Exploiting knowledge of DNA damage repair to improve treatment for patients with colorectal cancer


Year:

Session type:

Ricky Sharma1
1University of Oxford, Oxford, UK

Abstract

The dominant mechanism of action of radiotherapy and cytotoxic chemotherapies, such as oxaliplatin and mitomycin C, is damage to DNA. In the last decade, significant advances have been made in our biochemical understanding of the types of DNA damage caused by cancer therapies and the repair processes that cancer cells employ to process or bypass DNA lesions. There have been 2 types of output from this knowledge. Firstly, new selective therapies for cancer are being developed based on the concept of synthetic lethality, i.e. a combination of mutations in two or more genes that leads to cell death. An example of this strategy applied to DNA repair is the use of PARP inhibitors, cisplatin or 6-thioguanine to selectively kill BRCA-defective cancer cells. Secondly, predictive and prognostic biomarkers are in development, which offer a means to personalise cancer medicine based on molecular characteristics of the tumour.

In this talk, I will provide an overview of the DNA damage and repair concepts relevant to the treatment of colorectal cancer. Is colorectal cancer characterised by gene mutations that make it vulnerable to selective therapy akin to PARP inhibitors for BRCA-defective tumours? DNA biomarker tests currently being developed to personalize therapy will be discussed, including clinical evidence to support the use of mismatch repair testing. In order to demonstrate how a biological mechanism-based clinical biomarker can be identified and validated, the process will be illustrated using oxaliplatin as an example. Finally, an approach to optimising response to radiotherapy, by taking advantage of genetic defects that make colorectal cancer cells more sensitive to particular drug-radiation combinations, will be proposed.

It is timely for our extensive biochemical knowledge of DNA damage repair to be translated into new selective therapies for cancer and to develop new tests to personalise therapy for individual patients.