Biotech Strategy Blog

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

Posts tagged ‘LKB1’

It’s February 2nd, which means Groundhog Day in America. I was idly wondering how accurate the rodent Punxsutawney Phil was, after all, he’s got a 50:50 shot of being right or wrong.  Who knew someone had analysed the predictions already and what’s more – published them?!

Meanwhile we don’t need no predictions for today’s post, where we look at the evidence gleaned from several clinical studies in lung cancer and come to some important strategic conclusions about the findings.

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The past year has seen hype and hope over targeting KRAS mutant cancers and many challenges still remain to be addressed. We’ve seen the emergence of selective G12C inhibitors, as well as others targeting SOS1:RAS upstream and even related pathways to address cross-talk such as SHP2 and ULK1, for example. The oncology R&D ecosystem is beginning to motor again as new competitors start entering the niche.

Riding the KRAS wave

To put things into broader perspective, however, despite all the positive news in lung cancer, consider the colorectal carcinoma data was less impressive than lung because of more complex, heterogeneous disease.

Meanwhile, Lilly recently announced the discontinuation of their selective G12C inhibitor, LY3499446, due to adverse toxicity, so clearly it is not all going to be plain sailing in this landscape!

Let’s also not forget the G12C mutation is not the only viable target in this context. People with advanced lung cancer can also present with one or more of several co-occurring mutations such as the serine/threonine kinase 11 gene (STK11) and kelch like ECH associated protein 1 gene (KEAP1), for example.

Unfortunately those presenting with both STK11 and KEAP1 mutations – independent of KRAS status – often have a poorer prognosis and there remains an unmet medical need for effective new treatments.

In this fourth postcard in our summer mini-series on the potential of immunometabolism for cancer immunotherapy, we’re taking a look at a novel way to target KRAS mutant lung cancer and, in particular, those with an STK11 and KEAP1 mutation who tend to do poorly on current therapies.

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Not in San Diego – In normal times of past years, the AACR annual meeting generally takes place once a year in April before we haed onto oter events such as ASGCT, ASCO, and EHA. In these abnormal times in the middle of the COVID–19 pandemic, however, the virtual event was split into two, with the first online event in April covering mainly early clinical data, and now we get to learn from the meaty scientific presentations, which are being highlighted this week.

A network of mutations, tumour suppresses, metabolic and immune processes, as well as other hidden factors can unexpectedly impact therapy outcomes in NSCLC

We have a lot of translational researchers reading BSB, so I wanted to kick off the first of the AACR Virtual Meeting series with a scientific focus, which is likely of interest to many for a number of obvious reasons.

The good news is this a topic we have covered before and so there’s already a body of work to build on for reference since this latest round of information not only adds to what we know, but also highlights some additional unknown unknowns yet to be elucidated.

The dichotomy is an essential part of the very essence and fun of science – the more we think we know, the less we really know in practice, especially as the various layers of the onion get gradually peeled off over time.

This latest review mixes up translational research with clinical research…

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In wave 3 of the immuno-oncology surge things have slowed down, partly due to a raft of combination trials yet to read out and partly because the reality has finally hit that tumour heterogeneity means there will be variable patient responses.

Just getting from room to room on time can be a real challenge with 40,000 other people present!

This complexity can come about in many forms… immunosuppression, alterations in gene functions, resistance and immune escape, to name a few.

If we want to help more people respond to these therapies then before we can rush headlong into another round of combination trials, we first have to go back to looking carefully at the underlying biology of the diseases and listen to what the patient’s tumours are telling us in order to fix things.

To accomplish this feat requires considerable time, energy, effort, and a lot of bioinformatics.

In this post we explore five key talks that highlight different aspects of biomarkers of response and mechanisms of resistance.  From there, we may see additional validation and prospective testing to determine how best to segment people so that they have the greatest chance of responding to the therapy administered.

One thing that most people don’t have these days is time, which is how we can help you because here’s a handy short cut to finding out more about five complex and diverse areas on biomarkers or IO resistance quickly and easily…

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Henry Moore sculpture – looks like a protein binding pocket!

Cambridge, UK – It’s somewhat ironic that we headed across town today to chat with one of the world’s leading cell biologists on MYC and RAS with a post on KRASG12C inhibitors almost ready in the bag. More on that interview in a future mini-series.

There are a number of nuances and subtleties involved in this niche, which have been somewhat lost in the frantic hype over hope melêe of late.

This review discussing KRAS and various other co-mutations such as LKB1/STK11 is a long and thorough one,, and perhaps rather contrarian in nature.

That said, I do feel that it is very important to highlight a lot of issues that are being ignored in the rush to declare the latest expected winners and losers or even potential blockbusters, if the breathless signals are to be believed.

If nothing else, there are certainly several key issues that could have a bearing on the clinical results in patients that are worthwhile highlighting for discussion and adding to the watch list because some of these factors may well take time to develop.

This is one of those ‘Ground Control to Major Tom – take your protein pills and put your helmet on’ moments… Actually, I may well be needing the helmet as protection if the analysis and commentary turn out to be unpopular!!

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