Targeting DNA repair in chemotherapy

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Published: 21 Nov 2012
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Dr Chit Fang Cheok – IFOM-p53 Lab, Singapore

Dr Chit Fang Cheok discusses Synthetic Lethality where cancer cells with mutations lose one of the main BNA pathways. Dr Cheok’s main work centers on discovering novel therapeutic strategies targeting defects in tumour suppressor pathways and DNA repair pathways in tumours.

I belong to the IFOM group based in Singapore, we’re jointly funded by both IFOM and A*STAR p53 lab in Singapore. Our team has just started, a year ago, and now we have a good team of five people working in the area of oncology.

What is synthetic lethality and how can it be used in therapy?

The idea of synthetic lethality is a state whereby one could imagine that in a cancer cell which has suffered mutation such as mutation of p53 or BRCA and has as a result of the mutation lost one of the main DNA repair pathways. So how does a cancer cell survive with the loss of one of the main important DNA repair pathways? What happens is cancer cells rely on the other alternative DNA repair pathways for cancer cell survival and therefore the idea is that if one could identify what these alternative DNA repair pathways are one could target them specifically and hence the idea is to lead to an overall increase in specificity for tumour cell targeting. So the PARP inhibitors have been one very good example of synthetic lethality whereby it has been used to treat BRCA deficient tumour cells and patients with BRCA mutations, breast BRCA mutations in breast cancer, respond very well to PARP inhibitors. That is due to the idea of synthetic lethality whereby PARP basically abrogates the remaining DNA repair pathways which BRCA deficient cells have grown to be reliant on for survival.

What can you tell us about the p53 pathway?

p53 is a very important tumour suppressor gene and the idea that because it has been mutated, or it is frequently mutated, in a large majority of cancers so it becomes an obvious target for tumour therapy. So if one could actually target p53 mutation, target the loss of p53 functions, one could imagine that you could potentially use this method to target a large majority of cancers without affecting normal cells. So that’s the idea behind p53-based therapy.

What are you doing currently in your lab?

At the moment we are trying to look at the concept of synthetic lethality. If one could identify pathways that loss of p53 mutation cells have grown to be reliant on for survival and hence if we could identify these synthetic lethal pathways with p53 mutations we could target p53 mutated cells more specifically. So we found a very interesting subset of drugs, of DNA damaging drugs, that p53 mutated cells appear to be more sensitive to. So we are trying to suggest that this could be a form of targeted therapy whereby the loss of p53 functions could then become more sensitive to this cohort of drugs which are not currently investigated yet in the clinic.

Have you found specific chemotherapeutic agents?

They are specifically targeting a subset of DNA damage and we’re still investigating the mechanisms but it’s thought to act specifically in S phase, which is the replicating phase of the cell cycle. So one could imagine that this would have also increased specificity for tumour cells which are highly proliferative.

What does this mean for a patient with a mutation in p53?

Absolutely, you’re right. So now stratified medicine is a very popular term but what basically it means is that if one could identify the mutations in tumour cells or in tumours where there is a p53 mutation, BRCA mutation, p10 mutation, and one could understand how this mutation could lead to increased or decreased sensitivity to different chemotherapeutic drugs then one could stratify the patients according to their tumour genetic profile and suggest which are the drugs that these patients would most likely respond to. So that’s the idea of personalised and stratified medicine.