Oncogenic Transcription Laboratory

Discovery of predictive biomarkers of response of colorectal cancers to EGFR/HDAC inhibition.


Prof. John M. Mariadason, Prof Niall C. Tebbutt, Dr. Fiona Chionh


We have recently discovered that combined treatment of colorectal cancer cells with an EGFR inhibitor and a histone deacetylase (HDAC) inhibitor induces robust anti-tumour activity (apoptosis, differentiation) in pre-clinical models of colorectal cancer. Based on these findings, we are about to commence a phase II clinical trial (VADER) in which patients with KRAS wild type colorectal cancer will be randomized to receive either an EGFR inhibitor (cetuximab) alone, or in combination with a histone deacetylase inhibitor (valproate).

Currently, the specific mechanism of action of this treatment remains to be fully elucidated.  Furthermore, whether some patients will preferentially respond to this treatment and the mechanisms which underpin response or resistance remain to be determined. The aims of this PhD thesis therefore are the following:

Specific aims:

Aim 1: To determine the molecular mechanisms by which combined EGFR/HDAC inhibition induces differentiation and apoptosis of colorectal cancer cells.

Aim 2: To identify predictive biomarkers of response to EGFR/HDAC inhibition by analysis of tumour samples from patients enrolled in the VADER trial.

The project will provide critical insight into the mechanism of action of a potential new treatment for colorectal cancer and enable the refinement of its use by identifying biomarkers which can predict treatment benefit.

The project will provide the candidate with extensive knowledge of cancer biology, and the transcriptional and signaling pathways which drive the disease and response to drug treatment. The candidate will also gain expertise into the analysis of clinical trial samples using cutting-edge molecular profiling tools.