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.

产品说明：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的反应，许多潜在的治疗并行。其目的是确定对个体患者具有最大潜在价值的治疗子集，其时间尺度足够快以指导治疗决策。创新：我们已经开发了一种微流体灌注系统，该系统在培养中保持完整的原发性肿瘤切片组织，并能够将大量不同的药物、药物组合或药物方案阵列式递送到肿瘤的解剖学定义的区域。我们的系统改进了现有的用于筛选化疗药物活性的模型（例如，培养中的肿瘤细胞、小鼠异种移植物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，并允许在可以指导治疗初始阶段决策的时间范围内生成响应数据。重点/目标：我们建议的研究重点是人类脑肿瘤，特别是恶性胶质瘤，占大多数（70%）的原发性成人脑肿瘤。这些包括III级恶性胶质瘤和更常见的IV级多形性胶质母细胞瘤（GBM）。诊断为GBM的患者中位生存期约为1年，总5年生存率<5%，尽管数十年来一直在努力改善治疗结果。在这项提案中，我们认为，在治疗这些致命的难治性肿瘤方面取得进展的一个重要途径是开发一种方法，在个体患者的完整GBM标本上平行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的标志物成像来测量。由于单个肿瘤样本通常是异质的，因此我们的微流控系统能够在样本的不同区域进行多重药物测试至关重要。阳性药物反应在整个肿瘤中应该是一致和特异的。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异质性，完整的原发性肿瘤标本对一系列可能的治疗的反应，目的是为个体肿瘤和患者确定最有效的治疗子集。