CONTEMPORARY THERAPEUTICS FOR ANAPLASTIC GLIOMAS

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项1期干预性临床试验，一项42例胶质瘤组织分析确定了关键生长调节机制的缺失，一项332例病例对照遗传流行病学调查确定了两种HLA表型与胶质瘤缓慢或快速进展的显著关联。这一新的竞争性更新孢子应用的主题包括：抗凋亡抑制、溶瘤病毒治疗、抗体介导治疗、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年内启动一个或多个干预性临床试验。其中包括：1)靶向干预JAK2/STAT3信号轴用于间变性胶质瘤治疗，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合理基础；2)嵌合单纯疱疹病毒用于间变性胶质瘤治疗的优化将开发临床应用，cGMP raid制备的嵌合单纯疱疹病毒是安全的，同时其复制特性和感染和杀死胶质瘤细胞的整体能力显著增强；3)增强死亡受体抗体治疗间变性胶质瘤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，通过静脉注射或对流增强递送诱导肿瘤相关内皮细胞和细胞凋亡。神经胶质瘤细胞;4)间变性胶质瘤的溶酶体性治疗将表征诱导胶质瘤细胞自噬的氯喹和氟喹诺酮的血脑屏障渗透性类似物。这些项目将由5个核心提供支持：1)行政管理，2)脑肿瘤组织，3)临床试验，4)生物统计学/生物信息学，5)脑肿瘤动物模型。我们的职业发展计划已经招募了2名新的研究人员进行脑肿瘤转化研究，并将支持多达4人。我们将继续非常成功的发展研究项目，该项目支持了15名研究人员。其中9人是脑肿瘤研究的新手。本申请中的所有四个拟议项目最初都是发展性项目。大学，医学院和综合癌症中心强烈支持这个SPORE应用程序。我们将继续与其他脑肿瘤孢子进行多种积极合作，并将与其他非脑器官部位癌症孢子项目建立新的互动。

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.