FRRB Project 3439334 - Epigenetic modifiers of the GTF2I axis in thymomas and acute lymphoblastic leukemias: a new repurposing paradigm across rare tumors
The Coordinator of the project is Istituto Europeo di Oncologia S.r.l. IRCCS. The Lead Principal Investigator of the project is Prof. Giuseppe Testa.
| Pathology: | Thymoma and Acute Lymphoblastic Leukemia |
| Tematic Area: | Oncology - Rare Tumors |
| Project Start Date: | May 1, 2023 |
| Project End Date: | April 30, 2026 |
| Funding: | € 1.248.000,80 |
| Project Partners: | - Istituto Europeo di Oncologia S.r.l. IRCCS - Università degli Studi di Milano - Istituto FIRC di Oncologia Molecolare - IFOM - Ospedale San Raffaele S.r.l. IRCCS |
PROJECT SUMMARY
GTF2I is a transcription factor involved in the pathogenesis and progression of several rare cancers including thymic epithelial tumors (TETs), the most frequent adult mediastinal cancers, and acute lymphoblastic leukemia (ALL), the most common pediatric cancer and the major cause of cancer-related death before the age of 20. Both pathologies can be difficult to treat and pose a major public health concern.
TETs are caused mainly by a recurrent GTF2I driver mutation, known as p.L383H/L424H, occurring in up to 49% of patients, that has been proven oncogenic in murine thymic epithelial cells (TECs) (Kim et al. 2021). In ALL, recurrent rearrangements affecting the double homeobox 4 (DUX4) transcription factor and producing rearranged DUX4 (DUX4-r) 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, together with cutting edge transcriptomic, epigenomic and proteomic approaches, to characterize safety and efficacy of GTF2I pharmacological targeting at molecular and functional levels in pre-clinical settings. Our work will provide proof-of-concept for a novel targeted therapy for TETs and ALL associated to GTF2I.