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) 转移与美国患者生存率低相关女性，其中 30-40% 的病例报告为三重受体阴性 (TN) 和表皮生长因子尽管在诊断和治疗管理方面取得了进展，但受体阳性（ErbB2+）BC亚型。 BC，脑转移（BM）病例仍然显着增加，并且这些BCBM的生存率因此，迫切需要确定 BCBM 和 BCBM 的主要分子驱动因素。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。结果表明，脑热带 (BT) 细胞中分泌性凝胶形成粘蛋白 MUC5AC 的水平显着升高此外，计算机分析显示 MUC5AC 水平显着更高。与原发性肿瘤相比，存档的 BCBM 组织的 MUC5AC 水平有所增加。与非 BM BC 患者相比，这些研究强烈表明，在 BCBM 患者的血清中检测到。 MUC5AC 可能是早期检测 BCBM 的潜在预测生物标志物。敲低 (KD) 导致 BT 中运动性、细胞粘附性和血脑屏障 (BBB) 迁移减少重要的是，与对照细胞系相比，MUC5AC KD 细胞在心内表现出 BM 潜力减弱。我们对 MUC5AC 介导的 BM 的初步机制研究显示了 MUC5AC 的重要作用。 BT 细胞中的 CD44 和 cMET 通路与 cMET 的共同受体 CD44v6 相互作用。已证明用激活形式的 cMET 进行定位以建立 BCBM 和 cMET。使用透明质酸和肝细胞生长因子通过前馈循环优先增强 BM 我们还在小胶质细胞/星形胶质细胞存在的情况下观察到 MUC5AC 在 BT 细胞中的强烈表达。使用 PLB-1001 靶向 MUC5AC 可以降低 BT 细胞中的 MUC5AC 表达。认为“MUC5AC 通过 CD44v6/cMET 轴增强 BCBM”，因此可能是一个有用的标记在目标 1 中，我们将建立 MUC5AC 作为高风险 BC 中 BM 的新型预测生物标志物。患者，并检查原发性肿瘤中的高 MUC5AC 表达是否可以预测 BM，并与 Aim 2 研究将确定 MUC5AC 介导的调节作用。使用临床前小鼠模型通过 cMET/CD44v6/NF-κB 轴进行 BM 在目标 3 中，我们将使用 BBB。可渗透的 1 期测试 cMET 抑制剂单独或与顺铂或来那替尼联合作为新型治疗剂总而言之，拟议的研究将把 MUC5AC 确立为 TN 和 ErbB2+ 脑转移性 BC 的策略。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，目前尚无治愈方法。