Mechanisms of progression in malignant rhabdoid tumors

横纹肌样肿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，但也可累及其他部位。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，可能只有在罕见的单个病例中才能存活。据推测，SMARCB1基因编码的INI1蛋白的功能缺失在所有横纹肌样肿瘤的发展中起着重要作用。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肿瘤中几乎无法或根本无法检测到。因此，确定横纹肌样肿瘤进展和复发的分子机制是本研究的总体目标。首先，我们将检测在不同级别的复发中发展起来的特征。因此，我们将从遗传学、表观遗传学和形态学水平上分析复发性横纹肌样肿瘤标本，并将结果与相应种系和原发肿瘤的分析结果进行比较。此外，我们将把检测到的改变与临床参数联系起来，以确定这种改变的临床效果。在第二步中，我们将把检测到的改变引入人类横纹肌瘤细胞，以评估这种复发特异性特征的功能后果。然后将操纵的细胞植入宿主小鼠的大脑，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专门针对先前确定和验证的横纹肌样肿瘤复发分子原因的化合物。为此，我们将首先利用肿瘤切除、放疗、化疗或靶向治疗的现有数据，以确定临床和分子参数之间可能的相关性。此外，根据可用性，我们将系统地在体外和体内测试直接抑制改变蛋白或靶向下游改变途径的新化合物。综上所述，我们希望本研究项目能够在横纹肌样肿瘤复发的分子认识方面取得重大进展，为儿童横纹肌样肿瘤复发的靶向治疗提供第一个视角。

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.