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High-flow microfluidics of leukapheresis blood products for functional analysis of breast circulating tumor cells

白细胞分离血液制品的高流量微流体用于乳腺循环肿瘤细胞的功能分析

基本信息

批准号：
10327299
负责人：
Daniel A. Haber
金额：
$ 63.19万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-08 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10327299
关键词：
Active Sites Antibodies Antibody-drug conjugates Biological Biomedical Engineering Biopsy Blood Blood Cells Blood Circulation Blood Platelets Blood Screening Blood Volume Breast Breast Cancer Patient Breast Cancer therapy Cancer Patient Cell Count Cell Culture Techniques Cell Separation Cell surface Cells Clinical Complex DNA DNA Sequence Alteration Drug resistance Epitopes Excision Generations Genetic Goals Hematopoietic stem cells Hour Hypoxia Immunologics Immunotoxins Lesion Leukapheresis Leukocytes Magnetism Malignant Neoplasms Measures Metastatic breast cancer Microfluidic Microchips Microfluidics Molecular Monitor Mus Mutation Mutation Analysis Needles Neoplasm Circulating Cells Neoplasm Metastasis PD-1/PD-L1 Patient Selection Patients Performance Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Plasma Population Population Heterogeneity Primary Neoplasm Procedures Process Prognosis Property Reporting Resistance Sampling Sampling Biases Selection for Treatments Solid Neoplasm Sorting - Cell Movement Stream TACSTD1 gene Technology Therapeutic Therapeutic Intervention Time Tumor Antigens Tumor Burden Tumor Markers Tumor-Derived Whole Blood Woman antibody conjugate base blood product cancer care cancer cell cancer invasiveness cancer therapy checkpoint therapy clinical application design drug development drug sensitivity drug testing high throughput technology immunosuppressed individual patient individualized medicine insight liquid biopsy magnetic beads microfluidic technology molecular subtypes multidisciplinary neoplastic cell novel novel therapeutics patient subsets personalized cancer care pre-clinical precision oncology predictive marker response small molecule inhibitor stem-like cell success targeted treatment therapeutic target tool triple-negative invasive breast carcinoma tumor tumorigenic

项目摘要

Liquid biopsies are poised to revolutionize cancer therapies, by enabling frequent blood-based monitoring of tumor-derived materials, as cancers evolve in response to therapeutic interventions. Nowhere is this more evident than in triple negative metastatic breast cancer, where women may undergo multiple serial courses of therapy over many years, each associated with an initial response, followed by the acquisition of drug resistance. Plasma DNA (ctDNA) mutation analyses provide a measure of tumor burden and may identify targetable mutations for small molecule inhibitors, but they do not allow ex vivo culture of intact circulating tumor cells (CTCs) for individualized preclinical drug sensitivity (“precision oncology”). Isolation of CTCs has been achieved using small blood volumes (5-10 mL), but these cells are so rare that it has not been feasible to establish clinically robust ex vivo CTC cultures. Our hypothesis is that we can massively increase the amount of blood screened through standard clinical leukapheresis (1-2 L), and in return, achieve 100+-fold increase in the number of isolated CTCs to establish routine ex vivo culture of CTCs. It is also important to note that ex vivo CTC cultures obtained by sampling 1-2 L blood will reflect the “real time” molecular subtype, genetic composition, and evolving drug sensitivity profile of an individual patient's metastatic breast cancer, including multiple lesions that together contribute to the blood-borne CTC population and the patient's overall tumor burden. We will develop a high-throughput microfluidic technology that achieves highly efficient depletion of tagged blood cells away from unmanipulated single and clustered CTCs and provides “tumor independent enrichment” performance, which is applicable to cells disseminated from any solid tumor type without making any a priori assumption on the physical and/or biological properties of tumor cells. We will also establish the microenvironmental conditions conducive to high efficiency ex vivo CTC cultures from women with metastatic triple negative breast cancer. Success would be transformative both for new drug development and for individualized patient selection among existing therapies for breast cancer patients, and others.

液体活检有望彻底改变癌症治疗，通过频繁的血液监测，肿瘤源性材料，因为癌症响应于治疗干预而演变。没有比这更比三阴性转移性乳腺癌更明显，其中女性可能经历多个连续疗程，多年的治疗，每次治疗都与最初的反应有关，然后是药物的获得阻力血浆DNA（ctDNA）突变分析提供了肿瘤负荷的量度，并且可以鉴定小分子抑制剂的靶向突变，但它们不允许完整循环的离体培养。肿瘤细胞（CTC）的个体化临床前药物敏感性（“精确肿瘤学”）。CTC的分离具有使用少量血液（5-10 mL）实现，但这些细胞非常罕见，建立临床上稳健的离体CTC培养物。我们的假设是，我们可以大规模增加通过标准临床白细胞分离术（1-2 L）筛选的血液，作为回报，确定分离的CTC的数量以建立CTC的常规离体培养。同样重要的是要注意，通过采集1-2 L血液获得的CTC培养物将反映“真实的时间”分子亚型、遗传本发明涉及个体患者的转移性乳腺癌的药物敏感性特征，包括共同导致血源性CTC人群和患者总体肿瘤的多种病变负担我们将开发一种高通量的微流体技术，实现高效的消耗，标记的血细胞远离未操作的单个和成簇的CTC，并提供“肿瘤独立性”的细胞毒性。本发明提供了一种“富集”性能，其适用于从任何实体瘤类型播散的细胞，而不使细胞增殖。对肿瘤细胞的物理和/或生物学性质的任何先验假设。我们亦会设立微环境条件有利于来自转移性乳腺癌女性的高效离体CTC培养物三阴性乳腺癌成功将是变革性的，无论是新药开发，在乳腺癌患者的现有疗法中进行个体化患者选择等。