CONTEMPORARY THERAPEUTICS FOR ANAPLASTIC GLIOMAS

间变性胶质瘤的现代治疗方法

基本信息

批准号：
8337752
负责人：
G. YANCEY GILLESPIE
金额：
$ 70万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-23 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8337752
关键词：
Address Adopted Animal Model Antibodies Antibody Therapy Antimalarials Antiviral Response Apoptosis Apoptosis Inhibitor Apoptotic Automobile Driving Autophagocytosis Basic Science Bioinformatics Biology Biometry Blood - brain barrier anatomy Brain Neoplasms Caring Cell Death Cells Cessation of life Chloroquine Clinical Clinical Sciences Clinical Trials Collaborations Comprehensive Cancer Center Convection Cyclic GMP Development Diagnosis Endothelium Event FDA approved Face Fluoroquinolones Fostering Funding Genetic Glioma Goals Growth Human Incidence Indolent Inhibition of Apoptosis Intellectual Property Intervention Investments JAK2 gene Knowledge Laboratories Licensing Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of lung Measures Mediating Molecular Monoclonal Antibodies Morbidity - disease rate New Agents Newly Diagnosed Normal Cell Normal tissue morphology Oncolytic Oncolytic viruses Operative Surgical Procedures Organ Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Phase Phase I Clinical Trials Phenotype Preclinical Testing Process Property Qualifying Quality of life Quinacrine Radiation therapy Recruitment Activity Recurrence Reporting Research Research Design Research Personnel Research Project Grants Resources STAT3 gene Scientist Signal Pathway Signal Transduction Simplexvirus Skin Cancer Stress Surveys TNFRSF10B gene Therapeutic Time Tissues Translating Translational Research Translational Research Working Group Translations Tumor Biology Tumor Tissue United States National Institutes of Health Universities Validation Viral Drug Resistance Virus analog base cancer site career development case control chemotherapy clinical application cost drug development drug discovery effective therapy genetic epidemiology improved inhibitor/antagonist killings medical schools mortality novel outcome forecast prevent programs receptor response small molecule standard of care temozolomide transcription factor tumor

项目摘要

Previously, our SPORE investigators (5 projects) successfully translated their basic findings into 3 Phase 1 interventional clinical trials, a 42-patient glioma tissue analysis defining loss of a key growth regulatory mechanism and a 332 patient case-control genetic epidemiology survey defining significant associations of two HLA phenotypes with either indolent or rapid glioma progression. The themes of this, new competitive renewal SPORE application include: Anti-apoptosis Inhibition, Oncolytic Virus therapy, Antibody-mediated Therapy, Apoptosis, and Autophagy. Four translational research projects are proposed, each of which will initiate one or more interventional clinical trials within a 3- 5 year time frame. These include: 1)Targeted' Intervention of the JAK2/STAT3 Signaling Axis for Anaplastic Glioma Therapy \o develop a rational basis for inhibiting the JAK2/STAT3 pathway using small molecule inhibitor drugs to improve conventional therapeutic outcomes; 2) Optimized Chimeric HSV for Anaplastic Glioma Therapy will develop a clinical application for a cGMP RAID-produced chimeric herpes simplex virus is safe while significantly enhanced in its replicative properties and overall ability to infect and kill glioma cells; 3) Enhancing Death Receptor Antibody Therapy for Anaplastic Gliomas will evaluate two new pro-apoptotic drugs, AT-101 and AT-406, together with a UAB developed, humanized anti-DR5 monoclonal antibody administered either intravenously or by convection enhanced delivery to induce apoptosis in tumor-associated endothelium and. glioma cells; and 4) Lysosomotropic Therapy of Anaplastic Gliomas will characterize blood-brain barrier-permeable analogues of chloroquine and fluoroquinolone that induce glioma cell autophagy. These projects will be supported by 5 Cores: 1) Administrative, 2) Brain Tumor Tissue, 3) Clinical Trials, 4) Biostatistics/Bioinformatics, and 5) Brain Tumor Animal Models. Our Career Development Program has recruited 2 new investigators to brain tumor translational research and will support up to 4 more. We will continue the: very successful Developmental Research Program that supported 15 investigators, .9 of whom were new to brain tumor research. All four of the proposed projects in this application were originally Developmental Projects. The University, School of Medicine and Comprehensive Cancer Center strongly support this SPORE application We will continue our multiple, active collaborations with other Brain Tumor SPOREs and will foster new interactions with other non-brain organ site cancer SPORE programs locally and nationally.

此前，我们的 SPORE 研究人员（5 个项目）成功地将他们的基本发现转化为 3 个 1 期介入临床试验、一项 42 名患者的神经胶质瘤组织分析（定义了关键生长调节机制的丧失）和一项 332 名患者的病例对照遗传流行病学调查（定义了显着关联）具有惰性或快速神经胶质瘤进展的两种 HLA 表型。这一新的竞争性更新 SPORE 应用的主题包括：抗凋亡抑制、溶瘤病毒治疗、抗体介导的治疗、细胞凋亡和自噬。提出了四个转化研究项目，每个项目将在3-5年的时间内启动一项或多项介入性临床试验。其中包括： 1) 间变性胶质瘤治疗中 JAK2/STAT3 信号轴的靶向干预为使用小分子抑制剂药物抑制 JAK2/STAT3 通路以改善常规治疗结果奠定了合理的基础； 2）用于间变性胶质瘤治疗的优化嵌合HSV将开发cGMP RAID生产的嵌合单纯疱疹病毒的临床应用，该病毒是安全的，同时显着增强其复制特性以及感染和杀死胶质瘤细胞的整体能力； 3) 增强间变性神经胶质瘤的死亡受体抗体疗法将评估两种新的促凋亡药物 AT-101 和 AT-406，以及 UAB 开发的人源化抗 DR5 单克隆抗体，通过静脉注射或通过对流增强递送来诱导细胞凋亡在肿瘤相关内皮细胞中。神经胶质瘤细胞； 4) 间变性神经胶质瘤的溶酶体疗法将表征氯喹和氟喹诺酮的血脑屏障可渗透类似物，诱导神经胶质瘤细胞自噬。这些项目将得到 5 个核心的支持：1) 行政、2) 脑肿瘤组织、3) 临床试验、4) 生物统计学/生物信息学和 5) 脑肿瘤动物模型。我们的职业发展计划已招募 2 名新研究人员进行脑肿瘤转化研究，并将支持另外 4 名研究人员。我们将继续：非常成功的发展研究计划，该计划支持了 15 名研究人员，其中 0.9 名是脑肿瘤研究的新手。本申请中提出的所有四个项目最初都是开发项目。大学、医学院和综合癌症中心强烈支持这一 SPORE 申请。我们将继续与其他脑肿瘤 SPORE 开展多种积极的合作，并将促进与本地和全国其他非脑器官部位癌症 SPORE 项目的新互动。