EMT, and monitoring biodistribution in vivo via the incorporation of a near infrared chromophore. My previous work, targeting cytokine-activated endothelial cells, presents compounding evidence that vehicles that complement the cell surface enhance binding. I propose to use our knowledge and experience in chemical engineering, material science, and nanotechnology to develop therapeutics that will increase breast cancer patient survival by inhibiting tumor progression and metastasis.

乳腺癌是一个重大的全球健康问题;它是第二个最常见的癌症形式的妇女超过只有肺癌。目前的乳腺癌治疗受细胞表面呈递的调节;例如，表达雌激素受体α（ERα）和人表皮生长受体2（HER 2）的乳腺癌细胞在它们的表面上用激素（抗雌激素或芳香酶抑制剂）或靶向（赫赛汀）处理治疗，分别。在这个建议中，我们提出了一个个性化的方法来治疗四个转移性乳腺癌，癌症人群：黑人、白色、40岁以上和40岁以下。这些人群的选择是基于统计学存活率和诊断率的差异。我将描述两个G蛋白的表面密度和接近度，促进肿瘤趋化性的偶联受体，CXC趋化因子受体4型（CXCR 4）和CC 趋化因子受体7（CCR 7）。CXCR 4和CCR 7诱导肿瘤细胞沿着趋化因子梯度的方式类似于淋巴细胞归巢。此外，脂质运载蛋白-2（Lcn 2）已被证明诱导上皮细胞向间质细胞转化（EMT）。我建议合成互补的工程脂质体（CEL），其协同结合CXCR 4和CCR 7，并递送短干扰RNA（siRNA），击倒Lcn 2。均相和双相CEL旨在补充相对表面密度和乳腺癌细胞上受体的组织，通过允许缀合抗体在乳腺癌细胞上重排，凝胶相脂质结构域内的表面或聚集抗体。CEL疗法将被设计为增强与每种细胞类型的协同结合，并被评估以减少细胞迁移和侵袭。机械论研究将补充体外研究; RhoA、Rac 1、Erk 1、PI 3 K、E-钙粘蛋白、波形蛋白和纤连蛋白将评估CEL疗法对细胞迁移、活化、存活和EMT的影响。体内肿瘤进展和转移将在递送CEL疗法后评估。这项工作将证明 6种不同乳腺癌细胞系之间的异同，并提供一个平台技术专门针对肿瘤转移而设计。与靶向的抗体和拮抗剂相比，对于临床试验中的CXCR 4，该方法具有定位于肿瘤内的优势，结合多种趋化因子受体，阻断趋化性，递送Lcn 2 siRNA以阻碍EMT，以及通过掺入近红外发色团监测体内生物分布。我以前的工作，靶向精氨酸激活的内皮细胞，提出了复合证据，细胞表面增强结合。我建议利用我们在化学工程方面的知识和经验，材料科学和纳米技术，以开发治疗方法，提高乳腺癌患者的生存率通过抑制肿瘤进展和转移。