Novel Strategies for Brain Tumor Therapy

描述（由申请人提供）： 恶性脑肿瘤患者的预后在过去二十年中改善甚微;恶性胶质瘤（最常见的原发性脑肿瘤）患者的中位生存期不到一年。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理由。该项目的统一假设是，考虑到这些肿瘤的独特特征的新型治疗策略将诱导肿瘤消退，并增强常规治疗。每个项目都以实验为导向，共同目标是解决与肿瘤生长相关的基本生物学问题，并使用一系列临床前模型评估创新治疗方法，作为确定有前途的临床治疗策略的基础。项目1是基于这样的假设，即异常激活的信号转导通路的抑制，或凋亡信号的激活，将诱导胶质瘤细胞杀伤，可能在基因型特异性的方式，这种方法将在胶质瘤模型中具有独立的活性，并加强其他方法。项目2假设，与胶质瘤相关的抗原表位的疫苗接种，与旨在增强脑肿瘤微环境中的免疫反应性的全身性治疗相结合，将是抗原递送至抗原呈递细胞的有效机制，并且可以与项目1和3合作，使用促进树突状细胞成熟和功能的信号传导或载体介导的策略来优化免疫条件。项目3假设，使用溶瘤疱疹病毒载体将基因递送到脑肿瘤微环境，该载体结合了经工程改造以促进病毒掺入、传播和转导效率的新型多基因构建体，可以实现肿瘤杀伤并增强其他治疗策略的效果。该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）为本计划的活动提供必要的基础设施支持。细胞和组织成像核心（B）提供了在每个项目中使用的一整套先进的显微成像功能。免疫学监测和细胞产品实验室核心（C）提供组织和血清样本库、细胞系维护、生物制品制备和本项目临床方案所必需的治疗监测。相关性：总之，在这个项目中发展起来的多学科相互作用优化了我们识别和改进有前途的方法的机会，这些方法可以在临床上应用于改善恶性胶质瘤患者的预后。

DESCRIPTION (provided by applicant): The prognosis for patients with malignant brain tumors has improved minimally in the last two decades; median survival is less than one year for patients with malignant glioma, the most common primary brain tumor. These statistics provide a strong rationale for coordinated efforts to identify innovative approaches to treat these tumors. The unifying hypothesis of this program project is that novel therapeutic strategies that take into account the unique features of these tumors will induce tumor regression, and potentiate conventional therapies. Each project is translationally oriented, with a common goal of addressing fundamental biological issues relevant to tumor growth and evaluating innovative treatment approaches using a series of preclinical models, as a basis to identify promising strategies to advance into clinical therapies. Project 1 is based on the hypothesis that inhibition of aberrantly activated signal transduction pathways, or activation of apoptosis signaling, will induce glioma cell killing, potentially in a genotype-specific fashion, and that this approach will have independent activity in glioma models, and potentiate other approaches. Project 2 postulates that vaccination with glioma-associated antigen epitopes, in conjunction with systemic therapy designed to enhance immunoreactivity in the brain tumor microenvironment, will be an effective mechanism for antigen delivery to antigen-presenting cells, and that the conditions for immunization can be optimized using signaling or vector-mediated strategies that promote dendritic cell maturation and function, in collaboration with Projects 1 and 3. Project 3 postulates that gene delivery to the brain tumor microenvironment, using oncolytic Herpes virus vectors incorporating novel multigene constructs engineered to facilitate virus incorporation, spread, and transduction efficiency, can achieve tumor 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 activities of this program. The Cellular and Tissue Imaging Core (B) provides a panoply of advanced microscopic imaging capabilities used in each of the projects. The Immunological Monitoring and Cellular Products Laboratory Core (C) provides banking of tissue and serum samples, maintenance of cell lines, preparation of biological products, and therapeutic monitoring essential for the clinical protocols in this program. Relevance: Taken together, the multidisciplinary interactions that have evolved in this program optimize our chances to identify and refine promising approaches that can be applied clinically to improve the prognosis of patients with malignant gliomas.