Fn14-targeted Therapeutics for Invasive Brain Cancer

Fn14 靶向治疗侵袭性脑癌

• 批准号: 9134759
• 负责人: Anthony J. Kim
• 金额: $ 13.01万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9134759
• 关键词: Affinity; Apoptosis Promoter; Binding; Biological Assay; Brain; Brain Neoplasms; Brain region; Cancer Etiology; Cell physiology; Cell surface; Cells; Cessation of life; Clinical; Confocal Microscopy; Convection; Data; Diffusion; Disease; Distant; Dose-Limiting; Excision; Extracellular Domain; Fibroblast Growth Factor; Flow Cytometry; Fluorescence Microscopy; Focused Ultrasound; Formulation; Gene Expression; Gene Targeting; Gene Transfer; Genes; Glioblastoma; Glioma; Green Fluorescent Proteins; Health; Human; Immunohistochemistry; Implant; In Vitro; Infiltration; Injection of therapeutic agent; Intracranial Neoplasms; Invaded; Label; Life; Ligands; Malignant Glioma; Malignant neoplasm of brain; Mediating; Modeling; Modification; Molecular Target; Monoclonal Antibodies; Mus; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Penetration; Pharmaceutical Preparations; Polymers; Radiation; Resolution; Signal Pathway; Signal Transduction; Slice; Structure; Surface; Surface Plasmon Resonance; Survival Rate; System; TNF gene; Technology; Testing; Therapeutic; Therapeutic Uses; Tumor Cell Migration; Tumor Necrosis Factor Receptor; Update; Western Blotting; aggressive therapy; base; biodegradable polymer; brain tissue; cancer cell; cancer therapy; cell motility; cellular targeting; chemotherapy; density; design; factor A; improved; in vivo; knock-down; member; nanoparticle; neoplastic cell; overexpression; particle; prevent; rac1 GTP-Binding Protein; receptor binding; signal processing; small hairpin RNA; success; targeted treatment; therapeutic gene; trafficking; uptake; vector

DESCRIPTION (provided by applicant): Glioblastoma (GB) is the most common primary brain cancer with a 5 year survival rate of <15%, even with the most aggressive therapies. Malignant glioma cells are highly invasive and their efficient infiltration into adjacent normal brain tissue prevents complete surgical removal and limits the dosing of radiation and chemotherapeutic drugs. Unfortunately, local chemotherapy, provided by either biodegradable polymer implants or convection-enhanced delivery, has had limited clinical success; in part due to inefficient delivery of therapeutics to distant invading tumor cells. Fibroblast growth factor-inducible 14 (Fn14), a member of the tumor necrosis factor (TNF) receptor superfamily, is a promising molecular target for GB therapy. High Fn14 expression correlates with higher brain tumor grade and poor patient outcome, and is found in both migrating glioma cells in vitro and invading glioma cells in vivo. Hence, a delivery strategy designed to target Fn14+ tumor cells is a promising approach for treating distant invading tumor cells. Our pilot data show that gene vectors with bio-inert surfaces (via extremely dense PEG coatings) provide improved penetration and distribution in brain tissue, minimize non-specific binding, and therefore have a greater potential for cell-specific targeting in the brain. Our overall hypothesis is that Fn14-targeted gene vectors will suppress brain cancer invasion by delivering therapeutic gene constructs into the regions of the brain that contain infiltrating tumor cells and effectively inhibiting Fn14 signaling in invading Fn14+ glioma cells. This hypothesis will be tested in the following specific aims: (1) synthesize and characterize Fn14-targeting gene vectors and assess their Fn14 targeting, cellular trafficking, and in vitro gene expression in Fn14+ glioma cells, (2) using optimized gene vectors from Aim 1, evaluate brain tissue penetration and particle distribution in vivo, and (3) using therapeutic version of gene vectors from Aim 2, evaluate inhibition of Fn14 signaling and suppression of glioma cell invasion ex vivo and in vivo. These studies will provide an important next step in the application of brain- penetrating delivery technologies; specifically, directly targeting treatments to the key infiltrating tumor cells not accessible with surgery. Our next step would include: (1) identifying optimum therapeutic gene and cellular pathway targets, and (2) augmenting particle delivery and dispersion using convection-enhanced local delivery and focused ultrasound mediated systemic delivery.

描述(申请人提供)：胶质母细胞瘤(GB)是最常见的原发脑癌，5年生存率为15%，即使采用最积极的治疗也是如此。恶性胶质瘤细胞具有高度侵袭性，可有效侵袭邻近正常脑组织。 防止完全手术切除，并限制放射和化疗药物的剂量。不幸的是，通过可生物降解聚合物植入物或对流增强型给药提供的局部化疗临床效果有限；部分原因是给药效率低。 远距离侵袭的肿瘤细胞的治疗方法。成纤维细胞生长因子诱导因子14(Fn14)是肿瘤坏死因子受体超家族的成员，是GB治疗的一个有前景的分子靶点。Fn14的高表达与较高的脑肿瘤分级和较差的患者预后相关，并且在体外迁移的胶质瘤细胞和体内侵袭的胶质瘤细胞中都存在。因此，靶向Fn14+肿瘤细胞的递送策略是治疗远处侵袭性肿瘤细胞的一种有前途的方法。我们的试验数据表明，具有生物惰性表面的基因载体(通过极其致密的聚乙二醇涂层)可以改善脑组织的渗透和分布，最大限度地减少非特异性结合，因此在大脑中具有更大的细胞特异性靶向潜力。我们的总体假设是，以Fn14为靶向的基因载体将通过将治疗性基因构建送入大脑中包含浸润性肿瘤细胞的区域，并有效地抑制侵袭性Fn14+胶质瘤细胞中的Fn14信号，从而抑制脑癌的侵袭。这一假设将在以下特定目标中得到验证：(1)合成和鉴定Fn14靶向基因载体，并评估其在Fn14+胶质瘤细胞中的靶向、细胞转运和体外基因表达；(2)使用Aim 1的优化基因载体，评估体内脑组织渗透和颗粒分布；(3)使用Aim 2的治疗性基因载体，评估对Fn14信号的抑制和对胶质瘤细胞体外和体内侵袭的抑制。这些研究将为脑穿透递送技术的应用提供重要的下一步；具体地说，直接针对手术无法获得的关键浸润性肿瘤细胞进行治疗。我们的下一步将包括：(1)确定最佳的治疗基因和细胞途径靶点，以及(2)利用对流增强的局部传递和聚焦超声介导的全身传递来增强颗粒的传递和分散。