Targeting MUC5AC mucin in breast cancer brain metastasis

乳腺癌脑转移中靶向 MUC5AC 粘蛋白

• 批准号: 10553705
• 负责人: Mohd Wasim Nasser
• 金额: $ 45.21万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 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/10553705
• 关键词: Address; American; Archives; Astrocytes; Attenuated; Bioinformatics; Biological Models; Blood - brain barrier anatomy; Brain; Breast Cancer Cell; Breast Cancer Early Detection; Breast Cancer Patient; Breast Cancer Risk Factor; Breast cancer metastasis; CD44 gene; Cancer Etiology; Case Study; Cell Adhesion; Cell Line; Cells; Central Nervous System; 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; 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; 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; blood-brain barrier crossing; blood-brain barrier permeabilization; brain tissue; cancer cell; cancer subtypes; cell motility; cohort; design; high risk; improved; in silico; in vivo Model; inhibitor; knock-down; malignant breast neoplasm; migration; 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

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.

摘要