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Overcoming apoptotic resistance in glioblastoma by CP-d/n-ATF5, a novel tumor spe

通过 CP-d/n-ATF5（一种新型肿瘤特异性）克服胶质母细胞瘤的细胞凋亡抵抗

基本信息

批准号：
8756885
负责人：
MARKUS D SIEGELIN
金额：
$ 18.74万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8756885
关键词：
Adverse effects Affect Americas Animal Model Apoptosis Apoptotic Astrocytes BCL2 gene Blood - brain barrier anatomy Brain Neoplasms Cell Cycle Arrest Cell Death Cell Line Cell Therapy Cells Cellular biology Cessation of life Clinical Trials Combination Drug Therapy Combined Modality Therapy Convection Cultured Tumor Cells Cyclic AMP-Responsive DNA-Binding Protein Data Development Plans Diagnosis Disease model Dominant-Negative Mutation Drug Combinations Drug Delivery Systems Drug resistance Employee Strikes Exhibits Funding Glioblastoma Glioma Goals Homologous Gene In Vitro Induction of Apoptosis Life Expectancy Ligands Malignant neoplasm of brain Mediating Mentors Modality Modeling Mus Mutate Names Neuroglia Neurons Normal Cell Normal tissue morphology PTEN gene Pathology Patients Peptides Pharmaceutical Preparations Physicians Preclinical Drug Development Primary Brain Neoplasms Protein Family Protein p53 Proteins Publications Reagent Recombinants Recurrence Research Research Personnel Research Project Grants Resistance Resistance development Scientist Small Interfering RNA TNFRSF10B gene TNFSF10 gene TP53 gene Testing Therapeutic Training Transgenic Organisms United States United States National Institutes of Health Universities Up-Regulation Work Xenograft Model activating transcription factor base cancer cell career career development design dosage effective therapy in vivo killings loss of function member neurosurgery novel outcome forecast pre-clinical programs protein p73 public health relevance receptor research study small hairpin RNA transcription factor treatment strategy tumor tumor eradication

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma multiform WHO IV (GBM) is the most common primary brain tumor with no current curative treatment, rapid progression and recurrence, leading to death within 12-18 month. The transcription factor ATF5, a member of the activating transcription factor (ATF)/cAMP response-element binding protein (CREB) family, is over-expressed in GBMs compared to non-neoplastic astrocytes and neurons. In this proposal ATF5 is targeted by a novel designed peptide drug, called CP-d/n-ATF5 (cell penetrating dominant-negative ATF5). Preliminary data show that CP-d/n-ATF5 effectively kills GBM cells in vitro and in vivo. We will determine the mechanism by which CP-d/n-ATF5 elicits its anti-glioma effects and test its suitability for drug combination therapy in vitro and in vivo. In our preliminry data, we have shown that CP-d/n-ATF5 mediates striking increases in p73, DR5 (a pro-apoptotic receptor for death ligand TRAIL) and PUMA (a pro-apoptotic Bcl-2 family protein) protein levels. P73 is a homolog of the tumor suppressor p53, which, in contrast to TP53 is not commonly mutated in GBM, but which shares similar downstream targets, e.g. DR5 and PUMA, that enhance apoptosis (programmed cell death) and promote cell cycle arrest. Therefore, reagents that induce p73 are highly valuable tumor therapeutics. We will test the hypothesis that CP-d/n-ATF5 kills GBM cells by up- regulating p73 that in turn induces death via PUMA-dependent apoptosis. We will also evaluate the hypotheses that induction of DR5 by CP-d/n-ATF5 is dependent on p73 and that elevated DR5 will permit a combination GBM therapy of CP-d/n-ATF5 with the DR5 ligand TRAIL. Our preliminary data with the TRAIL/CP-d/n-ATF5 combination demonstrate synergistic killing of GBM cells as compared to single treatments. These effects were mediated by CP-d/n-ATF5-induced up-regulation of DR5, and coincided with an increase of p73 protein levels. Specific suppression of DR5 by siRNA mitigates CP-d/n-ATF5/TRAIL mediated cell death. The research program will be conducted under the guidance of Dr. Lloyd Greene (Department of Pathology and Cell Biology at Columbia University) who has a significant track record of training physician-scientists and who has launched many careers of successful and accomplished biomedical researchers. As Co-Mentors will serve Drs. Peter Canoll (Department of Pathology and Cell Biology at Columbia University) and Jeffrey Bruce (Department of Neurosurgery). Dr. Canoll and Dr. Bruce are leading the Brain Tumor Center at Columbia and are highly accomplished. Both have active NIH-funded research projects related to glioblastoma animal models with sophisticated drug delivery systems. This proposed project along with its renowned and accomplished mentors, course work, training opportunities and career development plan will train the applicant in glioblastoma-related research with an emphasis on preclinical drug development and assist him to become an independent investigator.

