CONTEMPORARY THERAPEUTICS FOR ANAPLASTIC GLIOMAS

此前，我们的孢子研究人员(5个项目)成功地将他们的基本发现转化为3个阶段1介入临床试验，42例患者的胶质瘤组织分析确定了关键生长调节机制的丧失，以及332例患者的病例对照遗传流行病学调查，该调查确定了两种人类白细胞抗原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：抗细胞凋亡抑制、溶瘤病毒治疗、抗体介导的治疗、细胞凋亡和自噬。四个转化性研究项目被提出，每个项目都将在3-5年的时间框架内启动一项或多项干预性临床试验。这些措施包括：1)针对JAK2/STAT3信号轴的靶向干预用于间变性胶质瘤治疗，为使用小分子抑制药物抑制JAK2/STAT3途径以改善传统治疗效果提供合理的基础；2)针对间变性胶质瘤治疗的优化嵌合HSV将为cGMP RAID产生的嵌合单纯疱疹病毒的临床应用开发一种安全的方法，同时显著增强其复制特性和感染和杀伤胶质瘤细胞的整体能力；3)加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，以及一种UAB开发的人源化抗DR5单抗，无论是静脉注射还是对流增强递送，以诱导肿瘤相关内皮和细胞的凋亡。4)间变性胶质瘤的溶酶体趋化疗法将以氯喹和氟喹诺酮类化合物的血脑屏障通透性为特征，这些类似物可以诱导胶质瘤细胞的自噬。这些项目将得到5个核心的支持：1)行政，2)脑瘤组织，3)临床试验，4)生物统计学/生物信息学，5)脑瘤动物模型。我们的职业发展计划招募了2名脑瘤翻译研究的新研究员，并将支持多达4名。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9人是脑瘤研究的新手。本申请中的所有四个建议项目最初都是开发项目。大学、医学院和综合癌症中心大力支持这一孢子应用我们将继续与其他脑瘤孢子进行多次、积极的合作，并将促进与当地和全国其他非脑器官站点癌症孢子项目的新互动。

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.