Novel Strategies for Brain Tumor Therapy

在过去的二十年中，儿童和成人恶性脑肿瘤的预后改善甚微；恶性神经胶质瘤是最常见的脑肿瘤，其患者的中位生存期仍不到一年。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依据。该项目的统一假设是，考虑到中枢神经系统肿瘤的独特特征的新治疗策略将诱导肿瘤消退，并将潜在的传统疗法的疗效。每个项目都以翻译为导向，其共同目标是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治疗方法，作为确定可推进临床治疗的有希望策略的基础。项目1基于以下假设：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，将诱导胶质瘤细胞死亡，可能以基因型特异性的方式，并且该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假设凋亡或坏死胶质瘤细胞，如项目1中有希望的药物产生的胶质瘤细胞，将构成抗原递送到抗原提呈细胞的最佳机制，并且可以优化这些细胞的主动免疫条件，以促进有效的抗肿瘤免疫应答。项目3假设基因传递，利用复制缺陷疱疹病毒载体结合新的多基因构建物，促进治疗相关基因产物的跨细胞转移，可以实现肿瘤细胞杀伤并增强其他治疗策略的效果。这个项目还将生成许多将在项目1和项目2中使用的向量构造。行政/生物统计/临床支持核心(A)为组成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)提供了在每个组成项目中使用的先进显微成像能力的全面垄断。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，维护原生和转导细胞系，制备生物产品，以及对纳入该项目的创新试点临床方案至关重要的综合治疗监测。总的来说，在这个项目的背景下发展起来的多学科互动优化了我们的变化，以确定和完善有前途的治疗方法，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.