Efficacy and toxicity of TRAIL against gliomas

TRAIL对抗胶质瘤的功效和毒性

• 批准号: 7340756
• 负责人: VINAY K PUDUVALLI
• 金额: $ 18.17万
• 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/7340756
• 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

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.

恶性神经胶质瘤具有高发病率和高死亡率。标准疗法，比如手术，放疗