Extensive preclinical validation of combinations of targeted treatment for peripheral T cell lymphoma

Peripheral T cell lymphoma (PTCL) is a rare T cell neoplasm for which no effective treatment is available other than chemotherapy. Previous data from our lab indicates that up to 50% of PTCL cases harbor mutations in components of T cell receptor (TCR) signaling, and we hypothesize that this could be targeted with an overarching approach. Therefore, the aim of this project is to further explore the possibility to target downstream effectors of the TCR signaling pathway in the in vivo pre-clinical models we have already generated. First of all, I will validate the role of TCR signaling pathway mutations in activating this pathway. Secondly, I aim to study the efficacy of (combined) targeted treatments in vivo, as we have preliminary in vitro evidence for the efficacy of specific compounds targeting NF-kB or MAPK signaling. We have also generated evidence that overactivation of TCR signaling leads to an increased sensitivity for compounds that target apoptosis. Therefore, I will perform an apoptosis compound screen, and select the most promising hits of this screen for further validation ex vivo and in vivo. Finally, we want to establish PTCL patient-derived xenograft (PDX) models, which I will use to validate our findings. This research aims to provide new rationales for the set-up of clinical trials for PTCL patients. Ultimately, we want to instigate investigator- driven trials at UZ Leuven and beyond, based on our findings from these pre-clinical studies.