Fn14-targeted Therapeutics for Invasive Brain Cancer

Fn14 靶向治疗侵袭性脑癌

• 批准号: 8679868
• 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/8679868
• 关键词: A-factor (Streptomyces); 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; Drug Formulations; Excision; Extracellular Domain; Fibroblast Growth Factor; Flow Cytometry; Fluorescence Microscopy; Focused Ultrasound Therapy; Gene Expression; Gene Targeting; Gene Transfer; Genes; Glioblastoma; Glioma; Green Fluorescent Proteins; 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; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Pathogenesis; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Polymers; Radiation; Resolution; Signal Pathway; Signal Transduction; Slice; Structure; Surface; Surface Plasmon Resonance; Survival Rate; System; Technology; Testing; Therapeutic; Therapeutic Uses; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Update; Western Blotting; aggressive therapy; base; biodegradable polymer; brain tissue; cancer cell; cancer therapy; cell motility; cellular targeting; chemotherapy; density; design; improved; in vivo; member; nanoparticle; neoplastic cell; overexpression; particle; prevent; public health relevance; rac1 GTP-Binding Protein; receptor binding; signal processing; small hairpin RNA; success; therapeutic gene; therapeutic target; 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（由申请人提供）：胶质母细胞瘤（GB）是最常见的原发性脑癌，即使采用最积极的治疗方法，5年生存率也<15%。恶性胶质瘤细胞具有高度侵袭性，可有效浸润邻近正常脑组织