Epigenetic modifiers of the GTF2I axis in thymomas and acute lymphoblastic leukemias: a new repurposing paradigm across rare tumors (THYMALL)

GTF2I is a transcription factor involved in the pathogenesis/progression of several rare cancers, including thymic epithelialtumours (TETs), the most frequent adult mediastinal cancer, and acute lymphoblastic leukaemia (ALL), the most common paediatric cancer and the major cause of cancer-related death before the age of 20. Both pathologies are challenging to treat and pose a major public health concern.TETs are caused mainly by a recurrent GTF2I driver mutation, known as p.L383H/L424H, found in up to 49% of patients, proven oncogenic in murine thymic epithelial cells (TECs). In ALL, recurrent, coding rearrangements affecting the double homeobox 4 (DUX4) transcription factor have been described in up to 10% of cases. We found that GTF2I is required for the activity of DUX4-r in ALL. Our published and preliminary data indicate that pharmacological targeting of GTF2I HDAC/LSD1 co-factors/regulators is a promising therapeutic avenue for TETs and ALL. Here, we will combine cellular, mini-organs and animal models with cutting edge transcriptomic, epigenomic and proteomic approaches,to characterise the safety and efficacy of GTF2I pharmacological targeting at molecular and functional levels in pre-clinical settings. We will test compounds that already dispose of a licenced marked authorisation for drug repurposing and new ones to be introduced in the market as compounds with superior activity to provide proof-of-concept for a novel GTF2I-targeted therapy for TETs and ALL.