I’m currently working on a new video for Cancer Research Demystified, where I’m going to attempt to answer this lofty question. What is the biggest challenge in cancer research today?
For the video, I’ll summarise a few different perspectives on this: the patients, the advocates, the funders, the institutions, the public, and the researchers ourselves. The most common answer so far is of course ‘there’s more than one!’ so I’ll cover as many as I can, and give my two cents on what could be considered the one single greatest challenge.
The NCRI cover their top priorities here – (of which there are of course more than one!) and you can see similar lists from many other groups. But what is the biggest one?! I’ve been asking around on Twitter, Instagram and Facebook, and I’ve gotten 24 responses so far, mostly from other cancer researchers, but some from patients & funders too. Before I compile, compare & contrast these, I wanted to ask you too – what do you think is the single greatest challenge in cancer research today? I’ll give you a head start by saying that the answers I’m getting are falling into two few common themes: biology & barriers.
Does one of these jump out at you as being a bigger challenge than the others? Do you have something to add? Comment below or DM me on Twitter/Facebook/Instagram/Reddit/LinkedIn and I’ll discuss your thoughts (anonymised if via DM) in our upcoming video!
It was the final year of my PhD, and I was presenting a poster at a conference, alongside my supervisor Dr Kathy Gately. We were showing off our new panel of PI3K inhibitor resistant lung cancer cell lines, which we had developed and begun to characterize. We were excited to tease out which signalling pathways might be playing a role in resistance to these drugs.
Along came Dr Michael O’Neill, the co-founder of Inflection Bioscience, who had recently licenced a drug that targeted the PIM kinases. At the time, I had never heard of PIM. He saw our poster, and suggested we should test their drug in our cell lines. It seemed straight forward enough.
After a couple of quick ‘look see’ experiments, we ended up submitting a grant.
Then some student projects.
Before we knew it, this ‘quick win’ was becoming a driving interest for Kathy, and she was gathering researchers along the way (notably Dr Gillian Moore). I had left Kathy’s lab at this stage, but as a wider team we were beginning to build up a picture of how best we could potentially develop these drugs in the lung cancer space.
PIM research didn’t stop for Kathy, and it didn’t stop for me either.
When interviewing for a postdoc position in University College London with Dr Hayley Whitaker, I was asked ‘if you had access to human prostate cancer specimens, what would you do with them?’ On a whim, and with interview pressure weighing down on me, I responded ‘well there’s this really exciting drug target called PIM in lung cancer, I think it looks like it might be promising in prostate cancer too, so I’d probably run some experiments on that’.
I arrived home to Dublin that night, exhausted after a long day of travel & interviewing, and found out immediately that I’d been invited to a second round interview. This was great – but it would be in London again, in just a few days! I purchased a second pair of flights, cried over my bank balance for a moment, and then hunkered down in our basement office for the weekend, trying to pull together a presentation that had been assigned for the second round. The challenge that had been set was of course ‘if you had access to human prostate cancer specimens, what would you do with them?’ How could I present on anything other than PIM after suggesting it in my previous interview?!
I rushed a project pitch, which by chance turned out quite promising. There were a good few papers looking at PIM in prostate cancer, but not many looking at drug treatments, and none looking at the same co-targets that we were working on in lung cancer. I checked with Kathy if it was ok with her for me to present this, while rushing out of the building to get to the airport – but our conversation got slightly side-tracked when she told me she was expecting a baby! Safe to say PIM got a bit overlooked that lovely day.
The presentation went well, I got the job, and to my delight I was offered the chance to actually work on the project that I had pitched in the interview. What a wonderful opportunity for a postdoc to be given that level of freedom!
In order to differentiate my new prostate cancer project from the work Kathy was leading on, I set out to investigate a wider panel of drugs, including the PIM inhibitors but also quite a few others. The aim was to test promising late stage pre-clinical drugs in human prostate cancer tissue, using ex vivo culture and new omics technologies. I gathered some preliminary data and submitted it as a fellowship proposal, trying to position myself as someone who worked on drug development in general. Thankfully, I was successful.
It wasn’t mean to be a ‘PIM project’. But as luck would have it, PIM wasn’t going away.
One by one, the other drugs dropped off for one reason or another. Some couldn’t be investigated in an ex vivo model because they needed to be metabolised within the body, some needed to build up for a few weeks before an effect would be seen, some failed during concurrent animal testing, and some just showed disappointingly little activity in my model. By the time the work was close to publication, we were down to just 4 different treatments, and they were a very similar panel to what Kathy was leading on in lung cancer. I hope she forgives me!
Now, years later, we’ve just had our first original article come out on PIM in prostate cancer1. This is our first ‘flag in the sand’ where we put forward the idea of co-targeting PIM with the PI3K pathway. There are bigger and more detailed works to come from this in the future. If you’d like to read about the paper itself, I wrote a tweetorial that you can read unfurled here: https://threadreaderapp.com/thread/1300721602854871040
This paper came off the back of a couple of reviews on PIM as a drug target3,4, and there is of course more on the way.
Now, plans are brewing for wider PIM collaborations, and who knows, maybe PIM will stick around in my world even longer.
Did I ever set out to become a PIM researcher? No, not particularly.
But I suppose the lessons learned here are to say yes to opportunities, and to follow the data – if something isn’t your ‘plan A’ but it might make a difference to cancer patients in the future, then why wouldn’t you follow it?
