Mechanisms of progression in malignant rhabdoid tumors

恶性横纹肌瘤的进展机制

• 批准号: 424984165
• 负责人: Professor Dr. Michael Frühwald, Ph.D.
• 金额: --
• 依托单位: Klinik für Kinder- und Jugendmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/424984165?language=en
• 关键词: Mechanisms; progression; malignant; rhabdoid; tumors

Rhabdoid tumors are aggressive malignancies of childhood primarily affecting the CNS and the kidney, but also in other locations. Although many tumors respond favourably to primary therapy, most children face recurrences that may only be survived in rare, single cases. It is assumed that a functional loss of the INI1 protein, which is encoded by the SMARCB1 gene, significantly contributes to the development of all rhabdoid tumors. Nevertheless, recent work indicates that tumor recurrences are generally initiated by a plethora of molecular alterations that were hardly or not at all detectable in the primary tumor. It is therefore the overall goal of this research proposal to identify molecular mechanisms, which are responsible for the progression and recurrence of rhabdoid tumors.First, we will detect features that have developed in the recurrence at various levels. Therefore, we will analyze specimens from recurrent rhabdoid tumors on a genetic, epigenetic, and morphological level and compare the results with analyses from corresponding germlines and primary tumors. Furthermore, we will correlate the detected alterations with clinical parameters in order to identify clinical effects of such alterations.In a second step, we will introduce the detected alterations into human rhabdoid tumor cells in order to evaluate the functional consequences of such recurrence-specific features. Manipulated cells will then be implanted into the brain of host mice in order to compare the effects on tumor growth, tumor distribution, and survival. Finally, we aim at providing patients, who suffer from recurrent rhabdoid tumors, with compounds specifically targeted at previously identified and validated molecular causes for rhabdoid tumor recurrences. To this end, we will first use existing data on the effects of tumor resection, radiotherapy, chemotherapy, or targeted therapies in order to identify possible correlations of clinical and molecular parameters. Furthermore, depending on availability, we will systematically test new compounds in vitro and in vivo that directly inhibit the altered protein or that target the altered pathway further downstream.Taken together, we hope that this research project will produce significant progress regarding the molecular understanding of rhabdoid tumor recurrences and first angles regarding targeted therapies for children with recurrent rhabdoid tumors.

横纹肌样瘤是儿童期侵袭性恶性肿瘤，主要累及中枢神经系统和肾脏，但也累及其他部位。虽然许多肿瘤对初级治疗反应良好，但大多数儿童面临复发，仅在罕见的单一病例中存活。据推测，由SMARCB 1基因编码的INI1蛋白的功能丧失显著促进了所有横纹肌样肿瘤的发展。然而，最近的研究表明，肿瘤复发通常是由过多的分子改变引起的，这些分子改变在原发性肿瘤中几乎检测不到或根本检测不到。因此，本研究的总体目标是确定横纹肌样瘤进展和复发的分子机制。首先，我们将检测不同水平复发的特征。因此，我们将在遗传、表观遗传和形态学水平上分析复发性横纹肌样肿瘤的标本，并将结果与相应种系和原发性肿瘤的分析结果进行比较。此外，我们将检测到的改变与临床参数相关联，以确定这些改变的临床效果。在第二步中，我们将检测到的改变引入人横纹肌样肿瘤细胞，以评估这些复发特异性特征的功能后果。然后将操作的细胞植入宿主小鼠的大脑中，以比较对肿瘤生长，肿瘤分布和存活的影响。最后，我们的目标是为患有复发性横纹肌样肿瘤的患者提供特异性靶向先前鉴定和验证的横纹肌样肿瘤复发的分子原因的化合物。为此，我们将首先使用肿瘤切除、放疗、化疗或靶向治疗效果的现有数据，以确定临床和分子参数之间可能的相关性。此外，我们还将在体外和体内系统地测试直接抑制改变的蛋白质或靶向下游改变的通路的新化合物，我们希望该研究项目将在横纹肌样瘤复发的分子理解方面取得重大进展，并为横纹肌样瘤复发儿童的靶向治疗提供第一个角度。