Identification of targetable pathways of prognostic relevance involved in the biology of atypical teratoid/rhabdoid tumors (AT/RT).

• Applicant: Professor Dr. Martin Hasselblatt
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 258565917

Atypical teratoid/rhabdoid tumors (AT/RT) are malignant brain tumors mainly affecting young children. Despite aggressive therapeutic approaches, the prognosis of AT/RT remains dismal. Genetic alterations resulting in functional loss of SMARCB1 or SMARCA4 are characteristic. These genes are members of the evolutionarily highly conserved ATP-dependent SWI/SNF chromatin remodeling complex, which plays a key role in the epigenetic regulation of cell proliferation and differentiation. Little is known, however, on targetable downstream pathways involved in the oncogenic effects of SMARCB1 inactivation or SMARCA4 inactivation. We thus assume that investigation of downstream signaling pathways is essential for a better understanding of the molecular pathogenesis of AT/RT. The majority of AT/RT shows SMARCB1 deficiency. Based on our previous results in a fly model of SMARCB1-deficiency, we will therefore further investigate the role of identified candidate genes in the biology of AT/RT. Specifically, we are interested to learn why the function of the genes merlin, kibra and expanded is essential for the phenotype associated with knockdown of snr1, the fly homolog of SMARCB1. To this end, we will investigate signaling pathways using reporter assays and gene expression profiling in Drosophila melanogaster and confirm the role of identified pathways in human SMARCB1-deficient rhabdoid tumor cell lines. Some AT/RT show retained SMARCB1 function, but genetic alterations causing functional loss of SMARCA4. We therefore also aim to identify pathways involved in the detrimental effects of SMARCA4 deficiency. To achieve this goal, we will establish a fly model of SMARCA4 deficiency using brm knockdown flies. Using a modifier screen and more than 1000 fly strains expressing various siRNA constructs, we will identify those genes functionally involved in the phenotype associated with brm knockdown. The functional role of identified candidate genes will be confirmed in human SMARCA4-deficient human rhabdoid tumor cell lines by exploring the effect of siRNA silencing and pharmacological inhibition on tumor cell proliferation and migration.After confirming the importance of identified genes and pathways in a mouse xenograft model as well as examining the consequences of their expression on prognosis and therapy response in human AT/RT samples obtained through the European Rhabdoid Tumor Registry EU-RHAB, we will be able to provide novel avenues for targeted therapies. In the long-term, our goal is to provide the prerequisites for a better treatment of children with AT/RT. Our results might also contribute to better treatment of other tumor entities showing functional loss of SMARCB1 or SMARCA4.

• DFG Programme: Research Grants
• Participating Person: Professor Michael Frühwald, Ph.D.