Keynote lecture: Mutation signatures and targeting the DNA damage response

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Published: 29 Oct 2018
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Prof Thomas Helleday - Sheffield Cancer Centre, Sheffield, UK

Prof Thomas Helleday speaks with ecancer at ESMO 2018 in Munich about mutation signatures and targeting the DNA damage response.

Prof Helleday explains that whole genome sequencing now allows us to have a greater understanding of mutations and rearrangements rather than using a single mutation as was the historical process.

He also describes how immunocology drugs are benefitting, with a refined method allowing for a more tailored treatment.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.

We know historically we’ve been using single mutations in order to tailor treatments to them but we know that that is insufficient. Now with whole genome sequencing data arising we can understand what type of carving mutational signatures have been carved into the genome. With that we can understand what mutations there are, what rearrangements there are, indels and so forth, and generate a whole cancer genome gestalt that we then can tailor to the treatment. This is a far superior way than just using a single mutation to tailor to a treatment. Now we know all of the rearrangements that are generated, that is much accurate to tailor to treatment. This is not just a theory, it is working. We know that, for instance, when it comes to homologous recombination defective cells they have a very high load of different rearrangements and we can tailor PARP inhibitors to them more accurately than just using the germline mutations that we have done in the past. So that is also a discovery that I discovered many years ago in my lab alongside the lab of Alan Ashworth and this is now standard practice and we’ve found new PARP inhibitors being FDA approved earlier this week. So this is very nice with talazoparib now approved as a fourth PARP inhibitor in this area.

We also know that these mutational signatures can be generated by, for instance, mismatch repair defective cancers. So there we have immune oncology drugs that then can tailor and treat these very accurately. A year ago immune oncology drug Keytruda was approved by the FDA regardless of cancer origin because it’s only tailored to this mutational signature or the microsatellite instable tumours that they use. But we can now use a more refined method to do this and this is what we will see in the future.

I also described targeting the DNA damage response. So we can do this with ATR inhibitors, with PARP inhibitors, with many other inhibitors, and it’s all coming down to boiling down to replication stress that is present in cancer but not in normal cells. So all of these treatments exploit the fact that cancer has a different replication phenotype than normal cells and then using these inhibitors we can kill them but not the patient.

Now we learn how these are progressing through the clinic and how we can use them either as stand-alone or in combination with immune oncology drugs or combinations with each other. So this is something that we are really interested in seeing what’s going to happen in the future.

Of course cancer therapy can induce mutations and that could generate new antigens and this could then make a tumour go from a cold tumour to a hot tumour. But it would require a lot of new mutations being generated and also translated in the cancer and these would not be on the stem, on the trunk, these would be on the branches. So that would not generate something to kill off all the cells, it would potentially kill off a few. So many in the field are a little sceptical about that approach, however causing DNA damage is going to generate a lot of DNA which is activating the innate immune system STING pathway, a cGAS, that then trigger an innate immune system that then will also make the cancer more immunogenic and that might, in combination with immune oncology drugs, be more effective.