Biotech Strategy Blog

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

Posts tagged ‘super enhancers’

Padstow, Cornwall – It’s May Day or ‘Obby ‘Oss, as it’s known locally in this little corner of south west England.  The quaint festival means that it’s the biggest day of the year as over 30,000 people crowd into the tiny fishing village.

Obby Oss Blue

Centuries old traditions are still alive and well in this part of the country and the big question of the day (are you red and white or blue and white?) is a far cry from the complex high tech world of cancer research.

Still, with all the time and attention focused on immunotherapy and targeted therapies of late, it is all too easy to forget what’s happening on the epigenetics front, which is quite a bit in practice.

We often see random allcomer approaches to clinical trials, which are find for phase 1 studies where you want to gather data on responders and non-responders in order to conduct PK/PD and immune profiling, as well as biomarker and signature development, but a potential recipe for disaster in phase 3 if you have no idea exactly what’s driving the efficacy since you can all too easily end up with unbalanced arms that you didn’t control for and thus skew your survival curves in a way you didn’t anticipate.

Why on earth would you use a targeted therapy in an untargeted fashion? Hmmm obvious question and yet, many companies still do this all the time.

There are some biotechs out there, I’m pleased to say, who do conduct extensive translational and biomarker research.  Obviously finding those markers is a lot more tricky than choosing red or blue.

One biotech company we have been keenly following for a while is Syros.

We first wrote about them in Spring 2014 and now, five years on, I thought it would be a nice idea to catch up with one of their founders and learn more about the science underpinning what they’ve done and where they’re going with future projects. Not only do they invest in smart medicinal chemists, profiling and translational research, but they also seek to identify rational reasons why people respond to their compounds.

The answers were rather interesting and there’s quite a bit that readers might be curious to learn more about…

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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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Have you ever sat in a freezing cold scientific session and been so engrossed in the compelling presentations that followed, you simply forgot to take notes? Not one. That actually happened to me at the American Association for Cancer Research (AACR) in Philadelphia this year in one of the many fringe sessions that I attended.

Reading Terminal Clock

Reading Terminal Clock, Philadelphia

Granted, the hot topic of the conference was undoubtedly checkpoint inhibition, but I was anxious to escape to the comfort of some meaty and familiar basic and translational science, namely MYC.  MYC is largely thought to be a difficult to target, even undruggable protein, and along with RAS and p53, represents a formidable challenge for cancer researchers.  These three oncogenic proteins alone are probably responsible for more drug resistance developing and even death from cancer than any other proteins in a patient with advanced disease.

For cancer patients with advanced disease, the clock is ticking on time they have left.

Solve these three problems (MYC, RAS and p53) and we may have a shot at dramatically improving outcomes. As Dr Gerard Evan (Cambridge) noted:

“I think it’s fair to say that we don’t really know why interruption of any oncogenic signal actually kills cancer cells, but one of the reasons that we’re interested in MYC is because it seems to be a common downstream effector of many, maybe all cancers.”

Sure, the road to success is paved with an enormous graveyard of failures, just as metastatic melanoma was before checkpoint blockade came along, ironically.  What I heard at AACR both inspired and filled me with greater confidence… we’re finally getting somewhere.

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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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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.

rick young

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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