Efficacy and toxicity of TRAIL against gliomas

TRAIL对抗胶质瘤的功效和毒性

• 批准号: 7167160
• 负责人: VINAY K PUDUVALLI
• 金额: $ 22.71万
• 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/7167160
• 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

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有关。诸如手术，放射疗法和化学疗法等标准疗法不能提供有效的选择，局部复发是常态。但是，作为局部恶性非转移性肿瘤，它们可能可以使用有效的肿瘤局部疗法来控制。 TNF相关的凋亡诱导配体（TRAIL/APO2L）在体外诱导神经胶质瘤的凋亡，并延长异种移植啮齿动物模型的生存。在包括灵长类动物在内的动物模型中，它对正常器官是无毒的。然而，局部颅内分娩的疗效，其对脑染色到肿瘤的毒性以及对人类神经胶质瘤的选择性的毒性仍有待充分的探索。在这项研究中，我们将在活着的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，可溶性步道在体外和体内对神经胶质瘤具有活性，并且其活性由AKT途径调节。我们假设：a）a）可溶性的未加入的径径将有效抵抗人神经胶质瘤，对正常脑的无毒2）抑制AKT可以使人神经胶质瘤敏感以在神经胶质瘤模型中趋向于trail和增加生存率3）对TRAIL的耐药性3）对正常和肿瘤细胞中的差异机制介导了抑制型号和肿瘤细胞，可选择性的抵抗机制，使其允许在抗电阻机构中进行抗球形机制。为了检验这些假设，我们提出以下特定目的1）确定腺病毒在小鼠颅内异种移植物中表达的可溶性未加密步道的疗效和毒性，并确定颅内异种移植物中的腺病毒和前活体人神经胶质瘤切片模型。 2）确定Akt抑制与trail诱导的神经胶质瘤中的体内效应和相关性。 3）确定正常脑和耐药性神经胶质瘤细胞在人类生活肿瘤/脑切片模型中的耐trail耐药性的机制，以及调节这些机制对跟踪灵敏度的影响。人类活着的脑切片和颅内异种移植模型的综合使用旨在提供有关针对人神经胶质瘤的疗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以潜在地为使用针对神经胶质瘤的TRAIL或类似物的临床试验提供基础，并允许理性选择剂来调节肿瘤对越野的阻力。