Efficacy and toxicity of TRAIL against gliomas

TRAIL对抗胶质瘤的功效和毒性

• 批准号: 7033212
• 负责人: VINAY K PUDUVALLI
• 金额: $ 23.39万
• 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/7033212
• 关键词: Adenoviridae; RNA interference; antineoplastics; apoptosis; astrocytes; athymic mouse; cell line; clinical research; cysteine endopeptidases; drug resistance; drug screening /evaluation; glioma; human tissue; immunocytochemistry; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nonhuman therapy evaluation; receptor expression; survivin; tissue /cell culture; transfection /expression vector; tumor necrosis factor alpha; xenotransplantation

DESCRIPTION (provided by applicant): 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.

描述（由申请方提供）：恶性胶质瘤与高发病率和死亡率相关。标准疗法如手术、放射疗法和化学疗法不能提供有效的选择，局部复发是常态。然而，作为局部恶性非转移性肿瘤，它们可能适合使用有效的肿瘤靶向局部治疗来控制。肿瘤坏死因子相关凋亡诱导配体（TRAIL/Apo 2L）在体外诱导胶质瘤细胞凋亡并在异种移植啮齿动物模型中诱导胶质瘤存活。在包括灵长类动物在内的动物模型中对正常器官无毒。然而，局部颅内递送TRAIL的功效、其对脑肿瘤邻近区域的毒性以及对人类胶质瘤的选择性仍有待充分探索。在本研究中，我们将在活体人脑胶质瘤和脑切片模型以及异种移植模型中测试TRAIL的疗效和毒性。我们的初步数据表明可溶性TRAIL在体外和体内对神经胶质瘤具有活性，并且其活性受Akt途径调节。我们假设：a）可溶性未标记的TRAIL将有效对抗人神经胶质瘤并且对正常脑无毒2）Akt的抑制可以使人神经胶质瘤对TRAIL敏感并且增加神经胶质瘤模型中的存活3）对TRAIL的抗性由正常细胞和肿瘤细胞中的不同机制介导，允许选择性靶向肿瘤中的抗性机制。为了测试这些假设，我们提出了以下具体目标：1）确定由腺病毒表达的可溶性未标记的TRAIL在小鼠颅内异种移植物和离体活的人神经胶质瘤切片模型中的功效和毒性。2)确定在胶质瘤中Akt抑制对TRAIL诱导的细胞凋亡的体内作用和相关性。3)在人活体肿瘤/脑切片模型中确定正常脑和抗性胶质瘤细胞中TRAIL抗性的机制以及调节这些机制对TRAIL敏感性的影响。人活体脑切片和颅内异种移植物模型的组合使用旨在提供关于TRAIL对人神经胶质瘤的功效及其对脑的毒性的直接和高度相关的数据。本研究的结果也可能为使用TRAIL或类似物治疗胶质瘤的临床试验提供基础，并允许合理选择药物来调节肿瘤对TRAIL的耐药性。