CCN5 Therapy for Triple Negative Breast Cancer

三阴性乳腺癌的 CCN5 疗法

• 批准号: 10515673
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10515673
• 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 Differentiation process; Cell Survival; Cells; Clinical; Combined Modality Therapy; Disease; Disease Resistance; Distant; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Drug resistance; ERBB2 gene; Epithelium; Estrogen Receptor alpha; Event; Female; Future; Goals; Growth; Half-Life; Hormones; Immunocompetent; In Vitro; Injections; Invaded; Knowledge; Life Extension; Maximum Tolerated Dose; Measures; Mediator; 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; Xenograft procedure; anticancer research; 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; intravenous administration; 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. .

人们坚信目前的乳腺癌（BC）疗法可以有效提高患者的生存率。 然而，三分之一的侵袭性三阴性乳腺癌（TNBC）患者可能会更频繁地复发 与激素受体阳性亚型相比，患者最终可能会发生远处转移 疾病和耐药性。目前尚无针对侵袭性和转移性肿瘤的靶向治疗方法 疾病，表明迫切需要改进治疗。我们发现 CCN5 具有肿瘤抑制因子的作用 TNBC 中的蛋白质，可能通过靶向细胞生长调节剂 p27Kip1 和 microRNA-10b (miR-10b) 它被称为侵袭、转移和耐药性的介质。然而，治疗应用 CCN5 仍未知；在开发基于 CCN5 的药物之前需要这些关键知识 进入临床环境。因此，该应用程序的目标是创建和建立一种创新方法 通过 CCN5 蛋白的合成修饰，用于 TNBC 生长和转移的 CCN5 疗法 聚乙二醇的合并（CCN5 聚乙二醇化；PEG-CCN5）。在我们的初步研究中，我们有 证明了所提方法的可行性。我们已经证明聚乙二醇化可降低血浆 CCN5蛋白的清除。用靶向 PEG-CCN5 的 p27Kip1 和 miR-10b 处理 TNBC 细胞，结果 阻断细胞生长、侵袭和球体形成能力，恢复 ER-α 表达并使其敏感 化疗。体内研究的结果表明，皮下递送 PEG-CCN5 至肿瘤 携带小鼠会导致强大的肿瘤摄取并抑制肿瘤生长和转移。这些初步的 研究结果构成了当前应用的基础，我们建议扩展这些研究以确定 通过确定功能功效和作用机制（目标 1）、MTD，优化 PEG-CCN5 衍生物， 生物分布以及体外和体内毒性（目标 2）。最后，抗肿瘤和抗转移功效 抗激素、化疗或两者的联合治疗也将在细胞源性原位确定 TNBC 异种移植、同基因模型和 PDX 模型（目标 3）。这些研究预计将确定最佳的 聚乙二醇化蛋白可抑制 TNBC 生长和进展并使 TNBC 细胞对他莫昔芬敏感 紫杉醇对健康细胞或器官的全身毒性或不良影响最小。这些方法应该 显着增进对 CCN5 治疗效用及其抑制机制的认识 TNBC 的。 。