Novel Strategies for Brain Tumor Therapy

在过去的二十年里，患有恶性脑瘤的儿童和成人的预后得到了极小的改善；恶性胶质瘤患者的中位生存期仍然不到一年，恶性胶质瘤是最常见的固有脑瘤。这些统计数据为协调努力确定治疗这些肿瘤的创新方法提供了强有力的理由。这项计划项目拨款的统一假设是，考虑到中枢神经系统肿瘤的独特特征的新治疗策略将导致肿瘤消退，并将潜在传统疗法的疗效。每个项目都以翻译为导向，有一个共同的目标，即解决与肿瘤生长过程相关的基本生物学问题，并使用一系列临床前胶质瘤模型评估创新的治疗方法，以此作为确定可推进到临床治疗的有希望的策略的基础。项目1基于这样的假设，即抑制恶性胶质瘤异常激活的信号转导通路或直接激活凋亡信号通路将诱导胶质瘤细胞杀伤，可能是以一种基因特异性的方式，并且这种方法将在临床前胶质瘤模型中具有独立的治疗活性，并增强其他方法的效果。项目2假设，凋亡或坏死性胶质瘤细胞，如项目1中有希望产生的那些细胞，将构成将抗原递送到抗原提呈细胞的最佳机制，并且这些细胞主动免疫的条件可以被优化，以促进有效的抗肿瘤免疫反应。项目3假设，使用复制缺陷疱疹病毒载体结合新的多基因结构，促进治疗相关基因产品的跨细胞转移，可以实现对肿瘤细胞的杀伤，并增强其他治疗策略的效果。该项目还将产生许多将在项目1和2中使用的载体构建。行政/生物统计/临床支持核心(A)为组成部分项目和其他核心的基础和临床研究活动提供必要的基础设施支持。细胞和组织成像核心(B)提供了用于每个组件项目的高级显微成像功能的全能。免疫监测和细胞产品实验室核心(C)为每个项目提供组织和血清样本库，维护本地和转导细胞系，制备生物产品，以及全面的治疗监测，这些都是纳入该计划的创新试点临床方案所必需的。综上所述，在这一计划的背景下发展起来的多学科互动优化了我们的变化，以确定和改进有希望的治疗方法，这些方法可以应用于临床，以改善恶性胶质瘤患者原本令人沮丧的预后。

The prognosis for children and adults with malignant brain tumors has improved minimally during the last two decades; median survival remains less than one year for patients with malignant glioma, the most common intrinsic brain tumor. These statistics provide a strong rationale for coordinate efforts to identify innovative approaches for the treatment of these tumors. The unifying hypothesis of this program project grant is that novel therapeutic strategies that take into account the unique features of central nervous system tumors will induce tumor regression, and will potential the efficacy of conventional therapies. Each project is translationally oriented, with a common goal of addressing fundamental biological issues relevant to the tumor growth process and evaluating innovative treatment approaches using a series of preclinical glioma models, as a basis for identifying promising strategies that can be advanced into clinical therapeutics. Project 1 is based on the hypothesis that inhibition of the aberrantly activated signal transduction pathways of malignant gliomas, or direct activation of apoptosis signaling pathways, will induce glioma cell killing, potentially in a genotype-specific fashion, and that this approach will have independent therapeutic activity in preclinical glioma models, and potentiate the effects of other approaches. Project 2 postulates that apoptotic or necrotic glioma cells, such as those produced by promising agents from Project 1, will constitute an optimal mechanism for antigen delivery to antigen presenting cells, and that the conditions for active immunization with such cells can be optimized to promote an effective anti-0tumor immune response. Project 3 postulates that gene delivery, using replication-defective Herpes virus vectors incorporating novel multi-gene constructs engineered to facilitate transcellular transfer of therapeutically relevant gene products, can achieve tumor cell killing and enhance the effects of other treatment strategies. This project will also generate many of the vector constructs that will be used in Projects 1 and 2. The Administrative/Biostatistics/Clinical Support Core (A) provides essential infrastructure support for the basic and clinical research activities of the component projects and other cores. The Cellular and Tissue Imaging Core (B) provides a panopoly of advanced microscopic imaging capabilities used in each of the component projects. The Immunological Monitoring and Cellular Products Laboratory Core (C) provides banking of tissue and serum samples for each of the projects, maintenance of native and transduced cell lines, preparation of biological products, and comprehensive therapeutic monitoring that are essential for the innovative pilot clinical protocols incorporated within this program. Taken together, the multi-disciplinary interactions that have evolved within the context of this program of this program optimize our changes to identify and refine promising therapeutic approaches that can be applied clinically to improve the otherwise discouraging prognosis of patients with malignant gliomas.