New Technologies in Molecular Pharmacology

Signal Transduction and Molecular Pharmacology Team

Section: Section of Cancer Therapeutics (including the Cancer Research UK Centre for Cancer Therapeutics)

We are developing and applying molecular techniques to allow us to identify genes and proteins that are responsible for sensitivity or resistance to drugs under development in the Centre as well as clinically used agents. Particular emphasis is on the use of gene expression microarrays and RNAi technology. We are building a database that will allow us to establish correlations between drug sensitivity and constitutive gene expression.

In addition, we study changes in gene expression induced by pharmacological agents in order to understand:

• Mechanism of actions and 'on-target' versus 'off-target' effects
• Identification of molecular biomarkers for use in preclinical development.

Selected examples are given in the project reports on HSP90, PI3 kinase and cyclin-dependent kinase inhibitors. In addition to studies on in-house and collaborative drug discovery projects, we have identified interesting gene expression changes in response to the novel agent ES285 which is undergoing clinical trial at our institution. Potentially important gene expression changes have also been characterised for platinum drugs and 5-fluorouracil.

We have published what is to our knowledge the first study using gene expression microarrays to profile global gene expression changes during drug treatment in the clinic. In rectal cancer biopsies, 5-fluorouracil caused the downregulation of a cluster of genes that are positively regulated by the oncogene c-MYC. Thus gene expression microarray profiling has identified a previously unknown anti-oncogenic mechanism for a widely used anticancer drug. We have used both gene expression microarrays and antisense technology to validate WT1 gene as a potential drug target.