HDAC inhibitors (HDACi) are an emergent class of epigenetic modifying agent (EMA), with multi-modal mechanisms-of-action in both tumour and tumour microenvironment (TME). This project aims to understand how these drugs modulate efficacy of 5-FU-based chemotherapy to counteract transcriptional plasticity and immune evasion that underpins emergence of treatment resistance.
Colorectal cancer (CRC) has one of the highest Worldwide incidences and mortality rates (>1.3 million new cases and ~610,000 deaths per annum). While 75% of patients with CRC present with operable disease (stages II and III), at least 40% of these patients still experience disease recurrence. Compared to surgery alone, adjuvant 5-Fluorouracil (5FU)-based Standard-of-Care (SoC) chemotherapy improves 5-year Hence, there is a critical need to develop new molecularly stratified, therapeutic approaches to improve outcomes in the adjuvant and advanced disease settings of CRC.
HDAC inhibitors (HDACi) are an emergent class of epigenetic modifying agent (EMA), that are attracting significant interest due to powerful anti-tumour and immunomodulatory effects. Our published preclinical studies and preliminary data have identified novel therapeutic strategies exploiting BOTH their tumour-intrinsic and immuno-modulatory effects in chemo-refractory CRC subtypes.
This project aims to better understand the mechanisms through which Class-I HDACs (HDAC1, 2 and 3) modulate the efficacy of 5-FU-based SoC to counteract the transcriptional plasticity and immune evasion of drug-tolerant persistor cells that underpins treatment resistance in specific genetic subgroups of CRC (namely MMR-proficient, KRAS mutant tumours that are either wild-type or mutant p53). In doing so, we aim to identify how best to clinically position these agents.
Start Date: October 2022