Efficacy and toxicity of TRAIL against gliomas

恶性胶质瘤具有较高的发病率和死亡率。标准疗法，如手术、放射治疗 治疗和化疗不能提供有效的选择，局部复发是常态。然而，作为一个本地的 恶性非转移性肿瘤，他们可能是服从控制使用有效的肿瘤靶向的局部治疗。肿瘤坏死因子- 相关凋亡诱导配体(TRAIL/Apo2L)体外诱导脑胶质瘤细胞凋亡并延长生存期 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，它对正常器官无毒。然而，这种药物的功效 TRAIL的脑内局部给药及其对脑邻近肿瘤的毒性和对胶质瘤的选择性 仍有待充分探索。在这项研究中，我们将测试TRAIL对活体人脑胶质瘤的疗效和毒性。 切片模型和异种移植模型。我们的初步数据表明，可溶性TRAIL在体外对胶质瘤具有活性。 并且在体内，其活性受到Akt通路的调节。我们假设：a)可溶的未标记的踪迹将 对人脑胶质瘤有效，对正常脑无毒2)抑制Akt可使人脑胶质瘤对 TRAIL与提高脑胶质瘤模型的存活率3)TRAIL抵抗是通过不同的机制在正常 肿瘤细胞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)确定可溶性未标记TRAIL的有效性和毒性 腺病毒在小鼠脑内移植瘤和体外活体人脑胶质瘤切片模型中的应用。2)体内测定 Akt抑制在TRAIL诱导的胶质瘤细胞凋亡中的作用及相关性。3)确定TRAIL的作用机制 人脑活体肿瘤/脑片模型中正常脑和脑胶质瘤耐药细胞的耐药及丹参的影响 调节这些机制对痕迹敏感性的影响。活体人脑切片与颅脑的联合应用 异种移植模型的目的是提供关于TRAIL抗人脑胶质瘤疗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潜在的基础 TRAIL或类似物抗胶质瘤，并允许合理选择药物来调节肿瘤对TRAIL的耐药性。

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.