Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘transcription factors’

We’re living in uncertain and challenging times as the coronavirus impacts healthcare providers around the world and puts them in the front line of exposure.

Meetings are being cancelled or postponed as companies and institutions batten down the hatches and restrict non-essential travel. Nobody wants their employees to bring back an infection, nor does anyone want to be stranded or quarantined in a far-flung place. I expect many hospitals will also want their staff to be readily available as the number of cases escalate in many countries.

We at BSB are also carefully considering our plans and which conferences in coming months we will attend in person, and expect it will be fewer than recent years. We’ve already cancelled attendance at a couple of international meetings and are actively considering whether we will cover others remotely too.

The worlds of oncology and the coronavirus are colliding in many ways, including on the scientific level too.

It turns out that key RNA transcription factors may have a role to play as therapeutic targets for both cancer and the coronavirus.

Science is very much about making connections. In this post, we’re taking a look at one transcription factor that could be a useful target in the context of both coronaviruses and oncology.

It’s time to look through an alternative window and see an entirely different perspective…

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It has to be said that this is one of the most jam-packed ESMO schedules that I’ve seen in a while!

Usually one has a few sessions they are interested in and lots of ‘free’ time to conduct interviews. That is definitely not the case this year with even parallel sessions at the same time as the Presidential (plenary) symposia, making for some very hard choices that need to be made.


Immune suppression can take the form of many targets – just taking out one of them may not be enough

As we start to see a renewed focus evolve on how to make immunotherapy work in or help more patients, there has been much attention on what we can learn from the addition of chemotherapy, additional checkpoint targets, immune agonists, various innate targets from KIR and NK cell checkpoints to TLRs and STING, neoantigen and dendritic cell vaccines, a telephone directory of cytokines, oncolytic viruses, etc etc to name a few, all with varying degrees of success.

What about exploring the inhibitory factors that induce immune suppression?  If we can reduce the cloaking and hostile tumour microenvironment, would that lead to more effectiveness with checkpoint blockade?  Maybe, maybe not.

In principle, it’s a sound idea yet these factors are both broad and incredibly varied in scope as a topic as to seem overwhelming at first.  The good news is that there are some emerging targets and hints of activity to come that are slowly beginning to emerge, making ESMO a good place from which to take stock of some new early stage developments.

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Yesterday we posted the first part of an extended interview with Professor Gerard Evan (Cambridge), where we discussed the oncogene MYC and what we have learned from his and others work in this emerging field.

It hard not to be in Cambridge and think of biology as anything but an seriously intellectual pursuit, and yet there are many lessons to be gained from a better understanding of why things do what they do – in both health and disease – if we are to even think about going about manipulating them therapeutically.

The river Cam in Cambridge earlier this year

Without much ado, here’s the second part of the interview with Prof Evan, where we channel our inner Socrates and focus on a lot of whys rather than hows.

We turn to discussing the biological principles around how MYC and KRAS behave in concert, what we do and don’t know about p53 as a tumour suppressor, plus a few other related topics of interest, including what happens to immune cells in their lung and pancreas cancer models.  There’s also the little secret of what Prof Evan describes as the ‘dark matter of cancer biology.’

I highly recommend reading the previous post before moving on to digesting this portion of our enlightening discussion…

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In the initial parts of the broader story on MYC, we have covered a basic primer on the MYC oncogene, including a look at the key work from the labs of Dean Felsher in Stanford (liver model) and Gerard Evan in Cambridge (lung and pancreas models) to set the scene.

We also heard from Dr Jay Bradner at NIBR about his work wth bromodomains and PRC2 and how deep transcription factors might interact with the immune system.

A couple of years ago at AACR, Prof Evan gave a wonderful talk about his Myc model in a session on ‘Drugging the Undruggable’ and happened to put up a dramatic slide that really caught my attention – MYC and RAS drive out T cells – and I was thinking why, how do they do that? I wanted to know more about this effect because unless we understand how and why it happens, that maybe we can possibly go about tackling cold/non-inflamed tumours in a more informed way when these oncogenes are actively controlling and driving the tumour growth.

Cambridge, UK

For me, the logical next step in this ongoing story on understanding MYC is actually to explore the biology a bit further – what have we learned from animal experiments that might teach us some clues about where to start looking if we want to go about drugging something therapeutically that’s not in the normal kinase domain like many so called ‘druggable’ targets are?

To answer this question and many others, we travelled over 7,000 miles as a the crow flies and tracked down the great man himself in Cambridge UK.  We ended up with one of my all time favourite interviews that we’ve been privileged to hear at BSB…

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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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Through the window of aiming at tough to hit targets – with new approaches will we soon see more than before?

