Biotech Strategy Blog

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

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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Cambridge – Amongst the historic colleges and cloistered walls of one of the world’s oldest universities there is pioneering research going on, and not only that, it’s potentially being translated into potential new cancer treatments.

Dr Laura Itzhaki (Twitter: @LauraItzhaki) is professor of structural pharmacology at the University of Cambridge. She is also founder and chief scientific officer of a start-up biotech company, which is focused on the discovery and development of a new class of drugs called polyproxin molecules.

University of Cambridge

Prof Itzhaki’s research is the basis of the science and intellectual property behind PolyProx Therapeutics, and the company earlier this year received £3.4 million in seed financing. This may not be a huge deal in US terms, where we’ve seen some truly mind blowing Series A financing rounds for start-up cell therapy companies, but it’s not inconsequential in UK terms. We’ve also seen with today’s £100M Series B funding announcement for Stevenage based Achilles Therapeutics (whom we profiled a year ago) that early stage UK companies can indeed go on to big things.

Basic science is the backbone of cancer research – let’s not forget that translating the new discoveries into the clinic is how new products are developed and it’s exciting to see an increasing number academics take the next step on that journey.

During a visit to Cambridge this year, Prof Itzhaki kindly spoke with BSB about her research and the direction PolyProx hopes to travel. It’s very early stages for the company, yet it’s a story we very much look forward to following, and one I expect we will hear more from, as other companies look to partner with them in the future….

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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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It’s the dog days of summer and yet there’s a lot happening on the DDR front from multiple angles.

After a short break from science, this makes now a really good time to reflect and take stock in order to explore some of the key issues facing the field, especially in terms of future combination approaches.

Research that’s appearing now may influence future trial designs – always a nagging worry in Pharmaland that the standard of care can change before you even get your own phase 3 readout! No one likes to be pipped to the post, after all.

With the early WEE–1 news this week and a raft of new PARP readouts, there is much to discuss and also plenty of nuance and subtlety to consider carefully because what looks obvious at first blush may not actually be the case based on prior evidence that many will have forgotten about.

So grab a cup of iced coffee and shades and settle down under your sunbrellas for a pleasant and easy to read review of the various trials, settings, combinations and DDR pathway considerations…

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In the enlightened realm of phase 1 oncology trials there generally more unknown unknowns than there are known unknowns, especially with new target approaches.

Who knew it was so beautiful outside of the cold dark halls?!

You could say that makes for a more interesting world, but it also makes for more caution, especially when the FDA is considering agonists that induce stimulatory effects.  What it means is that you start off very low – in this latest example it was 50µg and going up to 1600µg to determine the safety profile of a combination.

We have covered the STING pathway quite extensively over the last four or five years now, so it’s time for a new update and a look at some of the much awaited combination data. What can we learn?

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Yesterday afternoon BMS provided an announcement and update on the controversial phase 3 CheckMate-227 trial in first line non-small cell lung cancer (NDCLC).

Lightning bolt

Does lightning strike twice?

This large study compares the combinations of nivolumab with either ipilimumab or chemotherapy to chemotherapy alone in both squamous and non-squamous patients with previously untreated advanced disease.

Ahead of the data presentation what can we expect and what will the impact be on the broader landscape?

There is no doubt that BMS have had a chequered history in lung cancer since the miss with the earlier CheckMate-026 study. Is their run of missteps over or can we expect yet more controversy to befall them?

In our latest analysis we take a look at what going on in this niche.

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With the Jounce-Celgene announcement that the ICOS agonist, JTX–2011, is being returned and new priorities being pursued there is much to consider. There are quite a few nuances to this story to consider beyond the obvious that BMS already have an ICOS stimulating molecule.

Here we put together a synopsis and some commentary in looking at several relevant targets of interest in the context of the broader landscapes that are evolving.

Are Jounce left high and dry with this latest development or is there still a future in ICOS agonism?

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