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

描述（由申请人提供）： 胶质母细胞瘤是成人中最常见的脑肿瘤，预后不良，部分原因是尽管采取了积极的治疗策略，但肿瘤仍有复发的倾向。这种复发可能是由于脑肿瘤干细胞（BTSC）的持续存在，这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。调节正常参与神经干细胞（NSC）分化的途径可能在靶向这些细胞方面具有临床意义。在层粘连蛋白衍生的表位IKVAV结合后β-整联蛋白的活化是一种特别感兴趣的途径，因为它已显示促进神经元分化以及抑制肿瘤发生。此外，使用自组装肽两亲物（PA）纳米凝胶作为如本提案中所述的载体，除了提供当前工具所无法比拟的药物递送的新方法之外，还将使表位呈递的密度最大化。所附目的将全面评价IKVAV PA在体外以及异种移植模型中对BTSC的潜在分化诱导和抗肿瘤作用。此外，将研究这种效应的潜在机制，例如通过β-整联蛋白的信号传导。这些研究将进一步加深我们目前对脑肿瘤干细胞的理解，并为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：目前对恶性程度最高的原发性脑肿瘤（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。拟议的研究旨在通过使用纳米技术靶向导致肿瘤复发的细胞，为这种毁灭性疾病开发更有效的疗法。如果成功，这项工作将显著改善胶质母细胞瘤患者的护理。

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.