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Dual Inhibition of Mitochondrial Matrix Chaperones and Anti-Apoptotic Bcl-2 Family Members for Glioblastoma Therapy.

线粒体基质伴侣和抗凋亡 Bcl-2 家族成员的双重抑制用于胶质母细胞瘤治疗。

基本信息

批准号：
9190880
负责人：
MARKUS D SIEGELIN
金额：
$ 35万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9190880
关键词：
Adult Adverse effects Affect Animal Model Apoptosis Apoptotic Autophagocytosis BCL2 gene Biological Models Brain Neoplasms Cell Death Cells Clinical Clinical Trials Combined Modality Therapy Data Development Diagnosis Disease Drug Combinations Family member Geldanamycin Genetic Glioblastoma Glioma Goals Hematologic Neoplasms Heterogeneity In Vitro Inner mitochondrial membrane Life Expectancy MCL1 gene Malignant neoplasm of brain Mediating Membrane Mitochondria Mitochondrial Matrix Molecular Chaperones Mus Neoplasms Normal Cell Noxae Outer Mitochondrial Membrane Pathway interactions Patients Pharmacotherapy Population Primary Brain Neoplasms Protein Family Proteins Reagent Research Research Personnel Resistance Solid Neoplasm Staging Stem cells TP53 gene Testing Therapeutic Time Toxic effect Transgenic Organisms Treatment Efficacy Treatment Protocols United States Work Xenograft Model Xenograft procedure activating transcription factor 4 antitumor effect apoptosis deregulation combat cytotoxic effective therapy expectation falls improved in vitro Model in vivo in vivo Model individualized medicine inhibitor/antagonist innovation malignant breast neoplasm melanoma mimetics neoplastic cell novel outcome forecast patient stratification public health relevance receptor therapy resistant treatment strategy tumor tumor growth tumor heterogeneity tumor xenograft

项目摘要

Project Summary: Glioblastoma multiforme is the most common primary brain tumor with about 8500 cases diagnosed each year in the United States. Within a time frame of 15 month virtually all patients succumb to this detrimental disease despite treatment efforts. Therefore, novel, ideally tumor specific approaches are necessary to combat these tumors. While single reagents may efficiently target other tumors, such as hematological malignancies, Glioblastoma is strikingly different since it is a tumor that is characterized by extensive heterogeneity, demanding the simultaneous inhibition of ideally several deregulated pathways. Our previous research has shown that targeting mitochondrial matrix chaperones displays significant anti-glioma effects. In this proposal, an accomplished team of investigators will be characterizing a novel treatment concept for glioblastoma by dual targeting of two deregulated pathways in tumor mitochondria. In the first specific aim we will test this novel treatment concept, utilizing several in vitro model systems of glioblastoma with a special focus on so called stem cell-like glioma cells, a population of tumor cells that drive therapeutic resistance in these neoplasms. Our preliminary data indicate that our treatment concept efficiently targets this pivotal cell population. In order to further improve our treatment concept we will study the cell death mechanisms involved in the combination treatment. In the second aim, we will characterize the mechanisms that are involved in this treatment approach, which is a centerpiece of our proposal and may further allow us to better understand and tailor treatments and potentially to stratify patients that in particular may benefit from this treatment approach. In the third specific aim we will test this treatment concept in current in vivo model systems of glioblastoma, which will extend our preliminary data that suggest that this treatment concept is active in vivo. Overall, this research may enhance our understanding about the treatment of brain tumors and may potentially allow us to formulate a novel treatment strategy for glioblastoma.

项目总结：摘要多形性胶质母细胞瘤是最常见的脑部原发肿瘤，约8500例。在美国每年都会被确诊。在15个月的时间框架内几乎所有尽管做出了治疗努力，患者仍会死于这种有害的疾病。因此，小说，理想情况下，肿瘤特异性治疗方法是对抗这些肿瘤的必要手段。单身时试剂可以有效地针对其他肿瘤，如血液系统恶性肿瘤，胶质母细胞瘤是一种显著不同的肿瘤，它的特点是广泛异质性，需要同时抑制理想的几个解除管制小路。我们之前的研究表明，靶向线粒体基质伴侣具有显著的抗神经胶质瘤作用。在这个提案中，一个有成就的人一组研究人员将通过以下方式描述胶质母细胞瘤的新治疗概念肿瘤线粒体中两条非调控通路的双重靶向。在第一个具体的目的我们将利用几个体外模型系统来测试这一新的治疗概念。胶质母细胞瘤，特别关注所谓的干细胞样脑胶质瘤细胞，在这些肿瘤中驱动治疗耐药性的肿瘤细胞。我们的初步数据表明我们的治疗理念有效地针对这一关键细胞群体。按顺序为了进一步完善我们的治疗理念，我们将研究细胞死亡机制。参与联合治疗。在第二个目标中，我们将描述这种治疗方法涉及的机制，这是我们的核心建议，并可能进一步允许我们更好地了解和量身定做治疗和潜在地对可能从这种治疗方法中受益的患者进行分层。在第三个具体目标中，我们将在当前的活体模型中测试这一治疗概念胶质母细胞瘤系统，这将扩展我们的初步数据，表明这治疗理念在体内是活跃的。总的来说，这项研究可能会增强我们的对脑瘤治疗的了解，可能会让我们制定治疗胶质母细胞瘤的新策略。