Efficacy and toxicity of TRAIL against gliomas

描述（由申请人提供）：恶性胶质瘤具有高发病率和高死亡率。手术、放疗和化疗等标准疗法并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来控制。TNF-相关凋亡诱导配体（TRAIL/Apo2L）在体外诱导胶质瘤细胞凋亡并延长异种移植小鼠模型的存活时间。对包括灵长类动物在内的动物模型的正常器官无毒。然而，TRAIL局部颅内递送的有效性、对脑邻近肿瘤的毒性以及对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在体外和体内对胶质瘤有活性，其活性受Akt通路的调节。我们假设：a)可溶性无标记TRAIL将对人类胶质瘤有效，对正常大脑无毒；2)抑制Akt可使人类胶质瘤对TRAIL敏感，并增加胶质瘤模型中的存活；3)正常细胞和肿瘤细胞对TRAIL的抗性是由不同机制介导的，允许选择性靶向肿瘤中的抗性机制。为了验证这些假设，我们提出以下具体目标：1)确定由腺病毒表达的可溶性无标记TRAIL在小鼠颅内异种移植物和离体活体胶质瘤切片模型中的功效和毒性。2)确定Akt抑制与trail诱导的胶质瘤细胞凋亡的体内效应及其相关性。3)确定正常脑和人活体肿瘤/脑切片模型中耐药胶质瘤细胞的TRAIL耐药机制，以及调节这些机制对TRAIL敏感性的影响。人类活脑切片和颅内异种移植模型的联合使用旨在为TRAIL对人类胶质瘤的疗效及其对大脑的毒性提供直接和高度相关的数据。本研究结果也可能为临床试验使用TRAIL或类似物治疗胶质瘤提供基础，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.