Label free microfluidic isolation, characterization and ex vivo expansion of CTCs
CTC 的无标记微流体分离、表征和离体扩增
基本信息
- 批准号:9310696
- 负责人:
- 金额:$ 55.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-03-03 至 2022-02-28
- 项目状态:已结题
- 来源:
- 关键词:AftercareAlpha CellAntibodiesAntigensBenignBiologicalBiological AssayBiological MarkersBiologyBiopsyBloodBlood CellsBlood CirculationBlood specimenCancer PatientCategoriesCell CountCell SeparationCell SurvivalCellsClinical OncologyCoculture TechniquesDetectionDevelopmentDevicesDiagnosisDiseaseDrug usageEnsureEpithelialEquilibriumFeasibility StudiesFutureGenomicsGeometryGoalsHeterogeneityImmunofluorescence ImmunologicInstitutesLabelLabyrinthLeadLeukocytesMalignant NeoplasmsMalignant neoplasm of pancreasMeasuresMesenchymalMethodsMicrofluidic MicrochipsMicrofluidicsMolecular ProfilingNeoplasm Circulating CellsNeoplasm MetastasisOperative Surgical ProceduresPancreasPancreatic Ductal AdenocarcinomaPancreatitisPatient-Focused OutcomesPatientsPerformancePharmacodynamicsPhenotypePilot ProjectsPopulationPrimary NeoplasmProliferatingRNARadiology SpecialtyRecoveryRecurrenceResectableResistanceRestSamplingSolid NeoplasmStaining methodStainsSurfaceSurvival RateTACSTD1 geneTechnologyTestingTherapeutic UsesTimeTissuesTranscriptWhole BloodWorkbasecancer cellcancer diagnosiscancer typeclinical applicationclinically significantcohortdrug sensitivitydrug testingearly detection biomarkersgenetic signaturehydrodynamic flowimprovedimproved outcomemolecular subtypesneoplastic cellnew technologynovelperipheral bloodpersonalized medicinepersonalized therapeuticpharmacodynamic biomarkerpredictive toolsprotein expressionpublic health relevanceresponsestemtargeted biomarkertargeted treatmenttherapeutic targettooltreatment strategytumor
项目摘要
Project Summary/Abstract
To date, pancreatic cancer, beyond most other cancers has been categorically associated with the term
“lethal”. This association stems from the fact that pancreatic cancer has a median survival rate of less than 6
months after diagnosis, and a bleak 5-year survival rate of 3-5 percent. The most prevalent form of pancreatic
cancer, pancreatic ductal adenocarcinoma (PDAC), demonstrates a particularly aggressive biology with
resistance to both conventional and targeted therapeutics, so that by the time a patient receives the diagnosis,
the disease has already advanced to an incurable state. Furthermore, significant challenges exist in obtaining
tissue from pancreatic cancer patients, making it difficult to study tumors and their pharmacodynamic
responses during treatment. These facts highlight the unmet challenge of identifying the lethal cells that survive
and thrive even after treatment and are predisposed to recur. Ascertaining the mechanisms that drive the
disease and its recurrence can spur the development of new treatment strategies to improve outcomes for
these patients. One avenue that could lead to accurate predictive tools, therapeutic targets, and
pharmacodynamic biomarker information comes from the analysis of circulating tumor cells (CTCs). For over
two decades, studies have shown that tumor cells from primary solid tumors can be detected in the circulation.
These CTCs may be precursors to systemic metastases. The detection of CTCs in peripheral blood has been
recognized as a potential tool in the diagnosis of cancer and cell metastasis. Furthermore, the relative number
of CTCs in the blood appears to be an independent predictor of progression in several types of cancer.
However, before instituting CTCs as a reliable biomarker, one must answer fundamental questions regarding
their biological and clinical significance. Are all CTCs capable of proliferation, invasion, and metastasis? Are
there subpopulations of CTCs that are more aggressive than the rest? If so, do these aggressive CTCs carry
specific driver signature and how it is different or similar to primary tumor? Are these cells persistent through
therapy and capable of proliferation? Answers to these questions can reveal the earliest cells with metastasis-
initiating capability, providing a therapeutic target. Hence, to establish clinical applications of CTCs for
personalized therapy in pancreatic and other cancers, there is a compelling need for sensitive, accurate
approaches to distinguish metastasis-initiating driver CTCs from essentially “passenger” CTCs. We will
accomplish this goal through a sophisticated biomarker independent microfluidic platform “labyrinth” that not
only enables highly sensitive isolation of CTCs but also provides the novel capability to culture and expand the
low numbers of isolated CTCs. Most of the CTC isolation technologies depend on the known surface markers
and suffer from low throughput. Moreover, the presence of multiple sub-populations of CTCs (including those
of an EMT phenotype) with different metastatic potential requires a method for separating these cells from
blood that does not depend on specific antibodies such as EpCAM. In this proposal, we will develop, test and
optimize the efficacy of a novel antigen-independent microfluidic platform (the labyrinth) in the isolation,
characterization, ex vivo expansion and therapeutic targets testing of pancreatic cancer CTCs. Labyrinth takes
advantage of inertial forces in curved geometries to differentially focus cells based on their size to isolate CTCs
from whole blood at a high throughput of 2.5mL/min (150mL/hr) in a single step without any aid of a biomarker.
