It’s the dog days of summer and time for some meaty controversy to read!
For the longest time there have been several cancer types which have been incredibly difficult to treat therapeutically.
Metastatic melanoma and non-small cell lung cancer (NSCLC) both used to be in this category, as did glioblastoma and advanced pancreatic ductal adenocarcinoma (PDAC).
We have made great strides in changing the face (and more importantly outcomes!) for people with both metastatic melanoma and lung cancer, so what’s happening on the pancreatic cancer front?
The last two years gave certainly thrown up a series of disappointing clinical trial readouts such as RESOLVE, HALO–301, CanStemIIIP, and SEQUIOA, for example, where in each and every case the findings favoured the control arm of gemcitabine plus nab-paclitaxel over the experimental arm in terms of improving survival. Not one of them was able to raise the bar and show a significant improvement over standard therapy, which is pretty disappointing.
So what can be done to change the face of PDAC?
If we want to improve further then we need to go back to basics and enhance not only our understanding of the funadamental biological mechansisms and processes, but also the models we use to interrogate the systems involved.
In this post, we look at six key new areas of research in PDAC and explain what we’ve learned and why they matter if we are to see new therapeutic developments arise from the ashes of the past…
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A new dawn or a rapid sunset for epigenetics in oncology R&D?
Epigenetic therapies have had somewhat of a chequered history in oncology R&D, but new targets are always cropping up to tempt us to look further.
One emerging target we’ve come across – this is only the fourth mention here since January 2019 – is starting to gather steam with new players entering the landscape, as well as emerging preclinical and clinical evidence suggesting it might be well worth a serious look.
Here we look at the potential role this epigenetic target may have to play in a variety of difficult to treat cancers, as well as how it could enhance existing therapies in new combination approaches.
Could we combine these inhibitors with chemotherapy, with immunotherapy or DNA repair approaches? How does the therapeutic window stack up?
We look at the latest evidence from several sources and discuss where the opportunities might lie…
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In today’s post we answer some reader mailbag questions pertaining to targeting BET/bromodomain inhibitors and what we’ve learned since our original landscape review from early 2016 when they were an emerging new class in the oncology R&D space – how time flies!
Is it time-up for the bromodomain class?
Of course, as usually happens in the targeted therapy space we see a glut of pan inhibitors trying to block everything in sight to a greater or lesser degree… we’ve see this with BRAF, FGFR, PI3K, and even KRAS inhibitors, as well as numerous others, yet these rarely turn out to be the bees knees we’re secretly looking for. Bromodomains, I have long argued, were ripe to fall in this category as well.
Instead, it is better to patiently wait for the next generation molecules where they are much more selective in their actions and matched to the tumour target we are looking to hit.
Think about the BRAFV600E vs. pan BRAF inhibitors or KRASG12C/D vs. pan KRAS inhibitors, for example, or even FGFR2 or FGFR3 vs. pan FGFR inhibitors.
The same evolution may possibly happen in the BET/bromodomain space too.
The first generation of agents seemed to hit everything – BRD1, 2, 3, 4, and often BET as well. They suffered, however, with weak efficacy largely driven by challenges with the on-target, off-tumour effects that necessarily impact the therapeutic window.
Now we are starting to learn from a more focused approach with these agents. Four years on from our original landscape review, what’s hot and what’s not? Who’s in and who’s out? In terms of the magic roundabout of oncology R&D, are there any new gems we should eagerly be watching out for?
The short answer is yes… but what are they and who owns them?
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We’re continuing our mini-series on the MYC oncogene and associated super-enhancers and transcription factors, with a look at some of the molecular mechanisms driving epigenetic accessibility and how they interact with the immune system. It turns out that the two appear to be inextricably linked.
Dr Jay Bradner (NIBR)
It’s an exciting and emerging area in oncology R&D as companies and researchers begin to leverage basic science with a convergence between scientific fields to drive new opportunities for therapeutic intervention in cancer.
Included in this post are excerpts from an interview with Dr Jay Bradner from the Novartis Institutes of Biomedical Research. He’s most well known for his academic research on chromatin and bromodomain fields. As Dr Bradner told me during our discussion:
“MYC has so many target genes that I would imagine one might find any number of immune factors as augmented in their expression by MYC.”
As always, we covered a lot of ground and dived into more detail. There’s also been a number of recent research papers published since our discussion that have shed more light on the topic.
This is the second post in our latest mini-series. If you’d liked to read this and our coverage from the forthcoming ESMO, SITC and ASH annual meetings, do sign up to keep up to date…
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In our latest thought leader interview we explore the intersection between epigenetic therapy and immunotherapy.
Gems from the ASCO17 poster hall
Much of the IO focus to date has been on monotherapies rather than combos, although that situation is slowly changing.
What we can also expect to see are the emergence of regimens, long the bedrock of traditional cancer therapy approaches.
As we learn how to bucket more discrete populations based on the underlying biology of the tumour microenvironment, so we will see a more IFTTT (If this then that) approach evolve in order to fix or improve a situation before or after attempting the core therapy. It might require a focus on changing the immunosuppressive or inhibitory factors, for example, or addressing factors that induce primary resistance upfront. The possibilities are endless.