One of my big dislikes in oncology is the tendency to describe certain areas of R&D with the characterisation around the popular media epithet, “Drugging the undruggable.”

When we think of ‘undruggable’ in oncology R&D the first three targets that many people think of are MYC, RAS and TP53.

Quite aside from the issue that implies we can do little or nothing for those patients unfortunately affected is that it results in a more closed mind, a bit like half empty versus half full; it’s only undruggable in the context of what has gone before us and offers little in the way of future possibilities that lie ahead of us.

The RAS pathway is a great example of this phenomenon.

For years it was considered undruggable and yet despite that we now we have several selective BRAF mutation inhibitors, plus some nice approaches now emerging against KRAS mutations such as G12C (e.g. Amgen, Mirati, Araxes/J&J) and G12D, plus let’s not forget the potential for tipifarnib against HRAS mutant squamous cell carcinoma of the head and neck (SCCHN). All of these have shown some nice preclinical promise with some (BRAFV600E) already approved by Health Authorities.

There are other tough targets to think about too, including MYC and TP53, but rather than consider them undruggable, I’d rather think it just takes a little bit of time (and a lot research) before we understand the underlying biology better in order to figure what we can optimally target.

With that thought in mind, we have a new five part mini-series to share focusing on MYC. It’s actually been three or four years in the making ever since I heard a wonderful talk on the topic about improved mouse models that allow us to interrogate the biology more profoundly in order to understand how things work.

Not all of the interviews were theoretical in nature – we also talked to a leading scientist in this area involved in a largely unheard of start-up/spinoff with the goal of developing new therapeutic approaches against hard to target oncogenic drivers.

Before we go there on our journey, however, we need to begin with some basic understanding to set the scene…

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Philadelphia – Day 3 of the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics meeting continues to deliver on high quality talks with excellent data to discuss and parse.

Dr Jay Bradner (NIBR) at #Targets17

The session on epigenetics and transcription factors is always one of my favourites and this year didn’t disappoint.

There were also sessions on imaging, non-mutated genes, the tumour microenvironment and of course, a long poster session to browse.  Thankfully the poster halls weren’t as mobbed as they were at ASCO earlier in the year, but they were still pretty busy and well attended.

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Molecular biology was a hot new topic back in its infancy in the late 1980’s just as I was finishing my doctorate – cue moment of realising you’ve missed a big wave before it really even started!

Springtime in DC

These days scientists now delve in the realm of deeper molecular biology and go much further than mere genes… it’s all about transcription factors, super enhancers, chromatin complexes, bromodomains, and even chromodomains. In the past, many of these drivers were often considered ‘undruggable’ – think MYC or RAS, for example.

The world of molecular biology is rapidly changing as researchers understand pathways and processes associated with carcinogenesis better, thereby enabling new approaches to evolve and with it, valid new targets for therapeutic intervention.

This field is always one of my favourite ones to cover at AACR, where we not only learn about exciting new research from investigators, but also up and coming young biotech companies that are doing good work who deserve to be highlighted.

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We have written about small biotechs and big pharma a lot on this blog, particularly when they have exciting new developments in their pipeline to review and consider.  Increasingly, we have also begun to look at the early phase companies because often, that is where some fresh ideas and approaches are being developed and tested.

They’re also not beholden to the norm in terms of thinking that’s non-linear and many are academic start-ups that began life as thought leaders doing their own research and eventually VCs get interested, enabling financing to be raised.  The downside of this for some of our readers is that they’re usually not investable as a private company (sorry about that), but we have a broad church here on BSB and instead these small companies attract the interest of enlightened pharma companies who want to license early compounds in areas they are interested in or gain knowledge about a new field of research before buying elsewhere.  In other cases, the approach pays off in clinical trials and we see the IPOs emerge from companies such as Juno Therapeutics.

Syros Pharma LogoOne company that neatly fits this bill is Syros Pharmaceuticals, an academic spin-off from the Whitehead Institute of MIT and Dana Farber Cancer Institute in Boston based on the pioneering work of Drs Richard Young, Jay Bradner and Nathanael Gray.

Regular readers will remember our original article their the scientific work on gene transcription factors at AACR last year, which included a fascinating interview with Dr Young.  That was probably one of my favourite interviews of 2014 – I was inspired!

NancyHS201303wsdIt’s now time to look at the company and entertain some strategic thinking about where they’re coming from and where they’re going with clinical development.  The CEO, Dr Nancy Simonian, kindly agreed to an interview and be put in the ‘hot seat,’ so to speak.

This screenshot from the Syros website sums up their philosophy: Better medicines through gene control.

Syros Website Screenshot

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