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

项目摘要： 多形性胶质母细胞瘤是最常见的原发性脑肿瘤，约有8500例 每年在美国确诊。在15个月的时间内， 尽管进行了治疗，患者还是死于这种有害的疾病。因此，小说， 理想地，肿瘤特异性方法是对抗这些肿瘤所必需的。而单身 试剂可以有效地靶向其它肿瘤，例如血液恶性肿瘤， 胶质母细胞瘤是惊人的不同，因为它是一种肿瘤，其特征是广泛的 异质性，要求同时抑制理想的几个失调 途径。我们之前的研究表明，针对线粒体基质 分子伴侣显示出显著的抗神经胶质瘤作用。在这份报告中，一个成功的 一组研究人员将描述一种新的胶质母细胞瘤治疗概念， 肿瘤线粒体中两种失调途径的双重靶向。在第一个具体的 我们将测试这种新的治疗概念，利用几种体外模型系统， 胶质母细胞瘤，特别关注所谓的干细胞样胶质瘤细胞， 肿瘤细胞在这些肿瘤中驱动治疗抗性。我们的初步数据 表明我们的治疗概念有效地靶向了这一关键细胞群。为了 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 这种治疗方法所涉及的机制，这是我们的核心 建议，并可能进一步使我们能够更好地了解和定制治疗， 潜在地对特别可能受益于该治疗方法的患者进行分层。 在第三个具体目标中，我们将在目前的体内模型中测试这种治疗概念。 这将扩展我们的初步数据，表明这一点， 治疗概念在体内是有效的。总的来说，这项研究可以提高我们的 了解脑肿瘤的治疗，并可能使我们能够 为胶质母细胞瘤制定了新的治疗策略。

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.