Personalized therapeutics for inhibiting breast cancer metastasis

描述（由申请人提供） 摘要：乳腺癌是一个重大的全球健康问题;它是女性第二常见的癌症，仅次于肺癌。目前的乳腺癌治疗受细胞表面呈递的调节;例如，分别用激素（抗雌激素或芳香酶抑制剂）或靶向（赫赛汀）疗法治疗在其表面上表达雌激素受体（ER）和人表皮生长受体2（HER 2）的乳腺癌细胞。在这项提案中，我们提出了一种个性化的方法来治疗四种转移性乳腺癌人群：黑人，白色，40岁以上和40岁以下。这些人群是根据生存率和诊断率的统计学差异选择的。我将描述两个G蛋白偶联受体的表面密度和接近度，这两个受体促进肿瘤趋化性，CXC趋化因子受体4型（CXCR 4）和CC趋化因子受体7型（CCR 7）。CXCR 4和CCR 7以类似于淋巴细胞归巢的方式诱导肿瘤细胞沿着趋化因子梯度定向迁移。此外，脂质运载蛋白-2（Lcn 2）已被证明可诱导上皮向间充质转化（EMT）。我建议合成互补的工程脂质体（CEL），协同结合CXCR 4和CCR 7，并提供短干扰RNA（siRNA）敲低Lcn 2。均相和双相CEL被设计为通过允许缀合抗体在表面上重排或在凝胶相脂质结构域内聚集抗体来补充乳腺癌细胞上受体的相对表面密度和组织。CEL疗法将被设计为增强与每种细胞类型的协同结合，并被评估为减少细胞迁移和侵袭。机制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的表达将评估CEL治疗对细胞迁移、活化、存活和EMT的影响。将在递送CEL疗法后评价体内肿瘤进展和转移。这项工作将展示6种不同乳腺癌细胞系之间的相似性和差异，并提供专门针对肿瘤转移的平台技术。与临床试验中靶向CXCR 4的抗体和拮抗剂相比，该方法具有定位于肿瘤内、协同结合多种趋化因子受体、阻断趋化性、递送Lcn 2 siRNA以阻止EMT以及通过掺入近红外发色团监测体内生物分布的优点。我以前的工作，针对精氨酸激活的内皮细胞，提出了复合证据，补充细胞表面的车辆增强结合。我建议利用我们在化学工程、材料科学和纳米技术方面的知识和经验，开发通过抑制肿瘤进展和转移来提高乳腺癌患者生存率的治疗方法。 公共卫生相关性：乳腺癌是仅次于肺癌的女性第二大常见癌症。该提案将开发针对转移性乳腺癌细胞和控制转移机制的个性化疗法。我将从白色、黑色、40岁以下和40岁以上人群中鉴定乳腺癌细胞系，并合成专门设计用于补充这些乳腺癌细胞上受体的相对分子密度和组织的载体。

DESCRIPTION (Provided by the applicant) Abstract: 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-¿ (ER¿) 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 G- protein 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. Public Health Relevance: Breast cancer is the second most common form of cancer in women exceeded only by lung cancer. This proposal will develop personalized therapeutics that target metastatic breast cancer cells and mechanisms that govern metastasis. I will characterize breast cancer cell lines from white, black, under 40, and over 40 populations and synthesize vehicles specifically designed to complement the relative molecular density and organization of receptors on these breast cancer cells.