Robert Brown - Overview

Resistance to anticancer drugs is the main reason why current chemotherapies eventually fail. Our work focuses on how chemotherapy kills tumour cells by inducing cell death by apoptosis and how loss of this mechanism can lead to resistance to chemotherapeutic drugs. Ultimately, we wish to use our understanding of these mechanisms to develop approaches to overcome or circumvent drug resistance and improve the treatment of cancer.

Reduced expression of the human DNA mismatch repair gene, hMLH1, occurs in a number of tumour cell lines resistant to a variety of anticancer drugs and restoration of mismatch repair in hMLH1 deficient cells restores their sensitivity to anticancer drugs. Such studies have implicated mismatch repair in playing a role in signalling cell death from DNA damage through various apoptosis pathways but precisely how they are coupled is still unclear.

Loss of hMLH1 expression is associated with methylation of the gene promoter repressing hMLH1 gene transcription. We observe methylation of hMLH1 in tumours, particularly after chemotherapy, and have shown that chemotherapy for breast and ovarian cancer selects for cells that have lost hMLH1 expression. Methylation of multiple other genes, including tumour suppressor genes, also occurs. We are now examining whether methylation patterns in tumours helps to predict response to chemotherapy.

We have also shown that the DNA methyltransferase inhibitor, 2’-deoxy-5-azacytidine, can reverse methylation of hMLH1 and sensitise human tumour xenografts to a range of important anticancer agents. We are now examining the potential of further drugs involved in transcriptional activation and chromatin remodelling as novel approaches to cancer therapy.

We have shown that reduced hMLH1 expression correlates with poor survival for breast and ovarian cancer patients. To further validate these observations, prospective studies have now been started which link analysis of mismatch repair status with large international clinical trials in ovarian, breast and lung cancer. The mismatch repair status of tumours can be readily measured not only in tumour biopsies, but also from serum samples from patients. This provides the exciting possibility of being able to determine the appropriate therapy for a given patient based on his or her personal molecular genetic determinants of disease progression.