权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Rapid analysis of patient tumor cell drug responses to reduce metastatic risk

快速分析患者肿瘤细胞药物反应以降低转移风险

基本信息

批准号：
9563061
负责人：
STUART S MARTIN
金额：
--
依托单位：
BALTIMORE VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-10-01 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9563061
关键词：
Actins Affect Animals Antineoplastic Agents Area Behavior Biomedical Engineering Blood Circulation Blood Vessels Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Breast Cancer cell line Breast Cancer therapy Breast cancer metastasis Cancer Center Cells Cessation of life Characteristics Clinical Clinical Treatment Confocal Microscopy Core Biopsy Detection Distant ERBB2 gene Ensure Epithelial Epothilones FDA approved Female Growth Health Hour Image Incidence Individual Laboratories Legal patent Magnetic Resonance Imaging Malignant Neoplasms Mammospheres Maryland Measurement Measures Metastatic to Methods Microfluidic Microchips Microfluidics Microtubule Stabilization Microtubules Modeling Modification Molecular Molecular Profiling Mus National Cancer Institute Neoplasm Circulating Cells Neoplasm Metastasis Operative Surgical Procedures Patient Noncompliance Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Plasma Population Positron-Emission Tomography Publishing Recurrence Research Priority Residual state Risk Sampling Stem cells Surface Tail Technology Testing Time Study Tissues Translating Translations Transplantation Tubulin United States Universities Veins Veterans Woman Women&apos s Health Wound Healing Xenograft Model Xenograft procedure automated image analysis base cancer imaging cancer recurrence cancer risk cancer therapy cell growth chemotherapy clinical imaging clinically relevant confocal imaging drug testing effective therapy improved individual patient individual response individualized medicine malignant breast neoplasm molecular marker molecular phenotype mouse model multidisciplinary neoplastic cell new technology novel off-patent optical imaging phenotypic biomarker pressure prevent response response biomarker risk minimization taxane tissue culture treatment strategy tumor tumor growth wound

项目摘要

Rapid analysis of patient tumor cell drug responses to reduce metastatic risk Background: The current limitations of clinical cancer imaging prevent a clear understanding of how drugs aimed at cell growth affect the metastatic potential of circulating tumor cells (CTCs) in breast cancer patients. With more than 2.2 million female Veterans, the current incidence of breast cancer predicts that at least 275,000 female Veterans will confront breast cancer treatment and require effective treatments that minimize the risk of lethal metastatic spread. Recent advances in CTC analysis have shown that clusters of breast cancer CTCs have up to 50x higher metastatic potential. The Martin lab discovered unique microtentacles (McTNs) on the surface of breast tumor cells that increase cluster formation, and are indicative of the elevated stem cell characteristics that promote breast cancer metastasis. Current cancer therapies that stabilize tubulin (like taxanes and epothilones) can increase McTNs, stem cell characteristics, tumor cell clustering, and reattachment. These results emphasize the need to clarify how current drugs affect free-floating tumor cells so that therapies can be better tailored to individual patients and reduce long-term metastatic risk. Objective/Hypothesis: Bringing together a multidisciplinary team of tumor cell biologists, bioengineers, and breast cancer clinicians; the objective of this project is to use a novel microfluidic device to rapidly image free-floating breast tumor cells and define 3 phenotypes that are predictive of metastatic potential (McTNs, sphere formation, clustering) and key molecular markers. These phenotypes and molecular profiles will be related to metastatic potential and drug response using clinically-relevant PDX transplants in mice. This study will test the hypothesis that key functional phenotypes and molecular markers of freshly-isolated breast tumor cells can serve as immediate indicators of metastatic potential and provide a platform to rapidly test the responses of individual patient tumor cells to cancer drugs. Specific Aims: 1) Optimize microfluidic cell tethering to measure 3 functional phenotypes of metastatic potential. 2) Establish molecular framework for tumor cell drug responses in patient-derived xenograft (PDX) cells. 3) Define shared molecular and functional characteristics of fresh patient tumor cells, PDX and CTCs. Methods: This project will use confocal microscopy to examine 3 phenotypes (McTNs, sphere formation, and clustering) in breast tumor cell lines and a panel of existing patient-derived xenografts (PDX) supplied by the Translational Core Laboratory at the University of Maryland Greenebaum Cancer Center. In parallel, we will collect fresh patient tumor samples to compare molecular markers and phenotypes in the fresh cells with the PDX that eventually grow in mice. PDX recapitulate the metastatic behavior of the patient’s original tumor far more faithfully than any tissue culture model. Phenotypes and molecular markers of individual patient’s tumor cells will be compared to the molecular characteristics (ER/PR/HER2) of the original patient’s tumor, as well as growth and metastasis in the PDX model. Impact: The completion of this project will establish a framework for defining how the functional phenotypes of patient tumor cells predict metastatic potential and responses to breast cancer therapies. Current treatment strategies focus largely on inhibiting tumor growth, so this technology will open a new early window to help ensure drug treatments avoid inadvertently increasing metastatic risk while targeting tumor growth. Since this project will focus on FDA-approved breast cancer drugs, the findings can be more easily translated to impact the clinical treatment of breast cancer by tailoring therapies for individual female Veterans.

快速分析患者肿瘤细胞药物反应以降低转移风险