Efficacy and toxicity of TRAIL against gliomas

TRAIL对抗胶质瘤的功效和毒性

• 批准号: 7340756
• 负责人: VINAY K PUDUVALLI
• 金额: $ 18.17万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-05 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7340756
• 关键词: Adenoviruses; Animal Model; Apoptosis; Apoptotic; Astrocytes; BIRC4 gene; Brain; Brain Neoplasms; Bystander Effect; Caspase; Cell Line; Cell surface; Cells; Cessation of life; Chemicals; Clinical Trials; Data; Disease regression; Dominant-Negative Mutation; Down-Regulation; Family member; Glioma; Human; In Vitro; Induction of Apoptosis; Life; Ligands; Local Therapy; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Mediating; Modeling; Morbidity - disease rate; Mus; Nonmetastatic; Normal Cell; Normal tissue morphology; Nude Mice; Operative Surgical Procedures; Organ; Pathway interactions; Primates; RNA Interference; Radiation therapy; Recurrence; Relative (related person); Research Personnel; Resistance; Rodent; Rodent Model; Role; Slice; Standards of Weights and Measures; TNFSF10 gene; Testing; Therapeutic; Tissues; Toxic effect; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Xenograft Model; Xenograft procedure; analog; base; brain cell; chemotherapy; human TNF protein; improved; in vivo; inhibitor/antagonist; interest; mortality; neoplastic cell; novel; programs; receptor; resistance mechanism; response; survivin; tumor

Malignant gliomas are associated with high morbidity and mortality. Standard therapies such as surgery, radiation therapy and chemotherapy do not offer effective options and local recurrence is the norm. However, being locally malignant nonmetastatic tumors, they may be amenable to control using effective tumor-targeted local therapies. TNF- related apoptosis inducing ligand (TRAIL/Apo2L) induces apoptosis in gliomas in vitro and prolongs survival in xenograft rodent models. It is nontoxic to normal organs in animal models including primates. However, the efficacy of local intracranial delivery of TRAIL, its toxicity to brain-adjacent-to-tumor and selectivity towards gliomas in humans remain to be fully explored. In this study, we will test the efficacy and toxicity of TRAIL in a living human glioma & brain slice model and in xenograft models. Our preliminary data suggests that soluble TRAIL is active against gliomas in vitro and in vivo and that its activity is modulated by the Akt pathway. We hypothesize that: a) soluble untagged TRAIL will be effective against human glioma and nontoxic to normal brain 2) Inhibition of Akt can sensitize human gliomas to TRAIL and increase survival in a glioma model 3) resistance to TRAIL is mediated by differing mechanisms in normal and tumor cells permitting selective targeting of resistance mechanisms in tumors. To test these hypotheses, we propose the following specific aims 1) determine the efficacy and toxicity of soluble untagged TRAIL expressed by an adenovirus in a mouse intracranial xenograft and an ex-vivo living human glioma slice model. 2) determine the in vivo effect and relevance of Akt inhibition to TRAIL-induced apoptosis in gliomas. 3) determine the mechanisms of TRAIL resistance in normal brain and resistant glioma cells in human living tumor/ brain slice model and the effects of modulating these mechanisms on TRAIL sensitivity. The combined use of human living brain slices and intracranial xenograft models are aimed at providing direct and highly relevant data on the efficacy of TRAIL against human gliomas and its toxicity against the brain . The results of this study could also potentially provide a basis for clinical trials using TRAIL or analogues against gliomas and allow rational selection of agents to modulate the tumor resistance to TRAIL.

恶性神经胶质瘤与高发病率和死亡率相关。标准疗法，例如手术、放射 治疗和化疗不能提供有效的选择，局部复发是常态。然而，在本地 恶性非转移性肿瘤，可以使用有效的肿瘤靶向局部疗法来控制它们。肿瘤坏死因子- 相关凋亡诱导配体（TRAIL/Apo2L）在体外诱导神经胶质瘤细胞凋亡并延长神经胶质瘤的生存期 啮齿动物异种移植模型。它对动物模型（包括灵长类动物）的正常器官无毒。然而，功效 TRAIL 的局部颅内递送、其对肿瘤附近大脑的毒性以及对人类神经胶质瘤的选择性 有待充分探讨。在这项研究中，我们将测试 TRAIL 在活体人类神经胶质瘤和大脑中的功效和毒性 切片模型和异种移植模型。我们的初步数据表明可溶性 TRAIL 在体外具有抗神经胶质瘤活性 在体内，其活性受 Akt 途径调节。我们假设： a) 可溶性未标记 TRAIL 将 对人类神经胶质瘤有效且对正常大脑无毒 2) 抑制 Akt 可使人类神经胶质瘤对 TRAIL 和增加神经胶质瘤模型中的存活率 3) 对 TRAIL 的抵抗是由正常细胞中的不同机制介导的 和肿瘤细胞允许选择性靶向肿瘤中的耐药机制。为了检验这些假设，我们 提出以下具体目标 1) 确定可溶性未标记 TRAIL 表达的功效和毒性 小鼠颅内异种移植物和离体活人神经胶质瘤切片模型中的腺病毒。 2) 体内测定 Akt 抑制对 TRAIL 诱导的神经胶质瘤细胞凋亡的影响和相关性。 3）确定TRAIL的机制 正常脑和人类活体肿瘤/脑切片模型中的耐药神经胶质瘤细胞的耐药性以及 调节这些机制对 TRAIL 敏感性的影响。人活体脑片与颅内联合使用 异种移植模型旨在提供有关 TRAIL 对人类神经胶质瘤疗效的直接且高度相关的数据 及其对大脑的毒性。这项研究的结果也可能为临床试验提供基础 TRAIL 或类似物对抗神经胶质瘤，并允许合理选择药物来调节肿瘤对 TRAIL 的抗性。