4th EUTROC
AKT pathway and chemotherapy resistance ovarian cancer
Dr Euan Stronach – Imperial College London, UK
Our work focusses around the AKT pathway which is a key driver of cell growth and cell survival in ovarian cancer. Our work has shown that in cells that come from patients before and after they’ve relapsed with resistance to chemotherapy we see activation of the AKT pathway in the chemoresistant cells. So we’ve done a lot of work on targeting that pathway to restore response to chemotherapy to the cells that have adapted to become resistant to it and in doing that we’ve identified a novel driver of resistance which is a gene called DNA-PK which specifically activates AKT in response to DNA damage rather than in response to extracellular stimulation which is the more conventional way of activating AKT.
Are there any on-going clinical trials?
We did a phase I trial with GlaxoSmithKline using their AKT inhibitor. So after a fairly long process we managed to generate preclinical data which showed that the pathway that we’re targeting was exciting enough that we could take this into clinical trials. So teaming up with GlaxoSmithKline we did a small phase I trial of just a single agent AKT inhibitor given to patients and the great thing about this trial was we managed to get biopsies from patients before they were given the inhibitor and four weeks after they were given the inhibitor. So by comparing the clinical responses to the inhibitor with the molecular changes going on in the biopsies before and after treatment, we’ve been able to really unpick why some patients respond to the inhibitor and why some patients don’t. Using that information and taking this forward into the next trial, which has just opened, which is combining the AKT inhibitor with chemotherapy; so this is really testing the hypothesis that we’ve developed in cell lines, that if you combine chemotherapy with an AKT inhibitor you can reverse resistance, we’re now testing this hypothesis in a clinical trial setting so that’s really exciting. At the same time we’re working to develop inhibitors of DNA-PK rather than AKT to take this to an even more specific level, applying it to the data that’s coming through from the lab.
What happens when a patient becomes resistant to therapy?
The idea being that the patients have stopped responding to conventional chemotherapy and that’s because they’ve got an up-regulation of this AKT pathway. So if we then add in an AKT inhibitor along with the conventional chemotherapy you can make the chemotherapy start working again.
What are the clinical implications from these studies?
For the most common subtype of ovarian cancer, which is high grade serous, the ubiquitous clinical pattern is initial chemotherapy response followed by relapse with chemotherapy resistant disease so it’s an extremely big problem. So if we were able to improve the response rates to chemotherapy in the relapsed setting that would have big implications.
What were the results from the phase I study?
In the phase I trial we saw modest responses to the drug. The key point here is when we look in cell lines; if you give the single agent inhibitor all that happens is that the cells stop growing and then when you take the inhibitor away they start growing again. It’s only when you combine it with chemotherapy that you have the cell death induction of chemotherapy that because of the AKT pathway is not seen through to completion. So the chemotherapy should make the cells die but because of the AKT pathway they’re not dying; when you inhibit the AKT pathway you restore that cell death but you need the chemotherapy to induce it. So in the single agent trial it was never really geared up to induce the cell death that we are hoping to see so it’s this next trial where we combine the chemotherapy with an AKT inhibitor that we really expect to see the responses that we’re looking for.
Can this treatment be used in other cancer types?
Yes, the AKT pathway is, other than p53 gene mutations, the most frequently altered pathway in cancer. So the implications for AKT inhibition are way beyond ovarian cancer itself.
