Efficacy and toxicity of TRAIL against gliomas

描述(申请人提供)：恶性胶质瘤与高发病率和死亡率有关。手术、放射治疗和化疗等标准疗法不能提供有效的选择，局部复发是常态。然而，作为局部恶性的非转移性肿瘤，它们可能可以通过有效的肿瘤靶向局部治疗进行控制。肿瘤坏死因子相关凋亡诱导配体(TRAIL/Apo2L)体外诱导胶质瘤细胞凋亡，延长异种鼠移植瘤存活时间。在包括灵长类动物在内的动物模型中，它对正常器官无毒。然而，TRAIL的局部颅内给药的有效性、对脑瘤的毒性以及对人脑胶质瘤的选择性仍有待于充分的研究。在这项研究中，我们将测试TRAIL在活体人脑胶质瘤脑片模型和异种移植模型中的疗效和毒性。我们的初步数据表明，可溶性TRAIL在体外和体内都具有抗胶质瘤的活性，其活性受Akt途径的调节。我们假设：a)可溶的未标记TRAIL对人脑胶质瘤有效，对正常脑组织无毒；2)抑制Akt可增强人脑胶质瘤对TRAIL的敏感性，提高胶质瘤模型的存活率；3)TRAIL抵抗是由正常细胞和肿瘤细胞中允许选择性靶向肿瘤耐药机制的不同机制介导的。为了验证这些假说，我们提出了以下具体目标：1)确定腺病毒表达的可溶性非标记TRAIL在小鼠脑内异种移植瘤和体外活人胶质瘤切片模型中的有效性和毒性。2)确定Akt抑制对TRAIL诱导的胶质瘤细胞凋亡的体内作用及其相关性。3)探讨TRAIL在正常脑和人脑活体肿瘤/脑片模型中耐药的机制及其对TRAIL敏感性的调节作用。结合使用活体人脑切片和颅内异种移植模型，旨在提供关于TRAIL抗人脑胶质瘤疗效及其对脑的毒性的直接和高度相关的数据。这项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。

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.