Novel Strategies for Brain Tumor Therapy

脑肿瘤治疗新策略

• 批准号: 6786053
• 负责人: Ian F. Pollack
• 金额: $ 137.97万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6786053
• 关键词: clinical research; combination cancer therapy; glioblastoma multiforme; glioma; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neoplasm /cancer radioimmunotherapy

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.

在过去的二十年中，患有恶性脑肿瘤的儿童和成年人的预后最小。对于最常见的内在脑肿瘤，患有恶性神经胶质瘤的患者中位数仍不到一年。这些统计数据为确定治疗这些肿瘤的创新方法的协调努力提供了强有力的理由。该计划项目授予的统一假设是，考虑到中枢神经系统肿瘤的独特特征的新型治疗策略将诱导肿瘤回归，并可能潜在传统疗法的功效。每个项目都是以翻译为导向的，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神经胶质瘤模型评估创新的治疗方法，以此作为识别可以提出的有希望策略的基础，这些策略可以提出到临床治疗疗法中。项目1基于以下假设：抑制恶性神经胶质瘤的异常活化的信号转导途径，或直接激活凋亡信号信号传导途径，将诱导基因型特异性方式的神经胶质瘤细胞杀伤，并且这种方法将具有独立的治疗性活性。项目2假定凋亡或坏死胶质瘤细胞（例如由项目1的有希望剂产生的细胞）将构成一种抗原向抗原呈递细胞递送的最佳机制，并且可以优化使用此类细胞进行主动免疫的条件以促进有效的抗-0tumor免疫反应。项目3假设使用复制缺陷的疱疹病毒向量，这些基因递送构成了新型多基因构建体，该构造设计用于促进治疗相关的基因产物的跨细胞转移，可以实现肿瘤细胞的杀伤并增强其他治疗策略的影响。该项目还将生成许多将在项目1和2中使用的向量构造。行政/生物统计学/临床支持核心（a）为组件项目和其他核心的基本和临床研究活动提供了必不可少的基础设施支持。细胞和组织成像核心（B）提供了每个组件项目中使用的高级微观成像功能的泛滥。免疫学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品，维持天然和转导的细胞系，生物学产品的制备以及全面的治疗监测，这对于在此计划中纳入创新的试验临床方案至关重要。综上所述，在该计划的该计划的背景下演变的多学科相互作用优化了我们的变化，以识别和完善有希望的治疗方法，这些方法可以在临床上应用，以改善恶性神经胶质瘤患者原本令人沮丧的预后。