Inhibition of breast cancer cell metastases using a connexin43 mimetic peptide

使用 connexin43 模拟肽抑制乳腺癌细胞转移

基本信息

批准号：
10010920
负责人：
Samy Lamouille
金额：
$ 39.99万
依托单位：
ACOMHAL RESEARCH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10010920
关键词：
4T1 Affect Behavior Binding Biochemical Biological Assay Breast Cancer Cell Breast Cancer Prevention Breast Cancer Treatment Breast Cancer cell line Breast Carcinoma Cancer Etiology Cell Proliferation Cell membrane Cells Cessation of life Characteristics Collaborations Connexin 43 Data Diagnosis Disease Distant Drug Kinetics Early Diagnosis Epithelial Epithelial Cells Epithelium Extracellular Matrix Proteins FOXP3 gene Fibronectins Gap Junctions Goals Heterogeneity Human In Vitro Incidence Investigational Drugs Knowledge Laboratories Lead Legal patent Letters Licensing MDA MB 231 Malignant Epithelial Cell Malignant Neoplasms Mammary Neoplasms Mammary gland Maximum Tolerated Dose Mediating Medical Mesenchymal Metastatic breast cancer Microscopy Microtubules Modeling Molecular Target Mus Names Nature Neoplasm Metastasis Patient-Focused Outcomes Peptides Population Primary Neoplasm Process Property Publishing Recurrence Reporting Research Resolution Rivers Role Signal Transduction Site South Carolina Techniques Testing Therapeutic Therapeutic Effect Time Transitional Cell Carcinoma Tumor Cell Invasion Universities Woman Xenograft Model alpha Tubulin base breast cancer progression cancer cell cancer subtypes cancer type carcinogenesis cell motility cytotoxic efficacy testing experience improved in vitro Assay in vivo in vivo Model malignant breast neoplasm mortality mouse model neoplastic cell novel novel therapeutics orthotopic breast cancer outcome forecast peptidomimetics prevent protein protein interaction screening targeted treatment triple-negative invasive breast carcinoma tumor tumor growth tumor progression tumorigenic uptake

项目摘要

PROJECT SUMMARY Breast cancer is one of the most diagnosed type of cancer and second leading cause of cancer-related death among women in the U.S. Treatment remains challenging due to the heterogeneity and highly dynamic nature of breast tumors. Although early detection through screening has largely contributed to a decline in breast cancer-related mortality, tumor recurrence and metastasis still remain associated with poor prognosis. Once the disease becomes metastatic, the median survival is around 12 to 15 months. But more alarming is the incidence of the triple-negative subtype, the most aggressive type of breast cancer, in the younger population. Increasing evidence identifies the epithelial-mesenchymal transition process as a potential contributor of metastasis in this subtype. In fact, breast carcinoma cells that undergo EMT acquire invasive properties that contribute to the formation of metastases. In addition, EMT results in increased expression of extracellular matrix proteins including fibronectin that enhance tumor invasion, regulate cancer cell proliferation, and limit tumor cell responsiveness to therapies. Therefore, there is an urgent need to identify novel molecular targets in breast cancer-associated EMT, and develop new therapeutics to prevent triple-negative breast cancer progression through metastasis. In our previous published research we observed a loss of connexin43 (Cx43) gap junctions at the plasma membrane concomitantly with an increase in intracellular Cx43 expression during EMT. Despite several studies in the field, the role of Cx43 in breast cancer remains ambiguous with roles in suppressing tumor growth as well as facilitating tumor progression and metastasis. Our preliminary research identifies a tumorigenic role for Cx43 in EMT and triple-negative cancer cells through its interaction with microtubules. Regulating localization and activity of Cx43 is associated with the multiple sites for protein–protein interaction within the Cx43 carboxy-terminus (CT). The Cx43 CT includes a tubulin binding domain and we developed a novel Cx43 mimetic peptide named JM2 (juxtamembrane 2) composed of the Cx43 CT encompassing the microtubule binding sequence. Our goal is to assess the therapeutic effect of JM2 to target triple-negative breast cancer in cell-based assays in vitro and in metastatic breast cancer mouse models in vivo. Our proposed research aims to validate Cx43 as a novel molecular target in triple-negative breast cancer, and use JM2 to disrupt Cx43- microtubule interaction without affecting Cx43 expression, thus regulating Cx43 localization and activity more specifically. This proposal aims to fill a gap in knowledge, whereby no previous studies evaluated the tumorigenic role of Cx43 through interaction with microtubules in breast cancer cells and no efficient targeted therapeutics currently exist that can successfully ablate the metastatic potential of triple-negative breast cancer cells.

项目摘要乳腺癌是最诊断出的癌症类型之一，是与癌症相关死亡的主要原因在美国的妇女中，由于异质性和高度动态性，待遇仍然是挑战通过筛查的乳房肿瘤的早期检测有所减少与癌症相关的死亡率，肿瘤复发和转移仍然与差的程序病有关。疾病变成转移性，中位生存期约为12到15个月。在年轻人口中，三阴性亚型，最具侵略性的乳腺癌类型。证据确定上皮 - 间质转变过程是转移的潜在因素 supty。形成转移，EMT导致细胞外基质蛋白的表达增加含有纤连蛋白，从而增强肿瘤的发明，调节癌细胞的繁殖力并限制肿瘤细胞因此，对疗法的反应。与癌症相关的EMT和发展三阴性癌症计划的发展元素通过转移。在质膜上，在EMT期间，膜与细胞内CX43表达的增加该领域的几项研究，CX43在乳腺癌中的作用在肿瘤上仍然模棱两可增长以及促进肿瘤计划的进展和转移。 CX43在EMT和三阴性癌细胞中的作用通过其与微管的相互作用。 CX43的定位和活性与蛋白质 - 蛋白质相互作用的多个位点有关 CX43羧基末端（CT）。 cx43 CT的模拟肽（jm2）结合序列。我们的目标是评估JM2对目标阴性乳腺癌的治疗作用基于细胞的测定在体内的体外和转移性乳腺癌小鼠模型中。在三阴性乳腺癌中验证CX43高达较高的靶标，并使用JM2 Tosupr CX43-- 微管相互作用而不感染CX43表达，因此调节CX43定位和活动更多具体而言，该提案旨在填补知识的空白 CX43通过与微管相互作用在乳腺癌细胞中的作用，没有效率的靶向治疗方法目前存在可以成功烧毁三阴性癌细胞的转移潜力。