SMAD7 expression and radiotoxicity: Clarification of mechanisms for the observed correlation in fibroblasts with clinical toxicity and development of a cell model for evaluation of pharmacological interventions

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Despite intensive research efforts no biomarkers predictive for higher grade acute toxicity by radiotherapy could be established for clinical use so far. Following current literature reports and own pilot investigations expression of SMAD7, the endogenous autoinhibitor of the transforming growth factor beta signalling pathway, appears as a promising approach. Based on our observation that early induction of SMAD7 when radiochemotherapy was simulated in patient-matched fibroblasts was coincident with lower clinical acute toxicity the following issues should be addressed by this project proposal: 1) How is the observed SMAD7 induction in relation to the effects of simulated radiochemotherapy on the entire transcriptome in fibroblasts? 2) Given the strongest transcripts indentified by (1) how are they affected by specifically targeted overexpression and suppression of SMAD7, respectively? 3) How are the mechanisms by which radiation interacts with SMAD7 promoter activity to understand variable transcription induction? 4) Are there any inherited genetic polymorphisms modulating endogenous SMAD7 transcription? 5) How are the dynamic dose-time effects for SMAD7 transcription changes induced by radiochemotherapy to be analyzed in a cellular model to be engineered by the CRISPR/Cas9 technology? Are there established pharmaceuticals showing effective SMAD7 induction in this model system? The specific aim is to get detailed information for better understanding of the relevance of SMAD7 transcription occurring during radiotherapy and to apply relevant findings for soon clinical use. The direct relationship detected between clinical toxicity and transcriptional effects ex vivo in patient-derived fibroblasts on which this application is based represent a special feature of this translational approach. In this regard, the issues of this proposal represent the middle part of a bedside-benach-bedside sandwich. The major results of the applied investigations should then be prospectively tested in an investigator-initiated trial (IIT) to evaluate clinical relevance and feasibility.