Ep.5 with Sanjay Popat: The future of lung cancer care

Yeah.

The battle is still raging.

I think one of the papers that I read a couple of years ago that, that really struck me as fascinating in the lung case was that Charlie Swanton paper about particulate matter 2.5, um, I think back in 2023 during COVID he published that.

And he proposed a, a really interesting new mechanism which was nothing to do with carcinogens at all, where, um, small particulate matter of a- around the, the 2.5 micrometer size could come into the lungs, cause, uh, epithelial damage, uh, attract macrophages.

Those macrophages, uh, excreted, um, interleukin 1 beta, and that caused inflammation which for a subtype of genetic groups, I think EGFR and KRAS, could drive cancer through a completely non-carcinogen mechanism.

That struck me as a really important insight, and I'm wondering whether that's affected the way you think about patients both in the smoking and also the non-smoking subset of, of the people that you see in your clinic.

Yeah.

And I, and I think this is a really important new field of biology that we need to explore because, you know, his phenomenal work has impacted on the question that patients ask me in the clinic every day, which is, "Why did this happen to me?" That's the key issue that folk want to know about.

Now, if you've never smoked or you've had a few crafty cigarettes, you know, in university and you end up with lung cancer, it's clearly not tobacco related, which is by far the greatest cause of lung cancer.

And in those patients in whom tobacco probably hasn't played a role, Charlie's data is very clear that this inflammatory change that we see with 2.5 particulate matter drives this inflammatory change through CHIP, through macrophages, through IL-1 beta signaling.

And what's really interesting is that it biologically gives us an understanding for why some patients may develop somatic mutation as a driver where others may not.

Uh, working on the other foundational data that we have from Mike Stratton and others, which is that many of our cells develop somatic mutation in key drivers but never become malignant in those cells.

So the key issue is why biologically do some cells develop a driver but then that never becomes transformative to an established tumor and in some people it does.

And I think this whole IL-1 beta inflammasome, uh, hypothesis that, that Charlie's really, I think, quite eloquently demonstrated does support and drive that.

So I think this has huge implications, right? Because, you know, we can effectively inhibit IL-1 beta, right? We have drugs which do that.

Uh, there's a, there's a fantastic paper many years ago demonstrating that the NLRP-1 inflammasome, which is also driven in that sort of scenario by IL-1 beta, you know, may contribute to the formation of, uh, asbestos, uh, inflammasomes, which then can drive asbestos-related malignancy and asbestos-related other conditions.

So the whole concept of IL-1 beta is in carcinogenesis, I think is really, really mission critical.

Uh, and there's an opportunity I see here to, you know, try and test that and drug that with IL-1 beta inhibitors.

Now, they've not really proven effective in widespread metastatic disease, but, you know, we need to think about how we then select the right patients for the right trials in that right scenario, and maybe prevention type of study is what we need to start thinking about doing.

But these are very complex studies to set up and deliver on.