CCN5 Therapy for Triple Negative Breast Cancer

三阴性乳腺癌的 CCN5 疗法

• 批准号: 10063421
• 负责人: Sushanta K. Banerjee
• 金额: --
• 依托单位: KANSAS CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063421
• 关键词: Acute; Affinity; Animal Model; Anthracycline; Antitumor Response; Binding; Biodistribution; Biological Assay; Biological Availability; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer therapy; Cell Survival; Cells; Clinical; Differentiation and Growth; Disease; Disease Resistance; Distant; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Drug resistance; ERBB2 gene; Epithelial; Event; Female; Future; Goals; Growth; Half-Life; Immunocompetent; In Vitro; Injections; Intravenous; Knowledge; Life Extension; Maximum Tolerated Dose; Measures; Mediator of activation protein; Mesenchymal; Metastatic Neoplasm to Lymph Nodes; Metastatic Neoplasm to the Lung; Methods; MicroRNAs; Modeling; Modification; Molecular Weight; Mus; Neoplasm Metastasis; Organ; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Plasma; Polyethylene Glycols; Primary Neoplasm; Proteins; Recurrence; Regulation; Relapse; Resistance; Serum; Subcutaneous Injections; Tamoxifen; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Treatment Efficacy; Tumor Suppressor Proteins; Tumor Volume; Tumor-Derived; Xenograft procedure; anticancer research; base; breast cancer progression; cancer cell; cancer stem cell; cell growth; chemotherapy; cyclin-dependent kinase inhibitor 1B; drug development; effective therapy; experimental study; genetic manipulation; hormone receptor-positive; hormone therapy; improved; in vivo; in vivo imaging; innovation; insight; lead candidate; lead optimization; malignant breast neoplasm; migration; mouse model; neoplastic cell; patient derived xenograft model; pre-clinical; stemness; subcutaneous; systemic toxicity; targeted treatment; taxane; therapeutic target; therapy outcome; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor xenograft; tumorigenic; uptake

Current therapies for breast cancer (BC) are firmly believed to improve patient survival efficiently. However, one-third of aggressive triple-negative breast cancer (TNBC) patients may relapse more frequently compared to hormone receptor-positive subtypes, and patients may eventually develop the distant metastatic disease and drug resistance. There are no targeted therapies currently available for invasive and metastatic diseases, indicating a dire need for improved therapy. We revealed that CCN5 acts as a tumor suppressor protein in TNBC and possibly by targeting p27Kip1, which is a cell growth regulator, and microRNA-10b (miR-10b) which is known as a mediator of invasion, metastasis, and drug resistance. However, therapeutic application of CCN5 remains unknown; this critical knowledge is required before CCN5-based drugs can be developed and moved into a clinical setting. Thus, the goal of this application is to create and establish an innovative approach for CCN5 therapy for TNBC growth and metastasis by synthetic modification of CCN5 protein through the amalgamation of polyethylene glycol (CCN5 PEGylation; PEG-CCN5). In our preliminary studies, we have demonstrated the feasibility of the proposed method. We have shown that that PEGylation decreases plasma clearance of CCN5 protein. Treatment of TNBC cells with p27Kip1 and miR-10b targeting PEG-CCN5 results in blocking cell growth, invasion, and sphere-forming ability, restoring ER-α expression and sensitizing it to chemotherapy. The results of the in vivo studies suggest that subcutaneous delivery of PEG-CCN5 to tumor- bearing mice leads to robust tumor uptake and suppresses tumor growth and metastasis. These preliminary findings form the basis for the current application, in which we propose to extend these studies to identify an optimal PEG-CCN5 derivative by determining functional efficacy and mechanism of action (Aim 1), MTD, biodistribution, and toxicity in vitro and in vivo (Aim 2). Finally, antitumor and anti-metastatic efficacy in combination treatment of anti-hormone, chemotherapy or both will also be determined in cell-derived orthotopic TNBC xenograft, syngeneic models and PDX model (Aim 3). These studies are expected to identify an optimal PEGylated protein that will inhibit TNBC growth and progression as well as sensitize TNBC cells to tamoxifen and Paclitaxel with minimal systemic toxicity or ill effects on healthy cells or organs. These approaches should significantly advance knowledge on therapeutic utility of CCN5 and its mechanistic insights in the suppression of TNBC. .

首先据信乳腺癌（BC）的当前疗法有效地改善了患者的生存率。 但是，三分之一的侵略性三阴性乳腺癌（TNBC）患者可能会更频繁地中继 与同性受体阳性亚型相比，患者有时可能会发展遥远的转移性 疾病和耐药性。目前没有针对性疗法可用于侵入性和转移性 疾病，表明需要改善治疗的需求。我们透露CCN5充当肿瘤抑制剂 TNBC中的蛋白质，并且通过靶向P27KIP1，即细胞生长调节剂和microRNA-10B（mir-10b） 被称为侵袭，转移和耐药性的中介。但是，治疗应用 CCN5仍然未知；在开发基于CCN5的药物之前，需要这个关键的知识并 进入临床环境。这是该应用程序的目的是创建和建立一种创新的方法 通过合成CCN5蛋白的CCN5治疗，用于TNBC生长和转移 聚乙烯乙二醇的合并（CCN5 Pegylation; PEG-CCN5）。在我们的初步研究中，我们有 证明了所提出的方法的可行性。我们已经表明，Pegylation会下降等离子体 CCN5蛋白的清除率。用P27KIP1和靶向PEG-CCN5的miR-10b处理TNBC细胞导致 阻止细胞的生长，侵袭和形成球体的能力，恢复ER-α表达并将其致敏 化学疗法。体内研究的结果表明，皮下递送PEG-CCN5向肿瘤 - 轴承小鼠会导致强大的肿瘤摄取，并抑制肿瘤的生长和转移。这些初步 调查结果构成了当前应用的基础，我们建议在其中扩展这些研究以确定 通过确定功能效率和作用机理（AIM 1），MTD， 生物分布和体外和体内毒性（AIM 2）。最后，抗肿瘤和抗转移性效率 抗激素，化学疗法或两者的联合治疗也将在细胞衍生的原位上确定 TNBC特征，合成模型和PDX模型（AIM 3）。这些研究有望确定最佳 将抑制TNBC生长和进展以及灵敏度TNBC细胞对他莫昔芬的质量蛋白质 和紫杉醇对健康细胞或器官的最小全身毒性或不良影响。这些方法应该 对CCN5的热实用性及其在抑制中的机理见解有了明显的了解 TNBC。 。