Targeted Treatments for Invasive CNS Tumors

侵袭性中枢神经系统肿瘤的靶向治疗

基本信息

批准号：
8022887
负责人：
Marthe J Howard
金额：
$ 28.11万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8022887
关键词：
Affect Apoptotic Astrocytoma BMP4 Behavior Biological Assay Brain Neoplasms Brain region Cell Line Cell Proliferation Cell Survival Cells Central Nervous System Neoplasms Characteristics Clinical Clinical Trials DNA-Binding Proteins Data Development Diagnosis Distant Down-Regulation Doxycycline Drug resistance Effectiveness Engineering Failure Genetic Glioblastoma Glioma Goals Helix-Turn-Helix Motifs Human Implant In Vitro Invaded Longevity Malignant - descriptor Malignant Glioma Malignant neoplasm of brain Malignant neoplasm of central nervous system Mediating Modeling Molecular Mus Mutation Nature Neuraxis Operative Surgical Procedures Outcome Parents Patients Primary Lesion Primary Neoplasm Principal Investigator Property Proteins Recombinant Proteins Regulation Regulator Genes Resistance Serial Passage Signaling Molecule Site Stem cells Stimulus System Testing Therapeutic Transcript Treatment Efficacy Tumor Burden Tumorigenicity U251 United States Viral Viral Vector Virus Xenograft Model Xenograft procedure base brain tissue carcinogenesis combat cytotoxicity effective therapy expectation genetic regulatory protein implantation improved in vivo knock-down malignant phenotype migration mouse model neoplastic cell nerve stem cell neural precursor cell novel outcome forecast overexpression pre-clinical programs public health relevance small hairpin RNA stem therapy design transgene expression treatment strategy tumor tumor progression vector

项目摘要

DESCRIPTION (provided by applicant): In the central nervous system (CNS), malignant tumors appear to develop from neural stem cells and tumor stem-like cells. Gliomas, a heterogeneous group of highly invasive brain tumor are resistant to treatment and patients diagnosed with these tumors have a poor prognosis. In large part, the failure of treatments designed to combat gliomas is because these tumors are highly invasive and targeting all sites of tumor formation distant from the parent tumor has proven difficult. We have identified the basic helix-loop-helix (bHLH) DNA binding protein Hand2 as a potential targeted molecule for treatment of glioma. A normal functional partner of Hand2, Twist1, is highly expressed in glioma and has a function in regulating tumor progression and invasiveness. Loss of Twist1 function in glioma causes these tumors to regress and become significantly less invasive suggesting that treatment strategies based on a reduction of Twist1 expression would have a positive outcome. We present evidence that extrinsic signaling molecules that regulate Hand2, BMP4 and Wnt-11, induce Hand2 expression in glioma with a concomitant decrease in Twist1. Based on this exciting finding we propose to: 1) assess the effect of overexpression of Hand2 on Twist1 expression in 8 human-derived glioblastoma cell lines using a heterotopic- to-orthotopic propagation and implantation approach with the expectation that abrogation of Twist1 expression by Hand2 will reduce glioma cell invasiveness, viability and tumorigenicity; 2) determine the therapeutic efficacy of Hand2 in vitro using a novel targeting strategy; and 3) test the in vivo efficacy of Hand2 in an orthotopic glioma mouse model. We will take advantage of a novel viral delivery system to comprehensively bring Hand2 to all tumor cells in the CNS, with the goal of improving the therapeutic outcome for patients diagnosed with glioma. PUBLIC HEALTH RELEVANCE: Malignant gliomas constitute the majority of human brain tumors. Despite efforts to improve surgical, radiological and chemotherapeutic treatment strategies, the prognosis for patients with glioma remains poor. A major problem is that glioblastoma cells have a propensity to migrate away from the main tumor mass and invade the surrounding brain tissue. We propose to test a new treatment strategy that might be used to track down the dispersed glioma cells that escape from the primary lesion and transduce them with a regulatory protein that may inhibit their malignant characteristics. The long-term goal of this R21 application is to test the feasibility of a targeted treatment for glioma; we hope to develop our approach to the point where we can develop clinical trials for improved treatment of glioma.

描述（由申请人提供）：在中枢神经系统（CNS）中，恶性肿瘤似乎是由神经干细胞和肿瘤干细胞发展的。神经瘤是一种高度浸润性脑肿瘤的异质组对治疗具有抗药性，被诊断为这些肿瘤的患者的预后较差。在很大程度上，旨在对抗神经胶质瘤的治疗的失败是因为这些肿瘤具有高度侵入性，并且靶向与母肿瘤远距离肿瘤形成的所有部位已被证明很困难。我们已经确定基本的螺旋 - 环螺旋（BHLH）DNA结合蛋白手2是治疗神经胶质瘤的潜在靶向分子。 Hand2，Twist1的正常功能伴侣在神经胶质瘤中高度表达，并在调节肿瘤进展和侵袭性方面具有功能。神经胶质瘤中Twist1功能的丧失会导致这些肿瘤退化，并显着降低侵入性，这表明基于扭曲1表达的降低的治疗策略将具有积极的结果。我们提供了证据表明，调节手2，BMP4和WNT-11的外在信号分子在神经胶质瘤中诱导Hand2表达，而Twist1则伴随着降低。基于这一激动人心的发现，我们提出：1）使用异位 - 直接繁殖的传播和植入方法评估Hand2对8种人体胶质母细胞瘤细胞系中Twist1表达的影响，并期望通过HARD2废除Twist1表达的扭曲表达将降低Glioma瘤瘤细胞的侵入性，可依性，生存能力，可生活性，可生活性和肿瘤性； 2）使用新颖的靶向策略来确定Hand2在体外的治疗功效； 3）在原位胶质瘤小鼠模型中测试Hand2的体内功效。我们将利用一种新型的病毒输送系统，全面地将手动2带到中枢神经系统中的所有肿瘤细胞，目的是改善诊断为神经胶质瘤的患者的治疗结果。公共卫生相关性：恶性神经胶质瘤构成大多数人脑肿瘤。尽管努力改善了手术，放射学和化学治疗策略，但胶质瘤患者的预后仍然很差。一个主要问题是，胶质母细胞瘤细胞具有偏离主要肿瘤质量并侵入周围脑组织的倾向。我们建议测试一种新的治疗策略，该策略可能用于追踪从原发性病变中逃脱的分散神经胶质瘤细胞，并使用可能抑制其恶性特征的调节蛋白转导它们。该R21应用的长期目标是测试目标治疗胶质瘤的可行性。我们希望将我们的方法发展到可以开发临床试验以改善神经胶质瘤治疗的地步。