Biotech Strategy Blog

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

Posts tagged ‘drugging the undruggable’

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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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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MD Anderson, Houston

Houston, Texas – At the First Annual Symposium on Pancreatic Cancer organized by Ronald DePinho MD and colleagues at the MD Anderson Cancer Center on Monday, one of the presentations that caught my attention was on exosomes.

Raghu Kalluri MD PhD (@KalluriLab) gave an excellent talk on, Exploiting the Biology of Exosomes for Diagnosis and Therapy of Pancreatic Cancer.”

What were some of the key take homes from his presentation?

He kindly spoke to BSB in Houston and talked about the direction he is going in this rapidly evolving field of research.

Here’s a short snippet from the interview where he talks about one aspect of this approach and how it might be useful (the others are covered in more detail below):

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