Targeting microtubule stabilization to reduce breast tumor metastasis

靶向微管稳定以减少乳腺肿瘤转移

基本信息

批准号：
10437846
负责人：
STUART S MARTIN
金额：
$ 35.96万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-06 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10437846
关键词：
Acetylation Affect Animal Model Antineoplastic Agents Behavior Biomedical Engineering Blood Circulation Blood capillaries Breast Cancer Cell Breast Cancer Treatment CRISPR/Cas technology Cells Cessation of life Characteristics Chemicals Clinical Treatment Communities Confocal Microscopy Curcumin Data Disease Distant Drug Targeting Electron Microscopy Extracellular Matrix FDA approved Foundations Genetic Growth HDAC6 gene Histone Deacetylase Histone Deacetylase Inhibitor Hour Human Image In Vitro Invaded Ixabepilone Lung Lymphatic Mammary Neoplasms Mechanics Metastatic breast cancer Methods Microfluidics Microtubule Stabilization Microtubules Modification Molecular Mus Neoadjuvant Therapy Neoplasm Circulating Cells Neoplasm Metastasis Operative Surgical Procedures Organ Outcome Paclitaxel Patients Pharmaceutical Preparations Phenotype Post-Translational Protein Processing Prognosis Recurrence Risk Role Structure Surface System Testing Therapeutic Tissues Translating Treatment Efficacy Tubulin Xenograft procedure analog anticancer research base cancer therapy cell growth cell motility chemotherapy drug development drug discovery drug testing efficacy testing epithelial to mesenchymal transition improved in vivo innovation interest molecular marker mouse model neoplastic cell novel novel strategies novel therapeutics parthenolide patient derived xenograft model patient prognosis precision medicine pressure response side effect standard of care stem cells therapeutic evaluation therapeutic target treatment strategy tumor whole animal imaging

项目摘要

Targeting microtubule stabilization to reduce breast tumor metastasis. Breast tumor cells metastasize to distant organs through non-adherent microenvironments, such as the bloodstream or lymphatics. However, very little is known about the dynamic behavior and drug responses of non-adherent tumor cells, due to the challenges of imaging non-adherent cells without blurring from cell drift. The PI's lab discovered unique microtentacles (McTNs) on the surface of non-adherent tumor cells that promote the aggregation and retention of circulating tumor cells (CTCs) in the lung capillaries of living mice. This revised study will test the hypothesis that therapeutic targeting of 2 microtubule stabilization mechanisms (detyrosination, acetylation) can provide a novel strategy to suppress tumor metastasis and move beyond the current non-selective MT-targeting drugs that are aimed at tumor cell growth. Predictions of this hypothesis will be tested in the following specific aims with confocal and electron microscopy, whole-animal imaging of CTC metastasis and by testing drugs on patient tumor cells and CTCs. Specific Aim 1: Inhibit tubulin detyrosination to reduce McTNs, stem cell characteristics and metastasis. A) Alter tubulin detyrosination by targeting TTL or TCP and gauge effects on metastatic potential/EMT. B) Test efficacy of Curcumin and Parthenolide analog on EMT, stem cell characteristics and metastasis. C) Define whether microtubule-stabilizing therapies (Paclitaxel, Ixabepilone) promote metastatic potential. Specific Aim 2: Determine the effects of altering tubulin acetylation on metastatic phenotypes. A) Genetically alter tubulin acetylation (ATAT1, K40R, HDAC6) and gauge effects on metastasis in mice. B) Analyze tumor cell mechanics and McTN structure in cells with altered tubulin acetylation. C) Examine whether elevation of tubulin acetylation by HDAC inhibition increases metastatic potential. Specific Aim 3: Target microtubule stabilization mechanisms in live CTCs from mice and human patients. A) Test 2 prioritized drugs on xenografts, PDX and live patient CTCs to reduce McTNs and CTC clusters. B) Compare CTC metastasis with MT-stabilizing and MT-disrupting agents in isolation and combination. An innovative microfluidic cell tethering system will be used to rapidly determine drug responses in live patient CTCs in less than one hour. Inclusion of numerous FDA-approved therapies will increase the potential to rapidly translate the outcomes of this project to impact the clinical treatment of metastatic breast cancer.

靶向微管稳定以减少乳腺肿瘤转移。乳腺肿瘤细胞通过非粘附的微环境转移至远处的器官，例如血液或淋巴管。但是，关于动态行为和药物反应知之甚少非粘附肿瘤细胞，由于成像非粘附细胞而不会因细胞漂移而模糊的挑战。 PI的实验室在非粘附肿瘤细胞表面上发现了独特的微动杆菌（MCTN）促进活小鼠肺毛细血管中循环肿瘤细胞（CTC）的聚集和保留。这项修订的研究将检验以下假设：2微管的治疗靶向机制（驱散，乙酰化）可以提供抑制肿瘤转移的新型策略并超越针对肿瘤细胞生长的当前非选择性MT靶向药物。该假设的预测将在以下特定目的与共焦点和电子中进行测试显微镜，CTC转移的全动物成像，并通过对患者肿瘤细胞和CTC进行测试。具体目标1：抑制微管蛋白驱虫症可减少MCTN，干细胞特征和转移。 a）通过靶向TTL或TCP以及对转移电位/EMT的影响来改变微管蛋白驱虫。 b）姜黄素和parthenolide类似物对EMT，干细胞特征和转移的测试功效。 c）定义微管稳定疗法（紫杉醇，ixabepilone）是否促进转移潜力。具体目标2：确定改变微管蛋白乙酰化对转移表型的影响。 a）遗传改变微管蛋白乙酰化（ATAT1，K40R，HDAC6），并对小鼠转移的量表作用。 b）分析微管蛋白乙酰化改变细胞中的肿瘤细胞力学和MCTN结构。 c）检查通过HDAC抑制作用升高小管蛋白乙酰化是否会增加转移性潜力。特定目标3：来自小鼠和人类患者的活CTC中的靶向微管稳定机制。 a）测试2对异种移植物，PDX和活着的患者CTC进行测试，以减少MCTN和CTC簇。 b）将CTC转移与MT稳定和MT干扰剂进行隔离和组合进行比较。创新的微流体细胞绑扎系统将用于快速确定活着的患者的药物反应 CTC不到一小时。包括大量FDA批准的疗法将增加潜力迅速转化了该项目的结果，以影响转移性乳腺癌的临床治疗。