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

• 批准号: 10328493
• 负责人: Konstantinos Konstantopoulos
• 金额: $ 46.27万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-14 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328493
• 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 response; treatment strategy; tumor; tumor behavior; tumor progression

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/摘要 脑肿瘤是儿童实体瘤死亡的主要原因，也是癌症的主要原因之一 20-39岁青年男女的死亡率 .胶质母细胞瘤（GBM）是最常见的原发性 成人脑癌的总发病率为所有原发性脑肿瘤的20%。尽管目前的标准 治疗，其中包括手术和化疗，放疗，中位生存期只有14.6个月。由于高度 由于GBM细胞的侵袭性，采用肿瘤全切除的标准治疗不足以 由于肿瘤切除边缘外的肿瘤细胞复发率高，因此无法治愈。 此外，临床医生识别存活时间较短的患者的能力， 复发风险高。开发新的预后工具，用于确定患者生存率和识别 细胞亚群具有显著增加的运动性和侵略性，并驱动复发， 至关重要。基于对我们GBM患者的回顾性研究的有趣数据显示：1）我们的新 微流控侵入网络设备（MIND）基于GBM患者的生存率增加预测GBM患者的生存率。 异质群体中侵袭性细胞的百分比; 2）我们能够将侵袭性细胞与 使用MIND设备的非侵入性细胞，这将使我们能够了解潜在的分子差异， 更积极的亚群; 3）靶向转录因子TEAD 4选择性过表达 并且在GBM中过度活跃并促进受限的GBM迁移。根据这些研究结果，我们建议：i） 建立我们的MIND平台作为GBM患者前瞻性临床管理的辅助工具，ii） 发现GBM细胞侵袭的新驱动因素，以及iii）将其用作筛选潜在的 治疗药物为了实现这些目标，我们将努力实现以下具体目标： 在使用MIND的GBM患者的前瞻性队列中，有限空间迁移的预后能力（目的1）; 表征表型侵袭性脑癌细胞的受限空间迁移的分子驱动因素 使用MIND（目的2）;评价42种化疗药物的体内转化效力， 心智（目标3）。体外实验将使用前瞻性收集的患者源性原发性 来自100多名患者的GBM细胞系。我们的专有和新颖的MIND平台将用于研究受限的- 从这些患者的空间迁移，以确定预后不良和高复发的前瞻性与 为患者提供个性化治疗的未来目标。将使用我们的 在小鼠中建立原位人脑肿瘤起始细胞衍生的GBM模型。获得的结果 这项研究将导致开发一个精确医学平台，能够在一个特定的环境中测试药物。 使用新鲜分离的人体组织以高通量方式进行。

项目成果

3D bioprinting of glioblastoma models.

• DOI: 10.2217/3dp-2019-0027
• 发表时间: 2020-06
• 期刊: Journal of 3D printing in medicine
• 作者: Carolina Parra-Cantu;Wanlu Li;A. Quiñones‐Hinojosa;Y. S. Zhang

Detection of after-discharges during intraoperative functional brain mapping in awake brain tumor surgery using a novel high-density circular grid.

使用新型高密度圆形网格在清醒脑肿瘤手术的术中功能性脑映射过程中检测后放电。

• DOI: 10.1016/j.clinph.2019.12.416
• 发表时间: 2020
• 期刊: Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology
• 作者: Tatum,WilliamO;McKay,JakeH;ReFaey,Karim;Feyissa,AntenehM;Ryan,Dan;Ritaccio,Anthony;Middlebrooks,Erik;Yelvington,Kirsten;Roth,Grayson;Acton,Emily;Grewal,Sanjeet;Chaichana,Kaisorn;Quinones-Hinojosa,Alfredo
• 通讯作者: Quinones-Hinojosa,Alfredo

Phase 1, Dose Escalation, Nonrandomized, Open-Label, Clinical Trial Evaluating the Safety and Preliminary Efficacy of Allogenic Adipose-Derived Mesenchymal Stem Cells for Recurrent Glioblastoma: A Clinical Trial Protocol

• DOI: 10.1227/neuprac.0000000000000062
• 发表时间: 2023-12-01
• 期刊: NEUROSURGERY PRACTICE
• 作者: Ramos-Fresnedo，Andres;Al-Kharboosh，Rawan;Quinones-Hinojosa，Alfredo
• 通讯作者: Quinones-Hinojosa，Alfredo

Onco-Epilepsy: More Than Tumor and Seizures.

肿瘤性癫痫：不仅仅是肿瘤和癫痫发作。

• DOI: 10.1016/j.mayocp.2018.06.019
• 发表时间: 2018
• 期刊: Mayo Clinic proceedings
• 影响因子: 8.9
• 作者: Tatum4th,WilliamO;Quinones-Hinojosa,Alfredo
• 通讯作者: Quinones-Hinojosa,Alfredo

A microfluidic cell-migration assay for the prediction of progression-free survival and recurrence time of patients with glioblastoma.

用于预测胶质母细胞瘤患者的无进展生存时间和复发时间的微流体细胞迁移测定。

• DOI: 10.1038/s41551-020-00621-9
• 发表时间: 2021-01
• 期刊: Nature biomedical engineering
• 影响因子: 28.1
• 作者: Wong BS;Shah SR;Yankaskas CL;Bajpai VK;Wu PH;Chin D;Ifemembi B;ReFaey K;Schiapparelli P;Zheng X;Martin SS;Fan CM;Quiñones-Hinojosa A;Konstantopoulos K
• 通讯作者: Konstantopoulos K