Validation of the transcription factor MITF and melanosomal protein expression as therapeutic targets in atypical teratoid rhabdoid tumors (ATRT)

• Applicant: Professor Dr. Pascal Johann
• Subject Area: Hematology, Oncology ; Pediatric and Adolescent Medicine
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 419396088

Atypical teratoid, rhabdoid tumors (ATRT) are tumors of infancy and childhood that are all characterized either by the loss of SMARCB1 (95% of all cases) or SMARCA4 (5% of all cases) both of which are components of the SWI/SNF complex, an epigenetic remodeling protein complex. Mortality of children with ATRT is still high and the few survivors often suffer from debilitating long-term side effects. New therapeutic approaches are therefore urgently needed.Despite the genetic simplicity of these tumors, recent studies have found a high degree of epigenetic heterogeneity: Three subgroups were identified at the methylation level (named ATRT-TYR, ATRT-SHH, ATRT-MYC). One of these subgroups, ATRT-TYR, displays overexpression of melanosomal marker genes. In particular MITF is overexpressed, a well known oncogene in melanoma. Here way aim to delineate the suitability of MITF and coregulated proteins as potential drug targets in ATRT-TYR. We will perform in vitro studies with MITF inhibitors in cell lines to see if MITF downregulation impedes ATRT growth in vitro. Beyond this, we will knock-down MITF in ATRT cell lines and assess the effect on the transcriptome of the tumor cells. As an additional in vitro step, we will unravel proteins that co-bind to the DNA together with MITF. By this we seek to gain additional insights into MITF coregulatory proteins that may represent additional therapeutic targets. Translating these in vitro findings we aim to perform mouse treatment studies to see if MITF inhibition in xenograft models of ATRT leads to a survival benefit. Overall, by combining in vitro and in vivo treatment and knock-down studies we will comprehensively evaluate if MITF inhibition represents a viable strategy for ATRT-TYR tumors and thus seek to establish additional therapeutic avenues for this deadly disease.

• DFG Programme: Research Grants