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Inhibition of Brain Tumor Stem Cell Tumorigenicity using Self-assembling Nanogels

使用自组装纳米凝胶抑制脑肿瘤干细胞致瘤性

基本信息

批准号：
8259203
负责人：
Maya Srikanth Graham
金额：
$ 1.1万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2012-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8259203
关键词：
Adult Binding Biological Brain Neoplasms Cancer Biology Caring Cells Characteristics Data Development Diagnosis Disease Drug Delivery Systems Encapsulated Epitopes Evaluation Excision Extracellular Matrix Funding Glioblastoma Glioma Growth Health Human Immunocompromised Host In Vitro Integrins Knowledge Laminin MAP Kinase Gene MAPK14 gene Maintenance Malignant - descriptor Malignant Neoplasms Messenger RNA Methods Molecular Profiling Mus NanoGel Nanotechnology Neurologic Neuronal Differentiation Neurons Operative Surgical Procedures PTK2 gene Pathway interactions Patients Peptides Phosphotransferases Primary Brain Neoplasms Property Proteins Radiation Recurrence Relapse Research Role Signal Transduction Signaling Molecule Specificity Stem Cell Development Therapeutic Thymidine Time Tumor Stem Cells Tumorigenicity Work Xenograft Model analog base cancer stem cell cell behavior chemotherapy clinically relevant density effective therapy immunocytochemistry improved in vivo innovation interest nerve stem cell novel outcome forecast stem stem cell biology stem cell differentiation success tool treatment strategy tumor tumor initiation tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma is the most common brain tumor in adults and carries a poor prognosis, due in part to a propensity for tumor recurrence despite aggressive treatment strategies. Such relapse may be due to the persistence of brain tumor stem cells (BTSCs), a small subset of glioma cells with stem-like characteristics that have recently been proposed to underlie tumor initiation and progression. It is likely that modulation of pathways normally involved in neural stem cell (NSC) differentiation will be of clinical relevance in the targeting of these cells. Activation of betal-integrin after binding of the laminin-derived epitope IKVAV is one such pathway of particular interest, as it has been shown to promote neuronal differentiation as well as inhibit tumorigenesis. Furthermore, the use of self-assembling peptide amphiphile (PA) nanogels as a vehicle as described in this proposal would maximize the density of epitope presentation in addition to providing a novel method of drug delivery unparalleled by current tools. The enclosed aims will comprehensively evaluate the potential differentiation induction and anti-tumorigenic effect of the IKVAV PA on BTSCs, both in vitro as well as in xenograft models. In addition, the mechanisms underlying this effect, such as signaling via betal-integrin, will be investigated. These studies will further our current understanding of brain tumor stem cells and stand to significantly contribute to the application of nanotechnology to the treatment of glioblastoma. PUBLIC HEALTH RELEVANCE: Current treatments for the most malignant primary brain tumor (glioblastoma) are woefully inadequate, and the average survival is just over one year. The proposed research aims to develop more effective therapies for this devastating disease by targeting the cells responsible for tumor relapse using nanotechnology. If successful, this work stands to significantly improve the care of glioblastoma patients.

描述(由申请人提供)：胶质母细胞瘤是成人最常见的脑肿瘤，预后很差，部分原因是尽管采取了积极的治疗策略，但肿瘤容易复发。这种复发可能是由于脑肿瘤干细胞(BTSCs)的持续存在，BTSCs是一小部分具有干细胞样特征的胶质瘤细胞，最近被认为是肿瘤发生和发展的基础。正常参与神经干细胞(NSC)分化的通路的调节很可能在这些细胞的靶向方面具有临床意义。与层粘连蛋白衍生的表位IKVAV结合后，β-整合素的激活是其中一种特别感兴趣的途径，因为它已被证明促进神经元分化和抑制肿瘤的发生。此外，使用本提案中描述的自组装多肽两亲性(PA)纳米凝胶作为载体，除了提供目前工具无法比拟的一种新的药物输送方法外，还将最大限度地提高表位呈现的密度。所附的AIMS将全面评估IKVAV PA在体外和异种移植模型中对BTSCs的潜在分化诱导和抗肿瘤作用。此外，还将研究这种效应的潜在机制，如通过β-整合素传递信号。这些研究将进一步加深我们目前对脑肿瘤干细胞的理解，并将对纳米技术在胶质母细胞瘤治疗中的应用做出重大贡献。公共卫生相关性：目前对最恶性的原发脑瘤(胶质母细胞瘤)的治疗严重不足，平均生存期仅为一年多一点。这项拟议的研究旨在通过使用纳米技术瞄准导致肿瘤复发的细胞，为这种毁灭性的疾病开发更有效的疗法。如果成功，这项工作将显著改善对胶质母细胞瘤患者的护理。