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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.

靶向微管稳定减少乳腺肿瘤转移。