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：
10663790
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 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10663790
关键词：
Acceleration 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 Cell membrane Cells Cessation of life Characteristics Clinical Clinical Treatment Confocal Microscopy Core Biopsy Cytoskeleton Detection Distant ERBB2 gene Early Diagnosis Ensure Epothilones FDA approved Female Growth Health Hour Image Incidence Individual Institution Laboratories Legal patent Licensing Magnetic Resonance Imaging Malignant Neoplasms Mammospheres Maryland Measurement Measures Metastatic/Recurrent Methods Microfluidic Microchips Microfluidics 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 Population Positron-Emission Tomography Publishing Recurrence Recurrent Malignant Neoplasm Research Priority Residual state Risk Sampling Surface System Tail Technology Testing Time Study Tissues Translating Translations Transplantation Tubulin United States Universities Veins Veterans Woman Women&apos s Health automated image analysis cancer imaging cancer recurrence cancer risk cancer therapy cell growth chemotherapy clinical imaging clinically relevant confocal imaging drug testing effective therapy epithelial wound improved in vivo individual patient individual response individualized medicine malignant breast neoplasm microfluidic technology military veteran molecular marker molecular phenotype mouse model multidisciplinary neoplastic cell new technology novel optical imaging patient derived xenograft model phenotypic biomarker pressure prevent response response biomarker risk minimization stem cells taxane tissue culture treatment strategy tumor tumor growth wound healing

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性风险背景：临床癌症成像的当前局限针对细胞生长会影响循环肿瘤细胞（CTC）在乳腺癌中的转移潜力患者。当前的乳腺癌事件预测，有超过220万的女性退伍军人至少有275,000名女性退伍军人将面对乳腺癌治疗，并需要有效的治疗最小化致命转移性传播的风险。 CTC分析的最新进展表明乳腺癌CTC具有高达50倍的转移性潜力。马丁实验室发现了独特乳腺肿瘤细胞表面上增加簇形成的微动杆菌（MCTN），是指示性的促进乳腺癌转移的干细胞特征升高。目前的癌症疗法稳定小管蛋白（如紫杉烷和雌激素）可以增加MCTN，干细胞特征，肿瘤细胞聚类和保留。这些结果强调需要阐明当前药物如何影响自由浮动肿瘤细胞，使疗法可以更好地针对个别患者量身定制，并降低长期转移性风险。客观/假设：将肿瘤细胞生物学家，生物工程师组成的多学科团队组合在一起，和乳腺癌临床医生；该项目的目的是使用新型的微流体设备快速图像自由浮动的乳腺肿瘤细胞并定义3种可预测转移潜能的表型（MCTN，球体形成，聚类）和关键分子标记。这些表型和分子曲线将是与小鼠中临床上的PDX移植相关的转移性潜力和药物反应有关。这项研究将检验以下假设，即新鲜分离的乳腺肿瘤的关键功能表型和分子标记细胞可以作为转移潜力的直接指标，并提供一个快速测试的平台单个患者肿瘤细胞对癌症药物的反应。具体目的： 1）优化微流体细胞的束缚以测量转移电位的3个功能表型。 2）在患者衍生的Xenographic（PDX）细胞中建立用于肿瘤细胞药物反应的分子框架。 3）定义新鲜患者肿瘤细胞，PDX和CTC的共享分子和功能特征。方法：该项目将使用共聚焦显微镜检查3种表型（MCTN，球体形成，在乳腺肿瘤细胞系和一组现有患者衍生的Xenographictics（PDX）中的聚类）马里兰州格林鲍姆大学癌症中心的转化核心实验室。并行，我们将收集新鲜的患者肿瘤样品，以比较新鲜细胞中的分子标记和表型有时在小鼠中生长的PDX。 PDX概括了患者原始肿瘤的转移行为比任何组织培养模型更忠实。个体患者的表型和分子标记将肿瘤细胞与原始患者肿瘤的分子特征（ER/PR/HER2）进行比较，为以及PDX模型中的生长和转移。影响：该项目的完成将建立一个框架来定义如何功能患者肿瘤细胞的表型预测转移性潜力和对乳腺癌疗法的反应。当前的治疗策略主要集中在抑制肿瘤的生长上，因此该技术将早期开放新的帮助确保药物治疗的窗户避免在靶向肿瘤时无意间增加转移风险生长。由于该项目将重点放在FDA批准的乳腺癌药物上，因此发现更容易通过为个别女性退伍军人调整疗法来影响乳腺癌的临床治疗。