Novel Strategies for Brain Tumor Therapy

描述(由申请人提供)： 在过去20年里，恶性脑瘤患者的预后改善微乎其微；恶性胶质瘤患者的中位生存期不到一年，恶性胶质瘤是最常见的原发脑瘤。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。该计划项目的统一假设是，考虑到这些肿瘤的独特特征的新治疗策略将导致肿瘤消退，并加强传统治疗。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的治疗方法，作为确定进入临床治疗的有希望的战略的基础。项目1基于这样的假设，即抑制异常激活的信号转导通路或激活凋亡信号将诱导胶质瘤细胞杀伤，可能是以一种特定于基因的方式，并且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，以胶质瘤相关抗原表位接种，结合旨在增强脑瘤微环境中免疫反应性的系统治疗，将是将抗原递送到抗原呈递细胞的有效机制，并且与项目1和项目3合作，可以使用促进树突状细胞成熟和功能的信号或载体介导的策略来优化免疫条件。项目3假设，通过使用溶瘤疱疹病毒载体结合新的多基因构建来促进病毒的整合、传播和转导效率，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2中使用的载体构建。行政/生物统计/临床支持核心(A)为该计划的活动提供基本的基础设施支持。细胞和组织成像核心(B)提供了每个项目中使用的一整套先进的显微成像功能。免疫监测和细胞产品实验室核心(C)提供组织和血清样本的储存、细胞系的维护、生物制品的制备和治疗监测，这些都是该计划的临床方案所必需的。相关性：综上所述，该计划中发展起来的多学科互动优化了我们识别和改进有希望的方法的机会，这些方法可以应用于临床，以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.