Microfluidic Device to Profile Chemosensitivity in Glioma Slice Cultures

用于分析神经胶质瘤切片培养物化学敏感性的微流体装置

• 批准号: 9340082
• 负责人: ALBERT FOLCH
• 金额: $ 53.21万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9340082
• 关键词: Address; Adult; Algorithms; Anatomy; Animals; Antineoplastic Agents; Biological Assay; Brain; Brain Neoplasms; Cancer Biology; Cancer Intervention; Cell Culture Techniques; Cell Death; Cell Line; Cell Survival; Clinical Trials; Complement; Cultured Tumor Cells; Data; Decision Making; Development; Devices; Diagnosis; Drug Combinations; Drug Delivery Systems; Effectiveness; Environment; Fluorescent Dyes; Generations; Generic Drugs; Genetically Engineered Mouse; Genomic approach; Glioblastoma; Glioma; Goals; Growth; Heterogeneity; Human; Immune; Implant; Individual; Investigation; Lead; Liquid substance; Location; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Methods; Microfluidic Microchips; Microfluidics; Modeling; Molecular; Morphology; Mus; Outcome; Patients; Performance; Perfusion; Pharmaceutical Preparations; Phase; Phenotype; Preclinical Drug Evaluation; Primary Brain Neoplasms; Primary Neoplasm; Refractory; Regimen; Research; Sampling; Series; Slice; Specimen; Standardization; Stem cells; System; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Tumor-Derived; Validation; Variant; Work; Xenograft Model; Xenograft procedure; base; cancer prevention; cancer therapy; clinically relevant; combinatorial; comparative; cost effective; design; dosage; drug efficacy; drug sensitivity; drug testing; genomic profiles; imaging biomarker; improved; in vivo; individual patient; innovation; mouse model; neoplastic cell; novel; novel therapeutics; performance tests; pre-clinical; profiles in patients; prototype; public health relevance; quantitative imaging; response; screening; spatiotemporal; targeted cancer therapy; therapy resistant; tool; treatment response; tumor; tumor growth; tumor microenvironment; tumor xenograft

DESCRIPTION: Goal: We propose to develop a therapeutic screening platform that rapidly determines the response of intact human tumor samples to many potential therapies in parallel. The aim is to identify the subset of therapies of greatest potential value to individual patients, n a timescale rapid enough to guide therapeutic decision- making. Innovation: We have developed a microfluidic perfusion system that maintains intact primary tumor slice tissue in culture and enables the arrayed delivery of large numbers of different drugs, drug combinations or drug regimens to anatomically-defined regions of the tumor. Our system improves upon existing models for screening chemotherapeutic drug activity (e.g. tumor cells in culture, mouse xenografts, or genetically engineered mouse models): it uses intact tumor samples that retain the human tumor microenvironment and allows the generation of response data in a time frame that can guide decision-making for the initial phases of therapy. Focus/Aims: Our proposed research focuses on human brain tumors, specifically the malignant gliomas that comprise the majority (70%) of primary adult brain tumors. These include Grade III malignant gliomas and the more common Grade IV glioblastoma multiforme (GBM). Patients diagnosed with GBM have a median survival of ~1 year and an overall 5-year survival of <5 %, despite decades of effort to improve treated outcomes. In this proposal we argue that an important way to make progress in treating these lethal, refractory tumors is to develop a way to rapidly test many potential therapeutic agents or regimens in parallel on intact GBM specimens from individual patients. Tumor response to drugs will be measured by imaging of markers for cell death and for cell viability. As individual tumor samples are often heterogeneous, it is critical that our microfluidi system enables multiplexed drug testing across different regions of the sample. Positive drug responses should be consistent and specific across the tumor. The multiplexed platform will also enable investigation of specific drug combinations and dosages that might be therapeutically useful. Impact: This work addresses the urgent need to develop approaches and devices to rapidly and reliably assess the response of often heterogeneous, intact primary tumor specimens to a range of possible therapies, with the goal of identifying the most effective subset of therapies for individual tumors and patients.

目标：我们建议开发一个治疗筛选平台，快速确定完整的人类肿瘤样本对许多潜在疗法的反应。目的是在足够快的时间尺度内确定对个体患者最有潜在价值的治疗子集，以指导治疗决策。创新：我们开发了一种微流控灌注系统，可以在培养中保持原发肿瘤切片组织的完整，并能够将大量不同的药物、药物组合或药物方案排列递送到肿瘤的解剖定义区域。我们的系统改进了现有的化疗药物活性筛选模型（例如，培养的肿瘤细胞、小鼠异种移植或基因工程小鼠模型）：它使用保留人类肿瘤微环境的完整肿瘤样本，并允许在一定时间内生成反应数据，从而指导治疗初始阶段的决策。重点/目的：我们拟研究的重点是人类脑肿瘤，特别是恶性胶质瘤，占成人原发性脑肿瘤的大多数（70%）。包括III级恶性胶质瘤和更常见的IV级多形性胶质母细胞瘤（GBM）。尽管几十年来一直在努力改善治疗效果，但确诊为GBM的患者的中位生存期为1年，总体5年生存率< 5%。在这个提议中，我们认为在治疗这些致命的、难治性的肿瘤方面取得进展的一个重要方法是开发一种方法，在单个患者的完整GBM标本上快速测试许多潜在的治疗药物或方案。肿瘤对药物的反应将通过细胞死亡和细胞活力标记的成像来测量。由于单个肿瘤样品通常是异质的，因此我们的微流体系统能够在样品的不同区域进行多路药物测试是至关重要的。阳性的药物反应应该在整个肿瘤中是一致的和特异性的。该多路复用平台还将能够研究可能在治疗上有用的特定药物组合和剂量。影响：这项工作解决了开发方法和设备的迫切需要，以快速可靠地评估通常是异质性的，完整的原发肿瘤标本对一系列可能的治疗方法的反应，目标是确定针对个体肿瘤和患者的最有效的治疗子集。