Identifying molecular determinants of response to standard of care chemotherapy in colorectal cancer

Although precision medicine and targeted therapies have advanced, many CRC patients still depend on standard 5-Fluorouracil (5-FU)-based chemotherapy, which lacks reliable biomarkers for predicting treatment response. The transcription factor p53 plays a key role in CRC progression and therapy response, but its mutation status alone is an unreliable predictor due to the complexity of p53 functional regulation.<br><br>This thesis explores the hypothesis that p53 functional activity—rather than mutation status—better predicts CRC response to 5-FU. <br><br>Evaluation of transcriptional methods for p53 functional activity estimation highlighted the heterogeneity within published p53 related gene sets, for which functional activity estimation was significantly more accurate when incorporating target gene Mode of Regulation (MOR).

A novel “p53 Direct Activated Targets” (p53DA) gene set was developed which demonstrated similar accuracy to mutation status in stratifying p53 activity, in addition to further stratifying p53 Wild Type (WT) models. <br><br>The score was evaluated in preclinical and clinical datasets. High p53DA activity correlated with poorer outcomes in microsatellite stable stage II/III and IV CRC patients treated with 5-FU, outperforming mutation status.