The multiple turns (more than 50) ensure focusing of even the smaller cells while traversing through the
device, and hence achieve a remarkable separation between WBCs and CTCs resulting in high purity. The
unique ability to isolate CTCs in a label free manner at a high throughput, with greater sensitivity and reliably
expand few numbers of CTCs opens exciting, new opportunities for biologic, genomic, and functional analyses
of CTCs, which we expect will change the paradigm for use of CTCs in clinical oncology.
项目总结/摘要
到目前为止,胰腺癌,超过大多数其他癌症已明确与术语
“致命”这种关联源于胰腺癌的中位生存率低于6
诊断后数月,5年生存率为3- 5%。胰腺炎最常见的形式
胰腺导管腺癌(PDAC)是一种特别具有侵袭性的生物学,
对常规疗法和靶向疗法的抗性,因此当患者接受诊断时,
病情已发展到不治之症。此外,在获得
这使得研究肿瘤及其药效学变得困难,
治疗期间的反应。这些事实突出了识别存活的致命细胞的挑战
即使在治疗后也会茁壮成长,并且容易复发。确定驱动
疾病及其复发可以刺激新的治疗策略的发展,以改善预后,
这些病人。一种可能导致准确的预测工具,治疗目标,
药效学生物标志物信息来自循环肿瘤细胞(CTC)的分析。超过
二十年来,研究表明,原发性实体瘤的肿瘤细胞可以在循环中检测到。
这些CTC可能是全身转移的前体。外周血中CTC的检测已被广泛应用于临床。
被认为是诊断癌症和细胞转移的潜在工具。此外,相对数
血液中CTC的浓度似乎是几种类型癌症进展的独立预测因子。
然而,在将CTC作为可靠的生物标志物之前,必须回答以下基本问题:
其生物学和临床意义。所有的CTC都能增殖、侵袭和转移吗?是
CTC的亚群比其他的更具攻击性吗如果是这样,这些攻击性CTC是否携带
特定的驱动签名以及它与原发性肿瘤的不同或相似之处?这些细胞是否持续存在于
治疗和增殖能力?这些问题的答案可以揭示最早发生转移的细胞-
启动能力,提供治疗目标。因此,为了建立CTC的临床应用,
在胰腺癌和其他癌症的个性化治疗中,迫切需要灵敏、准确、
区分转移起始的驱动CTC与基本上“乘客”CTC的方法。我们将
通过复杂的生物标志物独立的微流体平台“迷宫”来实现这一目标,
不仅能够高度敏感地分离CTC,而且还提供了培养和扩增CTC的新能力。
分离的CTC数量少。大多数CTC分离技术依赖于已知的表面标记物
并且遭受低吞吐量。此外,CTC的多个亚群(包括那些
具有不同转移潜能的EMT表型的细胞)需要一种将这些细胞从
不依赖于EpCAM等特定抗体的血液。在本提案中,我们将开发、测试和
优化新型抗原非依赖性微流体平台(迷宫)在分离中的功效,
胰腺癌CTC的特征、离体扩增和治疗靶标测试。拉巴斯
弯曲几何形状中的惯性力的优势,以基于细胞的尺寸差异地聚焦细胞,从而分离CTC
以2.5mL/min(150 mL/hr)的高通量在单个步骤中从全血中分离,而无需任何生物标志物的帮助。
多圈(超过50圈)确保即使是较小的细胞在穿过
设备,并因此实现WBC和CTC之间的显著分离,从而产生高纯度。的
以高通量、无标记方式分离CTC的独特能力,具有更高的灵敏度和可靠性
扩增少数CTC为生物学、基因组学和功能分析带来了令人兴奋的新机会
我们预计这将改变CTC在临床肿瘤学中使用的范式。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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Sunitha Nagrath其他文献
Sunitha Nagrath的其他文献
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{{ truncateString('Sunitha Nagrath', 18)}}的其他基金
Engineering sensitive microfluidic multiplex technology for isolating circulating
用于隔离循环的工程敏感微流体多重技术
- 批准号:
7852275 - 财政年份:2009
- 资助金额:
$ 55.45万 - 项目类别:
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