CCN5 Therapy for Triple Negative Breast Cancer

目前乳腺癌(BC)的治疗方法被坚信可以有效地提高患者的存活率。 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，患者最终可能发展为远处转移 疾病和抗药性。目前还没有针对侵袭性和转移性的靶向治疗。 疾病，表明迫切需要改进治疗。我们发现CCN5是一种肿瘤抑制因子 可能通过靶向细胞生长调节因子p27Kip1和microRNA-10b(miR-10b) 它被认为是侵袭、转移和耐药的媒介。然而，治疗应用 CCN5仍然未知；在开发和开发基于CCN5的药物之前，需要这种关键知识 转移到临床环境中。因此，该应用程序的目标是创建和建立一种创新的方法 通过对CCN5蛋白的合成修饰来治疗TNBC生长和转移 聚乙二醇化(CCN5聚乙二醇化；聚乙二醇化聚乙二醇5)。在我们的初步研究中，我们有 论证了该方法的可行性。我们已经证明，聚乙二醇化可以降低血浆 清除CCN5蛋白。靶向PEGCCN5的p27Kip1和miR-10b对TNBC细胞的作用 阻断细胞生长、侵袭和球体形成能力，恢复ER-α的表达并使其增敏 化疗。体内研究结果表明，皮下注射聚乙二醇-CCN5对肿瘤- 荷瘤小鼠可导致强劲的肿瘤摄取，并抑制肿瘤的生长和转移。这些初步的 研究结果构成了当前应用的基础，在该应用中，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来优化聚乙二醇-CCN5衍生物(目标1)，MTD， 体内和体外的生物分布和毒性(目标2)。抗肿瘤和抗转移作用的研究 在细胞来源的原位移植中也将确定抗激素、化疗或两者兼用的联合治疗。 TNBC异种移植、同基因模型和PDX模型(目标3)。这些研究有望确定一种最佳的 聚乙二醇化蛋白抑制TNBC生长和进展，并使TNBC细胞对他莫昔芬敏感 和紫杉醇，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 显著提高了对CCN5的治疗作用及其在抑制中的机制的认识 是TNBC的。 。

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. .