Using Cell-Penetrant Peptides to Target ATF5 in Mouse Glioma Models

在小鼠神经胶质瘤模型中使用细胞渗透肽靶向 ATF5

• 批准号: 8999034
• 负责人: James M Angelastro
• 金额: $ 32.54万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8999034
• 关键词: Address; Adverse effects; Animal Model; Animals; Apoptosis; Apoptotic; Astrocytes; Awareness; Behavior; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Cardiotoxicity; Case Study; Cell Death; Cells; Cessation of life; Chemistry; Combined Modality Therapy; Data; Dominant-Negative Mutation; Dose; Excision; Gene Expression; Gene Expression Regulation; Genes; Glial Differentiation; Glioblastoma; Glioma; Goals; Health; Hepatotoxicity; Histology; Human; In Vitro; Kidney; Knowledge; Lead; Life; Liver; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Modeling; Molecular; Mus; Neoplasms; Neuroglia; Neuronal Differentiation; Neurons; Normal Cell; Normal tissue morphology; Operative Surgical Procedures; Organ; Outcome; Pathway interactions; Peptides; Pharmaceutical Preparations; Pilot Projects; Plasma; Platelet-Derived Growth Factor; Play; Predisposition; Proteins; Protocols documentation; Recombinants; Recurrence; Recurrent tumor; Resistance; Role; Route; Schedule; Serum; Small Interfering RNA; Stem cells; Stream; TP53 gene; Testing; Therapeutic; Therapeutic Index; Tissues; Toxic effect; Treatment Protocols; Tumor Stem Cells; Work; Xenograft procedure; activating transcription factor; base; brain cell; brain tissue; cancer cell; cancer stem cell; chemotherapy; efficacy testing; human stem cells; in vivo; insight; killings; mouse model; neoplastic cell; nephrotoxicity; nerve stem cell; neurotoxicity; novel; novel therapeutic intervention; pre-clinical; prevent; progenitor; relating to nervous system; small hairpin RNA; stem; temozolomide; transcription factor; transcriptome; treatment duration; tumor

DESCRIPTION (provided by applicant): Brain glioma tumors, unequivocally glioblastoma multiforme (GBM), are among the most incurable forms of cancer. Such tumors are thought to arise from brain neural stem cells and progenitors that have undergone transformation into neoplasias. Neoplastic stem cells are thought to contribute to the recurrence of the glioma after chemotherapy and surgical resection. We found that activating transcription factor 5 (ATF5) is highly expressed in neural stem/progenitor cells, including cancer stem cells and GBMs. Blocking ATF5 function by dominant negative ATF5 (d/n-ATF5) or siRNA-ATF5 promotes apoptosis of glioma tumor cells, but not of non- neoplastic cells, both in vitro and in vivo. Currently, we synthesize recombinant cell penetrant d/n-ATF5 peptide that crosses the blood brain barrier, and enters into glioma cells, promoting their rapid death. The long-term objectives of our study will be to further test, as well as determine the apparent therapeutic index, of cell penetrant d/n-ATF5 toward tumor regression or full eradication in a pre-clinical approach by using different glioblastoma mouse models. Our specific aims will be to 1) Define the most effective dosing schedule for delivery of the cell penetrant d/n-ATF5 that does not harm normal tissues; test efficacy in mouse glioma/glioblastoma models by creating brain tumors through de novo transformation of progenitors and by human GBM xenografts; determine whether treatment with the peptide can bring about long-term eradication of glioblastomas; and, in the case that tumors reappear after initial treatment, whether they can again be caused to regress by application of the d/n peptide. 2) To define the responsible molecular mechanistic pathways that mediate apoptotic actions of d/n-ATF5 in glioblastoma cells. To gain insight on these pathways will enlighten how neoplasm relies on ATF5 for survival that is not observed in non-transformed cells. Knowledge of the mechanistic routes will aid in predicting and circumventing off-target effects and will explain as well as promote avoidance of potential tumor resistance toward d/n-ATF5 therapy. Finally, synergy of d/n- ATF5 with other currently employed glioblastoma therapies will be more adequately addressed with awareness of such pathways.

描述（由申请人提供）：脑胶质瘤，明确地说是多形性胶质母细胞瘤（GBM），是最无法治愈的癌症形式之一。这种肿瘤被认为是由已经转化为肿瘤的脑神经干细胞和祖细胞产生的。肿瘤干细胞被认为导致化疗和手术切除后神经胶质瘤的复发。我们发现激活转录因子 5 (ATF5) 在神经干/祖细胞中高表达，包括癌症干细胞和 GBM。在体外和体内，通过显性失活ATF5(d/n-ATF5)或siRNA-ATF5阻断ATF5功能促进神经胶质瘤肿瘤细胞的凋亡，但不促进非肿瘤细胞的凋亡。目前，我们合成的重组细胞渗透性d/n-ATF5肽可以穿过血脑屏障，进入神经胶质瘤细胞，促进其快速死亡。我们研究的长期目标是通过使用不同的胶质母细胞瘤小鼠模型，在临床前方法中进一步测试并确定细胞渗透剂 d/n-ATF5 对肿瘤消退或完全根除的表观治疗指数。我们的具体目标是 1) 确定最有效的给药方案，用于递送不损害正常组织的细胞渗透剂 d/n-ATF5；通过祖细胞的从头转化和人类 GBM 异种移植物产生脑肿瘤，测试小鼠神经胶质瘤/胶质母细胞瘤模型的疗效；确定用肽治疗是否可以长期根除胶质母细胞瘤；以及，在初次治疗后肿瘤再次出现的情况下，是否可以通过应用d/n肽再次使肿瘤消退。 2) 确定在胶质母细胞瘤细胞中介导 d/n-ATF5 凋亡作用的分子机制途径。深入了解这些途径将揭示肿瘤如何依赖 ATF5 生存，而在非转化细胞中未观察到这一点。了解机制途径将有助于预测和规避脱靶效应，并将解释和促进避免肿瘤对 d/n-ATF5 治疗的潜在耐药性。最后，随着对此类途径的认识，d/n-ATF5 与其他目前使用的胶质母细胞瘤疗法的协同作用将得到更充分的解决。