描述（由申请人提供）：多形性胶质母细胞瘤WHO IV（GBM）是最常见的原发性脑肿瘤，目前无治愈性治疗，进展和复发迅速，导致12-18个月内死亡。转录因子ATF 5是转录激活因子（ATF）/cAMP反应元件结合蛋白（CREB）家族的成员，与非肿瘤性星形胶质细胞和神经元相比，在GBM中过表达。在该提案中，ATF 5被一种新设计的肽药物所靶向，称为CP-d/n-ATF 5（细胞穿透显性负性ATF 5）。初步数据显示，CP-d/n-ATF 5在体外和体内有效地杀死GBM细胞。我们将确定CP-d/n-ATF 5发挥其抗胶质瘤作用的机制，并测试其体外和体内药物联合治疗的适用性。在我们的细胞学数据中，我们已经表明，CP-d/n-ATF 5介导p73、DR 5（死亡配体TRAIL的促凋亡受体）和CD 4A（促凋亡Bcl-2家族蛋白）蛋白水平的显著增加。P73是肿瘤抑制因子p53的同源物，与TP 53相反，其在GBM中通常不突变，但其共享类似的下游靶点，例如DR 5和DR 4A，其增强细胞凋亡（程序性细胞死亡）并促进细胞周期停滞。因此，诱导p73的试剂是非常有价值的肿瘤治疗剂。我们将检验CP-d/n-ATF 5通过上调p73杀死GBM细胞的假设，p73又通过PUMA依赖性细胞凋亡诱导死亡。我们还将评估CP-d/n-ATF 5诱导DR 5依赖于p73和DR 5升高将允许CP-d/n-ATF 5与DR 5配体TRAIL联合GBM治疗的假设。我们关于TRAIL/CP-d/n-ATF 5组合的初步数据表明，与单一治疗相比，GBM细胞的协同杀伤。这些作用是由CP-d/n-ATF 5诱导的DR 5上调介导的，并且与p73蛋白水平的增加相一致。通过siRNA特异性抑制DR 5减轻了CP-d/n-ATF 5/TRAIL介导的细胞死亡。该研究计划将在Lloyd格林博士（哥伦比亚大学病理学和细胞生物学系）的指导下进行，他在培训医生科学家方面有着重要的记录，并且已经推出了许多成功和有成就的生物医学研究人员的职业生涯。作为共同导师将服务于彼得卡诺尔博士（病理学和细胞生物学系在哥伦比亚大学）和杰弗里布鲁斯（神经外科系）。卡诺尔博士和布鲁斯博士领导着哥伦比亚的脑肿瘤中心，他们非常有成就。两者都有积极的NIH资助的研究项目与胶质母细胞瘤动物模型与复杂的药物输送系统。这个拟议的项目沿着其著名的和有成就的导师，课程工作，培训机会和职业发展计划将培训申请人在胶质母细胞瘤相关的研究，重点是临床前药物开发，并帮助他成为一个独立的研究者。