Mechanisms of progression in malignant rhabdoid tumors

• Applicants: Professor Michael Frühwald, Ph.D.; Professor Dr. Ulrich Schüller
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Pediatric and Adolescent Medicine
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 424984165

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.

• DFG Programme: Research Grants