Hypoxia as a target for the treatment of brain tumors

缺氧作为治疗脑肿瘤的目标

• 批准号: 6322082
• 负责人: ERWIN G VAN MEIR
• 金额: $ 19.07万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-03 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6322082
• 关键词: Adenoviridae; angiogenesis inhibitors; antineoplastics; athymic mouse; biotechnology; brain neoplasms; cerebral ischemia /hypoxia; clinical research; cytolysis; gene induction /repression; gene therapy; genetic promoter element; human tissue; immunocytochemistry; neoplasm /cancer blood supply; nonhuman therapy evaluation; pediatric neoplasm /cancer; recombinant virus; reporter genes; technology /technique development; thrombospondins; tissue /cell culture; transfection /expression vector; virus genetics; virus infection mechanism; xenotransplantation

DESCRIPTION (provided by applicant): Primary brain tumors (mainly malignant gliomas, medulloblastomas and ependymornas) have become the main cause of death from cancer in children and young adults. Hypoxia is a physiological difference between normal and tumor tissue. We propose to exploit this difference to construct a novel type of cancer therapy adenovirus. We will conditionally regulate the replication ability of an adenovirus by placing the adenoviral EIA gene under the control of an exogenous hypoxia-regulated promoter (HYPR-Ad). Since adenoviruses have a cytolytic cycle, the selective replication of adenoviruses within hypoxic tumor cells will lead to oncolysis. Moreover, we will augment the antitumor capability of this oncolytic: virus by having it function as a therapeutic gene delivery vehicle. We will introduce into the HYPR viral vector an expression cassette for the angiogenesis inhibitor thrombospondin-1 (HYPRA-Ad). The production of this inhibitor by infected hypoxic cells will generate a field effect that should counteract the action of the angiogenic stimulators released by these cells in response to hypoxia. In addition, it should reduce the expansion of noninfected and normoxic tumor cells since they will not be able to recruit new vascular supply. These recombinant adenoviruses will be studied for their ability to infect, replicate, and induce cytolysis of cells derived from pediatric glioma, medulloblastoma and ependymoma under normoxic and hypoxic conditions in vitro. Subsequently, the therapeutic efficacy of these viruses against xenografts of these pediatric brain tumors will be examined, in both subcutaneous and intracerebral models in immunocompromised (nulnu) mice. The tumor therapy approach presented in this proposal is novel in that these viruses can provide direct oncolytic therapy as well as deliver adjuvant gene therapy. Although these viruses have broad applicability to treat ALL cancer types which develop hypoxia, regardless of their tissue of origin and genetic composition, funding of this application will enable us to specifically develop this strategy to treat/cure pediatric brain tumors. The translation of these preclinical studies have the potential to directly benefit human health by improving the survival of children and adults with cancer.

描述（由申请人提供）：原发性脑肿瘤（主要是恶性肿瘤 神经胶质瘤，髓母细胞瘤和心发膜）已成为死亡的主要原因 来自儿童和年轻人的癌症。缺氧是生理差异 在正常组织和肿瘤组织之间。我们建议将这种差异利用 构建一种新型的癌症治疗腺病毒。我们将有条件地 通过放置腺病毒EIA来调节腺病毒的复制能力 在外源性缺氧调节启动子（HYPR-AD）的控制下基因。 由于腺病毒具有细胞溶解周期，因此选择性复制 低氧肿瘤细胞中的腺病毒将导致肿瘤分解。而且，我们 将通过拥有这种溶瘤性的病毒的抗肿瘤能力来增强抗肿瘤能力 充当治疗基因递送工具。我们将介绍 HYPR病毒载体的表达盒用于血管生成抑制剂 血小板传播1（Hypra-AD）。被感染的抑制剂产生 低氧细胞将产生现场效应，应抵消 这些细胞对缺氧释放的血管生成刺激剂。在 此外，它应该减少未感染和静态毒性肿瘤的膨胀 细胞因为它们将无法募集新的血管供应。这些 将研究重组腺病毒感染能力， 复制并诱导来自小儿神经胶质瘤衍生的细胞的细胞解析， 在体外正常氧和低氧条件下，髓母细胞瘤和膜瘤。 随后，这些病毒对异种移植的治疗功效 这些小儿脑肿瘤将在皮下和 免疫功能低下（NULNU）小鼠的脑内模型。肿瘤疗法 该提案中提出的方法是新颖的，因为这些病毒可以提供 直接溶瘤治疗以及提供辅助基因疗法。虽然 这些病毒具有广泛的适用性来治疗所有发展的癌症类型 缺氧，无论其原产组织和遗传组成如何，资金 此应用程序将使我们能够专门制定此策略 治疗/治愈小儿脑肿瘤。这些临床前研究的翻译 有可能通过改善生存而直接受益于人类健康 儿童和成人癌症。