Obviously, there are a number of ways to do this from chemotherapy and radiotherapy to epigenetic agents to targeted therapies – these traditional treatments are not going to go away, but I can see a future where we see more integration based on a patient’s underlying immune status. It won’t be the zero sum game many analysts seem to think it might be.
In the past, we have covered chemotherapy, radiotherapy and targeted therapies and looked at how they might be employed with immunotherapies in various guises. In this latest thought leader interview, we look at a different approach, epigenetic therapy and other novel immunotherapies.
Here, we combine two popular types of posts – Gems from the Poster Halls with an Expert Interview – for detailed look at one particular area of research that is beginning to look quite intriguing.
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After exploring a mechanistic approach and a tumour type as part of our AACR annual meeting coverage, in our third preview today we turn to look at a novel target.
This particular target hasn’t received much attention at all but this could well change in the future as some of the compounds move into the clinic.
There are a few important questions to consider:
- Who’s going to be first to evaluate in humans?
- Which tumour types will be optimal?
- Which combinations are likely to be synergistic, tolerable and effective?
- What path to market strategies will avoid the enrollment problems now that checkpoint blockade is becoming much more ubiquitous?
This is an interesting niche that may well evolve into a competitive landscape going forward.
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There were so many posters worthy of further analysis and discussion at ASCO this year that we may well need to write a longer series than usual on some of these hidden gems!
If you’re anything like me, just getting round the massive poster hall melée each day in one piece to nab the QR codes and chat to some KOLs felt like an achievement in itself, never mind having the time to read and digest them properly. This is why it’s nice to sit down and process some of the findings afterwards because there was actually quite a lot to learn on the nuances with later reflection.
So what’s on deck in the hot seat today?
Here, we focus on the importance of the tumour microenvironment and how that can be manipulated so that subsequent therapy can be more effective.
Fortunately, there are a number of different approaches that can potentially achieve this lofty goal, at least preclinically, but what happens in the real world when these concepts are actually tested in people with cancer?
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In our post AACR analysis, I noticed some consistent observations across multiple talks and informal discussions with thought leaders.
Some of these ideas are pretty important and help us see the big picture for the near and medium term future in the cancer immunotherapy space.
The “Claws” sign we saw at the University of New Orleans sums things up!
Without much ado, it seems a good point to capture and summarise these ideas so that readers can compare notes and debate their thoughts too.
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San Francisco – “Manic Monday” is what I call Monday at the annual meeting of the American Society of Hematology. It’s when the majority of oral presentations take place in multiple parallel sessions that require you to run between meeting rooms if you want to follow a particular drug across different blood cancers.
It’s even more challenging this year by the fact the conference is in three buildings at the Moscone Center in San Francisco. While Moscone North and South are interconnected thanks to an underground atrium, to get to sessions in Moscone West from North/South you have to go out of the building, cross one or two main roads, then go up elevators to the second or third floors. Not ideal! I think ASH is now too big for the venue.
Looking back on yesterday, it was a privilege to be in the audience when Dr Kanti Rai received a well-deserved lifetime achievement award for his work in chronic lymphocytic leukemia (CLL). A visibily moved Dr Rai was given a standing ovation by the thousands present in the plenary hall.
Expect the #ASH14 Twitter stream today to be like opening the tap to run a bath. I congratulate all the hematology experts who have shared data and commentary from sessions via social media. #ASH14 stands out in terms of expert engagement and a high signal to noise ratio.
If there was an award for best conference coverage of #ASH14 on Twitter I would nominate @drmiguelperales.
Not only does Dr Perales from Sloan-Kettering share tweets from the sessions that he is in that are accurate and informative, but he frequently offers links to relevant papers for those that want to learn more. In addition to showcasing his expertise, this is a really good way to use social media to educate and inform. I look forward to his commentary, particularly if I am in another session at ASH. A must follow on Twitter!
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Sometimes you get lucky before a conference and catch an interview with a thought leader ahead of time when it’s more relaxed and less fraught with all the demands of meetings etc while there.
Dr R Young, Source: WI
That good fortune happened to me on the Friday before the recent AACR conference in San Diego, when I recorded an interview with Dr Richard Young, (Whitehead Institute & MIT and scientific co-founder of Syros), who was giving a plenary talk on the Sunday at AACR entitled, “Transcriptional and Epigenetic Control of Tumor Cells.”
Epigenetics and transcriptional changes are fascinating concepts to me because they get right to the heart of what’s going on deep in the oncogenes and how they control processes in cancer. Clearly, in simplistic terms, if we can understand how things change and evolve, then we can potentially devise better strategies to overcome them. Instead of targeting a protein kinase with a small molecule or a cell surface antigen with a monocloncal antibody, this is an altogether different approach. Protein-protein interactions such as MYC, RUNX1, p53/TP53 etc have long been the bugbear and frustration of many good researchers, precisely because they are challenging to target with conventional approaches.
So what’s new and why am I really excited about these new developments?
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