Invasion and Angiogenesis in Malignant Gliomas

描述(申请人提供)：迫切需要新的脑瘤治疗方法。弥漫性胶质瘤细胞侵袭周围脑组织和血管生成是脑胶质瘤的基本特征，传统治疗方法无法有效控制脑肿瘤患者的肿瘤生长。目前积极的局部治疗，如手术、放射治疗和化疗，在控制脑内局部肿瘤细胞团块方面是有效的。这种成功只是暂时的，因为肿瘤细胞已经侵入周围的大脑，成为肿瘤重新生长的种子。这些肿瘤细胞侵入大脑的过程还不是很清楚。能够控制这些侵袭的肿瘤细胞的新的治疗方法可以对患者的预后产生巨大的影响。我们已经开发了体外和体内的分析方法，使我们能够研究侵袭性胶质瘤和血管内皮细胞。 我们的长期目标仍然是干扰肿瘤的侵袭和血管生成，以减少肿瘤的生长。为此，我们建议1)确定内皮细胞和胶质瘤细胞迁移的机制；2)研究两种格尔达霉素类似物在体内外对胶质瘤的作用机制和治疗潜力。 我们的建议旨在利用新的分子生物学技术来提高我们对这一过程的理解。总的来说，拟议的实验将分析肿瘤侵袭和血管生成所必需的细胞和分子途径。这些实验的结果将导致未来设计出抑制这些关键过程中涉及的特定分子成分的策略。

DESCRIPTION (provided by applicant): There is a dire need for novel therapy for brain tumors. Diffuse glioma cell invasion into surrounding brain tissue and angiogenesis are fundamental features of gliomas that have not been successfully addressed by conventional therapy to control tumor growth in brain tumor patients. Current aggressive local treatments such as surgery, radiotherapy and chemotherapy are effective at controlling the localized mass of tumor cells in the brain. This success is only temporary, because tumor cells that have already invaded into the surrounding brain and serve as seeds by which the tumor re-grows. The process by which these tumor cells invade into the brain is not well understood. New treatment approaches that are capable to control these invading tumor cells can have a dramatic impact on patient outcome. We have developed assays in vitro and in vivo that allow us to study invading glioma and endothelial cells. Our long-term goal remains to interfere with tumor invasion and angiogenesis to diminish tumor growth. To this end we propose i) to determine mechanisms involved in the migration of both endothelial and glioma cells; and ii) to investigate the mechanism and therapeutic potential of two geldanamycin analogues on glioma in vitro and in vivo. Our proposal seeks to take advantage of new molecular biologic techniques to improve our understanding of this process. Collectively, the proposed experiments will analyze the cellular and molecular pathways necessary for tumor invasion and angiogenesis. Results from these experiments will lead to future strategies designed to inhibit specific molecular components implicated in these critical processes.