Title: Molecular and pharmacological characterisation of pathways which determine the sensitivity of cells to anti-cancer drugs and chemopreventive agents
Funder: Cancer Research UK

Abstract: Multiple inducible metabolic pathways, including the cytochrome P450-dependent_x000D_ monooxygenases (P450s), glutathione S-transferases (GSTs) and signalling cascades_x000D_ regulated by the Nrf2 transcription factor have evolved to protect cells from the toxic effects of_x000D_ environmental chemicals. These pathways are therefore major determinants of the metabolic_x000D_ fate of prescribed drugs and have also been implicated in anti-cancer drug resistance. Interindividual_x000D_ differences in P450, GST or Nrf2 gene expression can therefore influence drug_x000D_ efficacy and/or the incidence of treatment-associated side effects. We are particularly_x000D_ interested in the role of these enzymes in the personalised treatment of cancer, as an_x000D_ increased understanding of the mechanisms by which these pathways are regulated will_x000D_ make treatment response more predictable, will improve strategies for cancer_x000D_ chemoprevention and will facilitate future anti-cancer drug development. In previous work, we_x000D_ have developed a variety of transgenic mouse models to better understand how these_x000D_ enzymes function in vivo. Our future research will use these models to study mechanisms of_x000D_ human P450 gene regulation and will investigate how variability in enzyme activity relates to_x000D_ anti-cancer drug efficacy. We will also investigate how chemotherapy support drugs, e.g._x000D_ steroids and anti-emetics, modulate drug efficacy and side effect profiles. These studies will_x000D_ establish the relative importance of metabolic variability in anti-cancer drug response and will_x000D_ allow us to develop novel prescribing paradigms for future clinical evaluation. We will also_x000D_ continue our studies on GSTP, an enzyme which has been linked with cancer susceptibility_x000D_ and which may also influence treatment outcome. We will build on our published data,_x000D_ demonstrating that GSTP alters cancer susceptibility in genetically initiated tumour models_x000D_ and will study the mechanisms involved. We will also use transgenic models to evaluate the_x000D_role of human GSTP1 in cancer susceptibility and will investigate how GSTP1 is regulated. In_x000D_ studies on Nrf2 signalling, we will focus on pharmacological and toxicological aspects of this_x000D_ chemopreventive antioxidant signalling cascade. In particular, we will investigate which_x000D_ chemicals, including anti-cancer drugs, are protected from metabolic inactivation by Nrf2 and_x000D_ will use a variety of reporter models to assess pharmacodynamic aspects of the Nrf2_x000D_ response in vivo and to investigate the cell types in which this pathway is active. As the Nrf2_x000D_ pathway is constitutively activated in lung cancer (as a consequence of somatic mutations in_x000D_ the accessory protein Keap1), we will also extend our collaborative programme to identify and_x000D_ evaluate the potential of novel Nrf2 inhibitors as anti-cancer drugs.


Research activity codes: 5.1 PHARMACEUTICALS;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CANCER AND NEOPLASMS