Functional genomics of drug resistance

Previous and current research
Ovarian cancer has a disproportionately high health care burden because of low cure rates and frequent symptoms caused by recurrent bulky abdominal disease after primary therapy. The fundamental clinical problem remains the acquisition of drug resistance, and studies on clinical samples to identify common mechanisms are of the utmost importance to improve treatment and survival.

Our approach to identifying critical pathways in resistance has been to develop novel phase II clinical trials with sequential collection and profiling of ovarian cancer tissues before and during therapy.

Array-based expression profiling and bioinformatic analysis has identified misregulated extracellular matrix proteins in association with resistance. Array comparative genomic hybridisation is also being used to identify copy number changes associated with chemoresistance.

From these studies we are now studying a novel secreted protein that is significantly underexpressed in taxane-resistant ovarian cancer samples. Somatic cell knock-out experiments and cell biology approaches are currently being used to define the signalling pathways involved.

Future projects

• Characterisation of ECM ligands that modulate taxane sensitivity.
• Further development of chemotherapy response studies in ovarian cancer using dynamic contrast enhanced MRI and sequential tissue sampling.