Targeting MUC5AC mucin in breast cancer brain metastasis

乳腺癌脑转移中靶向 MUC5AC 粘蛋白

基本信息

批准号：
10334526
负责人：
Mohd Wasim Nasser
金额：
$ 45.15万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10334526
关键词：
Address American Archives Astrocytes Attenuated Bioinformatics Biological Models Blood - brain barrier anatomy Brain Breast Cancer Cell Breast Cancer Patient Breast cancer metastasis CD44 gene Cancer Etiology Case Study Cell Adhesion Cell Line Cells Cisplatin Development Diagnosis Diagnostic Distant ERBB2 gene Early Diagnosis Early identification Epidermal Growth Factor Receptor Epigenetic Process Evaluation FDA approved Failure Gel Genetic Genetic Engineering Growth HGF gene Hyaluronic Acid In Vitro Lead Ligands MUC5AC gene Malignant Neoplasms Malignant neoplasm of brain Mediating Metastatic Neoplasm to the Central Nervous System Metastatic breast cancer Metastatic malignant neoplasm to brain Microglia Molecular Mucins Neuraxis Organ Pathway interactions Patient-derived xenograft models of breast cancer Patients Pharmaceutical Preparations Polymers Pre-Clinical Model Predictive Factor Prevention strategy Preventive Primary Neoplasm Process Proteins Regulation Relapse Role Serum Signal Transduction Survival Rate Therapeutic Therapeutic Effect Tissues Woman base blood-brain barrier permeabilization brain tissue cancer cell cancer subtypes cell motility cohort design early detection biomarkers high risk in silico in vivo Model inhibitor knock-down malignant breast neoplasm mortality mouse model novel novel therapeutic intervention patient derived xenograft model phase 1 testing pre-clinical predictive marker receptor targeted treatment therapeutic target transcriptome sequencing transcriptomics treatment response triple-negative invasive breast carcinoma

项目摘要

Abstract Breast cancer (BC) brain/central nervous system (CNS) metastasis is associated with poor survival among U.S. women, with 30-40% of these cases reported as triple receptor-negative (TN) and epidermal growth factor receptor-positive (ErbB2+) BC subtypes. Despite the progress in the diagnostic and therapeutic management of BC, there is still a significant increase in brain metastasis (BM) cases, and the survival rate among these BCBM patients is very bleak. Therefore, there is an urgent need to identify primary molecular drivers of BCBM and novel predictive biomarker(s) for the early detection of BM. In this regard, our global transcriptomic analysis showed that levels of a secretory gel-forming mucin, MUC5AC, is significantly higher in the brain tropic (BT) cells than the parental BC cells. Additionally, an in silico analysis revealed significantly higher levels of MUC5AC in the archived BCBM tissues compared to the primary tumors. Most importantly, the augmented levels of MUC5AC were detected in the serum of BCBM patients compared to non-BM BC patients. These studies strongly suggest that MUC5AC could be a potential predictive biomarker for the early detection of BCBM. Furthermore, MUC5AC knockdown (KD) resulted in reduced motility, cell adhesion, and blood-brain barrier (BBB) transmigration in BT cell lines relative to controls. Importantly, MUC5AC KD cells showed diminished BM potential in an intracardiac mouse model. Our initial mechanistic studies on the MUC5AC-mediated BM showed an important role of the CD44 and cMET pathways in BT cells. MUC5AC interacted with CD44v6, a co-receptor for cMET, and co- localized with the activated form of cMET to establish BCBM. CD44v6 and cMET have been shown to preferentially enhance BM through a feed-forward loop using hyaluronic acid and hepatocyte growth factor pathways. We also observed robust expression of MUC5AC in BT cells in the presence of microglia/astrocyte conditioned media. Targeting MUC5AC with PLB-1001 reduces MUC5AC expression in BT cells. We hypothesize that “MUC5AC enhances BCBM through CD44v6/cMET-axis” and could thus be a useful marker to predict BCBM. In Aim 1, we will establish MUC5AC as a novel predictive biomarker for BM in high-risk BC patients, and examine whether high MUC5AC expression in primary tumors predicts BM, and correlates with response to therapy, overall survival, and relapse. Aim 2 studies will define the regulation of MUC5AC-mediated BM through the cMET/CD44v6/NF-κB-axis using preclinical mouse models. In Aim 3, we will use a BBB penetrable phase 1 tested cMET inhibitor alone or in combination with cisplatin or neratinib as novel therapeutic strategy for TN and ErbB2+ brain metastatic BC. Altogether, the proposed studies will establish MUC5AC as a novel predictive biomarker for high-risk BM and will help in developing preventive strategies for BCBM, which currently has no cure.

抽象的乳腺癌（BC）脑/中枢神经系统（CNS）转移与美国生存不良有关妇女，其中30-40％的病例报告为三重受体阴性（TN）和表皮生长因子受体阳性（ERBB2+）BC亚型。尽管在诊断和治疗管理方面取得了进展 BC，脑转移（BM）病例仍然显着增加，这些BCBM的存活率仍有显着增加病人非常黯淡。因此，迫切需要识别BCBM的主要分子驱动因素和用于早期检测BM的新型预测生物标志物。在这方面，我们的全球转录组分析表明，脑热带（BT）细胞中秘密凝胶粘蛋白Muc5ac的水平显着更高比父母BC细胞。此外，一硅分析显示，MUC5AC水平明显更高与原发性肿瘤相比，存档的BCBM组织。最重要的是，MUC5AC的增强水平与非BM BC患者相比，在BCBM患者的血清中检测到它们。这些研究强烈建议该MUC5AC可能是早期检测BCBM的潜在预测生物标志物。此外，MUC5AC 敲低（KD）导致BT中的运动能力，细胞粘合剂和血脑屏障（BBB）传播降低细胞系相对于对照。重要的是，MUC5AC KD细胞在心脏内显示BM潜力降低鼠标模型。我们对MUC5AC介导的BM的最初机械研究表明 BT细胞中的CD44和CMET途径。 MUC5AC与CD44V6相互作用，CD44V6是CMET的共受体，并且用激活形式的CMET定位以建立BCBM。 CD44V6和CMET已显示为优先使用透明质酸和肝细胞生长因子通过馈送前回路增强BM 途径。我们还观察到在小胶质细胞/星形胶质细胞存在下，MUC5AC在BT细胞中的稳健表达条件媒体。用PLB-1001靶向MUC5AC可降低BT细胞中的MUC5AC表达。我们假设“ MUC5AC通过CD44V6/CMET轴增强BCBM”，因此可以是有用的标记预测BCBM。在AIM 1中，我们将建立MUC5AC作为BM中BM的新型预测生物标志物患者，检查原发性肿瘤中高的MUC5AC是否预测BM，并与对治疗，整体生存和救济的反应。 AIM 2研究将定义MUC5AC介导的调节 BM使用临床前小鼠模型通过CMET/CD44V6/NF-κB轴。在AIM 3中，我们将使用BBB 可穿透的1期测试CMET抑制剂或与顺铂或Neratinib结合作为新疗法 TN和ERBB2+脑转移性BC的策略。总共提出的研究将建立MUC5AC作为一个高风险BM的新型预测生物标志物，将有助于制定BCBM的预防策略，该策略目前无法治愈。