Extra credit to my friend AJ (@AyoksAJ) for his very inspiring ‘Say Yes’ presentation to our postdoc networking group a few years ago, which still sticks around in my mind, and lead me to say YES to an opportunity that came my way this morning – let’s see where this one goes!
Thank you to Kathy, and to all the PIM friends I’ve made over the years.
This was one of the very first research questions I ever set out to answer, way back as a final year undergraduate in Trinity College Dublin, in 2010/2011.
Since then, over many years, a few papers, and with an ever expanding global team, it has remained at least a side project (and in some cases a driving interest) for some of my oldest friends in research!
For me, it began with my final year thesis project, which involved comparing a panel chemosensitive and chemoresistant lung cancer cell lines, developed by Dr Martin Barr as a tool to investigate response to chemotherapy.
We wanted to understand how lung tumours develop resistance to chemotherapy over time, so that we could find better ways to treat them!
We screened the cell lines using qPCR arrays, and identified a few potential genes of interest including NFKBIA, which is involved in regulating NFkB.
NFkB is a well studied transcription factor that seems to play a flexible and complex role in many biological processes.
This initial finding caught the eye of my project supervisor Dr Kathy Gately, who immediately began to wonder if NFkB could be a potential therapeutic target in chemoresistant lung cancer. The project ended up winning the Margaret Ciotti medal as the highest marked thesis in the School, and with the excitement of a new finding (and this early recognition boosting my confidence), it was an easy decision to stick around in Dr Gately’s lab to begin my PhD.
While the PhD project itself was focused more upstream on PI3K/AKT/mTOR, we did further develop our NFkB finding, and it ended up becoming both my first research paper and the first chapter of my PhD thesis. In this work, we used a drug called DHMEQ, which is an inhibitor of NFkB translocation developed by a Japanese collaborator, and we found that it was more effective in treating chemoresistant lung cells than chemosensitive ones.
I have fond memories of this work, as I got to try out a range of new molecular techniques for the first time, including the obligatory ones like cell culture, drug treatments, qPCR and Western blotting, but also things like high content immunofluorescence imaging, proliferation and apoptosis assays, and I even got to run some Sanger sequencing on a machine named ‘Spongebob’!
It was clear from the data that this work opened up a whole range of possibilities, and it was time to expand. My colleagues Peter Godwin and Dr Anne-Marie Baird each took aspects of this forward, with Peter publishing a great review on the topic that remains the most highly cited paper on my Google Scholar profile (thanks Peter!) and Anne-Marie being awarded a fellowship from the International Association for the Study of Lung Cancer to investigate a new take on the work down in Brisbane, Australia.
Anne-Marie’s work (alongside Dr Sarah-Louise Ryan) brought a fresh and exciting angle, interrogating the role of inflammatory pathways in NFkB mediated cisplatin resistance, as well as confirming that the NFkB translocation inhibitor wasn’t just more effective in chemoresistant cells, but in fact could be used to resensitise those cells to the effects of the chemotherapy itself.
Well, we’re certainly not the only ones investigating NFkB in chemoresistance…
With groups all over the world also teasing out the role that NFkB is playing in this setting, things are becoming increasingly clear, and also increasingly complex.
It turns out NFkB is quite a promiscuous player in cancer development and aggresivity!
With seemingly endless feedback loops, regulation and cross-talk with other pathways, it seems to have the capacity to drive wide ranging and even opposing phenotypes. Equally, it often appears to be a mere passenger, caught up in attempts at cell survival during times of stress.
With these flexible abilities, can we truly say that NFkB itself is a viable target for drug development?
Sadly, probably not.
But we do hope that our growing understanding of the role that it plays in chemoresistance will help us to identify better targets that work alongside it, and ultimately better ways to treat these tumours.
As ever, we keep searching.
Big thanks to Kathy, Anne-Marie, Martin, Peter and Sarah-Louise, as well as all the other researchers involved in these projects!
Times are strange due to #Covid19 – so we’re coming to you not from our lab, but on a virtual blackboard instead, from home! This video aims to give a whistle-stop tour of the costs involved in carrying out cancer research. We get asked about this a lot – so we’re here to show you where those valuable funds raised in pub quizzes, sponsored walks & raffles all go! Do you have a guess at how much it costs to carry out a full PhD? Watch the video to find out!
After adamantly refusing to blog for a very long time… it’s time to give in.
Let me introduce myself. I’m Susan. I’m a cancer researcher. My passion is understanding how to exploit vulnerabilities within tumours so that we can find better ways to treat the disease.
Over the last 13 years I’ve been developing my skills, learning more and more about cancer, and working towards the ultimate goal of starting my own research lab.
Now, it is finally happening!
As I work towards building ‘Heavey Lab’ in University College London, where I’ve recently been appointed as a Lecturer in Translational Medicine, I’ll endeavor to pop in now and then, chronicling each of the ‘firsts’ that come along with being a brand new member of faculty.
I’ve enjoyed communicating my research over the years, both online and in the real world, so that cancer patients, advocates, carers and students alike can get a taste of what the world of cancer research is really like. A lot of this #scicomm activity has been through Cancer Research Demystified, which I co-founded and run. I’ll share some of the material that we created for CRD here too, with brief introductions on why we wanted to share these aspects of our work with the world.
I’ll also share our publications, along with plain English explanations of what we found, why it was interesting to us, and with the benefit of hindsight – what happened next.