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（由申请人提供）：恶性神经胶质瘤与高发病率和死亡率相关。手术、放射治疗和化疗等标准疗法无法提供有效的选择，局部复发是常态。然而，由于它们是局部恶性非转移性肿瘤，因此可以使用有效的肿瘤靶向局部疗法来控制它们。 TNF 相关细胞凋亡诱导配体 (TRAIL/Apo2L) 可在体外诱导神经胶质瘤细胞凋亡，并延长异种移植啮齿动物模型的存活时间。它对动物模型（包括灵长类动物）的正常器官无毒。然而，TRAIL 局部颅内递送的功效、其对肿瘤邻近大脑的毒性以及对人类神经胶质瘤的选择性仍有待充分探索。在这项研究中，我们将在活体人类神经胶质瘤和脑切片模型以及异种移植模型中测试 TRAIL 的功效和毒性。我们的初步数据表明，可溶性 TRAIL 在体外和体内均具有抗神经胶质瘤活性，并且其活性受 Akt 途径调节。我们假设：a) 可溶性未标记的 TRAIL 将有效对抗人类神经胶质瘤，并且对正常大脑无毒 2) 抑制 Akt 可以使人类神经胶质瘤对 TRAIL 敏感并增加神经胶质瘤模型的存活率 3) 对 TRAIL 的耐药性是由正常细胞和肿瘤细胞中的不同机制介导的，从而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）确定腺病毒在小鼠颅内异种移植物和离体活人神经胶质瘤切片模型中表达的可溶性未标记TRAIL的功效和毒性。 2) 确定 Akt 抑制对 TRAIL 诱导的神经胶质瘤细胞凋亡的体内作用和相关性。 3)确定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TRAIL抵抗机制以及调节这些机制对TRAIL敏感性的影响。人类活体脑切片和颅内异种移植模型的结合使用旨在提供有关 TRAIL 对人类神经胶质瘤的功效及其对大脑的毒性的直接且高度相关的数据。这项研究的结果还可能为使用 TRAIL 或类似物对抗神经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。