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A novel microfluidic device to predict brain cancer prognosis and response to therapy

一种预测脑癌预后和治疗反应的新型微流体装置

基本信息

批准号：
10090576
负责人：
Konstantinos Konstantopoulos
金额：
$ 47.48万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-14 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10090576
关键词：
3-Dimensional Accounting Adult Age Applications Grants Basement membrane Biological Biological Assay Biomedical Engineering Biometry Brain Brain Neoplasms Cancer Etiology Cancer Prognosis Cell Line Cells Cessation of life Characteristics Child Clinical Clinical Management Clinical Trials Collagen Confined Spaces Coupled Data Development Devices Distal Drug Screening Economic Burden Excision FDA approved Female Future Genetic Genetic Transcription Glioblastoma Goals Human Hyperactivity In Vitro Incidence Knowledge Lead Libraries Light Malignant Neoplasms Malignant neoplasm of brain Methods Microfluidic Microchips Microfluidics Modeling Molecular Molecular Biology Mus Nature Neuroglia Oncology Operative Surgical Procedures Patient-Focused Outcomes Patients Pharmaceutical Preparations Phenotype Population Population Heterogeneity Predictive Value Primary Brain Neoplasms Primary Neoplasm Prognosis Prospective cohort Radiation therapy Recurrence Retrospective Studies Sensitivity and Specificity Signal Transduction Site Solid Neoplasm Technology Testing Therapeutic Time Treatment Cost United States Vascular Smooth Muscle Work base brain tissue burden of illness cancer cell cell motility chemoradiation chemotherapeutic agent clinical outcome assessment drug testing effective therapy efficacy testing experimental study genetic signature high risk high throughput screening human model human tissue improved in vitro testing in vivo male microfluidic technology migration multidisciplinary neoplastic cell neurosurgery new therapeutic target novel overexpression patient subsets personalized medicine precision drugs precision medicine preclinical study predicting response prognostic tool prognostic value programs prospective response screening standard care standard of care stem cell migration survival prediction tool transcription factor treatment strategy tumor tumor behavior tumor progression

项目摘要

PROJECT SUMMARY/ABSTRACT Brain tumor is the leading cause of solid tumor death in children and one of the top leading causes of cancer death in young male and female adults with ages of 20-39 . Glioblastoma (GBM) is the most common primary brain cancer in adults with an overall incidence of 20% of all primary brain tumors. Despite current standard of care, which includes surgery and chemo-radiation, the median survival is only 14.6 months. Due to the highly invasive nature of GBM cells, standard treatment with gross total resection of the tumor is insufficient to achieve a cure because of the high rate of recurrence by tumor cells outside the tumor resection margins. Moreover, there is an unmet need in the ability of clinicians to identify patients with lower survival times and high risk of recurrence. Developing novel prognostic tools for determining patient survival and for identifying cell subpopulations that have a significantly increased motility and aggressiveness, and drive recurrence is of utmost importance. Intriguing data based on a retrospective study of our GBM patients reveal that: 1) our novel Microfluidic Invasion Network Device (MIND) predicts survival in GBM patients based on the increased percentage of invasive cells in the heterogeneous population; 2) we are able to separate the invasive from non-invasive cell using MIND device, which will allow us to understand the underlying molecular differences of the more aggressive subpopulations; 3) the targetable transcription factor TEAD4 is selectively overexpressed and hyperactive in GBM and promotes confined GBM migration. In light of these findings, we propose to: i) establish our MIND platform as an adjunct tool to the clinical management of GBM patients prospectively, ii) uncover novel drivers of GBM cell invasion, and iii) utilize it as a high-throughput assay for screening potential therapeutic drugs. To achieve these goals, we will pursue the following specific aims: to determine the prognostic power of confined space migration in a prospective cohort of GBM patients using MIND (Aim 1); to characterize the molecular drivers of confined space migration of phenotypically aggressive brain cancer cells using MIND (Aim 2); to evaluate the in vivo translational efficacy of 42 chemotherapeutic agents tested in MIND (Aim 3). In vitro experiments will be conducted using prospectively collected patient-derived primary GBM cell lines from over 100 patients. Our proprietary and novel MIND platform will be used to study confined- space migration from these patients to identify poor prognosis and high recurrence prospectively with the future goal of achieving personalized treatments for patients. In vivo studies will be conducted using our established orthotopic human brain tumor initiating cell-derived GBM model in mice. The results obtained from this study will to lead to the development of a platform for precision medicine with the ability to test drugs in a high throughput fashion using freshly isolated human tissue.

项目总结/文摘