NCRI 2015 highlights
Prof Charles Swanton - Cancer Research UK's London Research Institute, London, UK
We’ve had a pretty diverse and exciting few days, I have to say; it’s been a great meeting. Yesterday we heard from Alberto Bardelli talking about clonal evolution and drug resistance in colorectal cancer, illustrating some of the vast complexity of resistance in patients with colorectal cancer, principally alluding to this issue of polygenic drug resistance. What that means is that resistance isn’t just mediated by one somatic event in a tumour but by multiple somatic events that can occur within the same lesion or spatially separated between lesions. That has an impact for how we think about using targeted therapies and the recurrent theme that we’re hearing, both from Alberto Bardelli and from Charles Sawyers earlier on Sunday is this issue of efficient and effective combination therapies up front that will prevent tumours from going down distinct evolutionary routes when single therapies are used. So the illustration that Alberto Bardelli used in his talk yesterday was that resistance to cetuximab and EGFR monoclonal antibody is invariably mediated by somatic mutations in pathways downstream of EGFR, including KRAS or mutation of the EGFR protein itself. And they all converge upon this kinase called MEK1 and they’ve shown very nicely in elegant studies that if you provide mice with colorectal xenografts with a monoclonal antibody to EGFR called cetuximab and a MEK inhibitor you can essentially render these mice disease free up to 200-250 days where with single agent therapy these tumours in mice will have progressed very much before that. So I think it’s a nice proof of principle that if you get the combination therapies up front correct, predict the resistance mechanisms and treat the cancer effectively, blocking the resistance mechanisms from occurring, you can potentially prolong progression free survival outcomes. I think that’s a nice way of thinking about cancers in general. Evolutionary rulebook is something we’re very interested in in the lab, thinking about cancer evolution and battling cancer evolution and grasping it head on when it comes to trying to improve patient outcomes will be extremely fruitful in the next few years.
So that was one of the big highlights for me but added to that we heard from Richard Treisman yesterday really how much more complex the RAS MAP kinase ERK pathway is than perhaps we’re familiar with and the context of cartoon diagrams of this pathway. We heard about SRF signalling and the way in which signalling mechanisms are integrated into the SRF pathway through G- and F-actin which was really, very thought provoking. And how this pathway may be involved in the invasive and migratory properties of cells as they leave their primary site and migrate to distant organs. There’s accumulating and almost overwhelming evidence now that the importance of this pathway in generating invasive migratory edge of tumours. So, again, areas there to explore potentially with future targeted therapy approaches to try to block activity of the SRF pathway to limit invasive and migratory properties of cells.
From a societal level we heard from Harpal Kumar on Sunday about problems with early diagnosis, how we’re still lagging behind the one year survival outcomes in the UK from solid tumours and the question is why. This is a very complex process, it’s a combination of late diagnosis, the issues of the fact that we have, as a nation, less access to imaging technology so it’s harder for GPs to refer patients in for diagnostic work-up. But also there are ways in which we can get around this by having red flag symptoms that prompt earlier referral to medical care which we hope will help bring our survival rates back up to the levels of, say, Scandinavia and Australia at the top of the league table. So there’s a lot of work to be done there, there’s a lot of investment that’s required but Harpal made the point that if you get it right this can be very cost effective and from a quality adjusted life year perspective it’s an extremely cost effective way of improving outcomes for our patients. It’s about £7,000 per QALY which is extremely good value when we’re talking about saving lives because we’re diagnosing cancers earlier.
Will this require more funding?
Yes, several hundred million a year probably. But that money, if you think about it, will be more than recouped in the costs of treating end stage disease which is, as everybody knows, very, very expensive. Here we’re talking about investing money up front to diagnose tumours earlier to cure patients as opposed to putting that money into late stage disease, into palliative care, where we know we can’t cure patients. So it’s an extremely cost effective approach and Harpal presented a very compelling health economics argument for investing in this extremely important disease area.
We had phenomenal immunotherapy sessions from Carl June and Sergio Quezada showing the huge breakthroughs in CAR T-cell therapy, for Carl June, in liquid tumours which are having very real and measurable benefits already. I think that field is primed to explode over the next five years. We heard from Sergio around checkpoint blockade and exactly how CTLA-4 monoclonal antibodies work and thoughts and visions for the future. So there’s great excitement there, that field is just beginning to take off now. Obviously there’s a lot of hype and excitement there but I think we’ll be seeing increasing and measurable, tangible benefits for patients over the next few years so watch this space carefully.
We heard from Dennis Slamon and from Tim Hunt around cell cycle developments. As you know, Tim Hunt is the sort of doyenne of this field, he was the man who essentially discovered these oscillating protein sub-units called cyclins in the '80s and, as you know, won the Nobel Prize for medicine in 2000 for his discoveries. It’s only now that we’re seeing the fruits of his labour being rewarded in the clinic and we heard from Dennis Slamon the introduction of CDK inhibitors that block the kinase components of the cyclin, CDK interacting complex, block the kinase from phosphorylating Rb releasing E2F to allow cells to go into cell cycle and divide. As you know, in cancer cells this process is subverted in many solid tumours, either through disruption and mutation of Rb or through disruption of the cyclin dependent kinase inhibitory factors, B16, B21, B27 and what have you. We’ve heard from Dennis Slamon in the introduction to CDK inhibitors that he really got off the shelf from Pfizer have been introduced into the clinic now, we see phase II and phase III trials over the last two years showing really profound benefit in the context of oestrogen receptor positive breast cancer.
So huge hope there and really a beautiful illustration where basic science developments can go from the bench to the bedside in 10-15 years extremely efficiently that are resulting in survival improvements for our patients. So, for me as a great advocate of basic science and its impact upon disease biology, our understand of disease and the way in which we can lead developments in basic science now all the way through to the clinic very quickly, it’s hugely exciting and as an oncologist very rewarding to be able to see.