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

• 批准号: 10045933
• 负责人: STUART S MARTIN
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 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/10045933
• 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; 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; Surface; Tail; Technology; Testing; Time Study; Tissues; Translating; Translations; Transplantation; Tubulin; United States; Universities; Veins; Veterans; Woman; Women' s Health; 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; epithelial wound; improved; individual patient; individual response; individualized medicine; malignant breast neoplasm; 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

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 背景：目前临床癌症成像的局限性阻碍了我们清楚地了解药物如何 旨在影响乳腺癌循环肿瘤细胞（CTC）的细胞生长的转移潜力 有超过 220 万女性退伍军人，目前乳腺癌的发病率预计将达到 至少 275,000 名女性退伍军人将面临乳腺癌治疗，并需要有效的治疗 最大限度地减少致命转移扩散的风险 CTC 分析的最新进展表明，集群 马丁实验室发现乳腺癌 CTC 的转移潜力高达 50 倍。 乳腺肿瘤细胞表面的微触手（McTN）可增加簇的形成，并且具有指示性 促进乳腺癌转移的干细胞特性的提高。 微管蛋白（如紫杉烷和上噻酮）可以增加 McTN、干细胞特征、肿瘤细胞 这些结果强调需要澄清当前药物如何影响自由漂浮。 肿瘤细胞，以便更好地针对个体患者制定治疗方案并降低长期转移风险。 目标/假设：汇集肿瘤细胞生物学家、生物工程师、 乳腺癌人群；该项目的目标是使用新型微流体装置快速成像 自由漂浮的乳腺肿瘤细胞并定义了 3 种可预测转移潜力的表型（McTN、 球体形成、聚类）和关键分子标记将是这些表型和分子谱。 这项研究使用临床相关的 PDX 移植来研究小鼠的转移潜力和药物反应。 将检验新分离的乳腺肿瘤的关键功能表型和分子标记的假设 细胞可以作为转移潜力的直接指标，并提供一个快速测试转移能力的平台。 个体患者肿瘤细胞对抗癌药物的反应。 具体目标： 1) 优化微流体细胞束缚以测量转移潜力的 3 种功能表型。 2) 建立患者来源的异种移植（PDX）细胞中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 的共同分子和功能特征。 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、 和聚类）在乳腺肿瘤细胞系和一组现有的患者来源的异种移植物（PDX）中提供 马里兰大学格林鲍姆癌症中心的转化核心实验室同时，我们。 将收集新鲜的患者肿瘤样本，以将新鲜细胞中的分子标记和表型与 最终在小鼠体内生长的 PDX 再现了患者原始肿瘤的转移行为。 比个体患者的任何组织培养模型更忠实。 肿瘤细胞将与原始患者肿瘤的分子特征（ER/PR/HER2）进行比较，如 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，用于定义功能如何 患者肿瘤细胞的表型预测转移潜力和对乳腺癌治疗的反应。 目前的治疗策略主要集中在抑制肿瘤生长，因此这项技术将开启新的早期治疗途径 帮助确保药物治疗在靶向肿瘤的同时避免无意中增加转移风险的窗口 由于该项目将重点关注 FDA 批准的乳腺癌药物，因此研究结果会更容易。 通过为个别女性退伍军人量身定制治疗方法，转化为影响乳腺癌的临床治疗。