Biotech Strategy Blog

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

Posts tagged ‘MYC’

Can we build up a storm against hard to treat cancers?  The initial evidence suggests, yes we can!

Today’s focus is on an emerging new biotech company with potential to make an impact in difficult to treat solid tumours with a more selective and focused approach to oncology drug development.

We’ve talked about the so-called ‘drugging the undruggable’ targets in the past, but what if we could circle back and use a different approach in combination with existing selective inhibitors currently in the clinic?

These possibilities – and others – caught my attention and they may pique yours too, so what’s this all about?

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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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It is becoming increasing obvious in these challenging times as the pandemic spreads globally that no corner of the earth (except perhaps the Antartica) is being left untouched.  As lockdowns begin or continue depending the phase the spread is at, this also has numerous implications for clinical trials, both academic and company funded studies alike.

Which direction should we be considering for early anti-cancer therapeutics?

One of the broader effects of the coronavirus pandemic likely means we won’t see much new data on many of the clinical trials after the currently scheduled presentations for AACR, ASCO, ESMO and ASH for a while yet, perhaps well in to 2021, which in turn is a strong reminder if we want to see how much progress is being made then we need to look at what data is available now.

I can well imagine many folks are already completely Zoomed or WebExed out from constant online meetings dealing with the implications of the pandemic on research and clinical development, as well as what happens to new and existing trials, so the idea of listening to two days of a virtual meeting on top is probably a bit daunting for the time-challenged observers amongst you.

AACR’s virtual meeting is a wonderful opportunity for smart folks to take some careful snapshots of where we are now, and how some of the early pipeline agents are shaping up.

The good news is we while your online internal meetings continue apace, we will be posting many reviews, summaries, discussion and analysis of the data here on BSB, hopefully sparing many of the additional stress in busy times. We plan to make the process of analysis and commentary relatively easy so you can follow along with us.

For reference, you can access all of our ongoing AACR20 conference coverage here. Future posts will also be added to this magazine page as they are posted.

In our fourth AACR Preview series, we take a keen look at some additional early products in development of interest, as we continue our updates on the never ending oncology R&D journey.

We highlight 10 emerging agents in early stage development to watch out for…some are new and others we previously reviewed preclinically and have moved along in their R&D journey into the clinic, with good and bad results to think about.

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Part of the next wave of early immuno-oncology agents are focused on addressing the tumour microenvironment and inhibitory factors that dampen down immune responses.

As we look at all the options available, there are a few obvious ones such as physical barriers and inhibitory cytokines or chemokines, but beyond that are a vast array of other potential targets we can aim at therapeutically.

We have covered quite a few of these already, but here’s a new one to add to the list.

One particular advantage is that because it is early in development, few competitors have cottoned on to the concept yet. First mover advantage can have quite a few benefits, after all.

Here’s an important question to consider in terms of oncology R&D – would you rather explore a blue ocean strategy or follow the lemmings off the cliff and be 14th to market in a highly competitive red ocean?

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Orlando bound for ASH!

What is old is new again…

I have that distinct feeling of deja vu with the ASH asbtract drop yesterday on several fronts. It’s quite a few years now since we wrote about the runners and riders in the BTK/PI3K race to market in CLL and by weird coincidence a topic I was covering by interview yesterday on the RAS pathway came up in one of the first ASH asbtracts I was reading, which was rather spooky. Clearly Halloween came slightly late to Florida this year!

So how do all these disparate topics hang together and why are we excited about a small cap biotech company that is largely under many people’s radar?

They have some unexpected unifying threads…

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Time for some reflection

Before we get to the World Congress in Lung Cancer (WCLC) taking place this weekend, I want to take a moment to reflect on some of the things we have learn over the last few weeks.

It’s time for a reader mailbag as we answer reader questions on the recent MYC mini-series, as well as covering bromodomain inhibitors (what’s going on there?) and discuss a new PROTAC compound in early development that looks quite interesting.

We also explain why that is the case…

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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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