Efficacy and toxicity of TRAIL against gliomas

恶性胶质瘤的发病率和死亡率高。标准治疗，如手术，放疗 治疗和化疗不能提供有效的选择，局部复发是常态。然而，在当地 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， 异种移植啮齿动物模型。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， 肿瘤坏死因子相关凋亡诱导配体的颅内局部给药及其对脑肿瘤的毒性和对人脑胶质瘤的选择性 仍有待充分探索。在这项研究中，我们将测试TRAIL在活体人脑胶质瘤中的疗效和毒性。 切片模型和异种移植模型。我们的初步数据表明可溶性TRAIL在体外对胶质瘤有活性 并且其活性由Akt途径调节。我们假设：a）可溶性未标记的TRAIL将 对人脑胶质瘤有效，对正常脑无毒2）抑制Akt可使人脑胶质瘤敏感， 3）对TRAIL的抗性是由正常胶质瘤中不同的机制介导的， 以及允许选择性靶向肿瘤中抗性机制的肿瘤细胞。为了验证这些假设，我们 提出以下具体目的：1）确定由一种表达的可溶性未标记的TRAIL的功效和毒性， 腺病毒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表达。2)测定体内 Akt抑制对TRAIL诱导胶质瘤细胞凋亡影响及其相关性3)确定TRAIL的机制 人活体肿瘤/脑切片模型中正常脑和耐药胶质瘤细胞中的耐药性以及 调节这些机制对TRAIL的敏感性。人活体脑片与颅内 异种移植模型旨在提供关于TRAIL对人神经胶质瘤的功效的直接和高度相关的数据 以及它对大脑的毒性这项研究的结果也可能为临床试验提供基础， TRAIL或类似物对神经胶质瘤的作用，并允许合理选择调节肿瘤对TRAIL耐药性的药物。

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.