Malignant cutaneous melanoma is one of the most aggressive cancer diagnoses - around 2,500 patients are diagnosed with it every year in the Czech Republic alone. Its research has long been devoted to Mgr. Stjepan Uldrijan, CSc. from the Department of Biology, Faculty of Medicine, Masaryk University. After several years of testing, he and his team were finally able to publish a study describing the importance of the eIF4F protein complex in cancer cells and how it affects the ERK signaling pathway, a process that controls their growth and division. It has been published in one of the most cited scientific journals, Proceedings of the National Academy of Sciences, which only proves how crucial the work of the Brno scientists can be for future drug development.
In your research, you focused on the eIF4F protein complex in skin melanomas. The link between it and cancer cell growth was described years ago. So what exactly is your new focus?
It was known that eIF4F was somehow involved in the resistance of melanoma cells to treatment, but the mechanism was not completely clear. And because current treatments target the ERK signaling pathway, which is important for tumor cell division, that's where we focused. We found that the activity of this pathway is significantly altered when the eIF4F complex is not functioning. In other words, the activity of eIF4F is necessary to properly adjust the activity of the ERK signaling pathway that drives cancer cell division. So our finding is an addition to the existing knowledge about the regulation of the signaling pathway in melanoma, but it seems to be quite important (smiles).
How does the ERK signaling pathway work in normal cells and how does it change in cancer cells?
Normal cells have a low activity of the ERK pathway and only when they receive a signal in the form of a so-called growth factor, they ‘turn on’ the pathway and can divide. But tumour cells have mutations in the pathway that activate it a lot - maybe a hundredfold compared to normal cells - so then they keep growing regardless of these growth factors. For a long time, it was thought that the more active the pathway was, the more the tumour cells would divide. But our research builds on more recent work showing that this is not quite the case, that it is, as they say in Czech, ‘vocaď pocaď’(note: meaning it has a limit). When the pathway is too low, the tumor doesn't grow, and conversely, when it is too high - as in mutant cells - and also lacks the brake of eIF4F, its activity shoots up several orders of magnitude.
Is it a correct assumption that if we learn to regulate eIF4F, we will be able to regulate the activity of the ERK signaling pathway?
We show that this is possible. Our primary concern is that cancer cells don't grow. That is, to find a drug that will act as a drug by targeting eIF4F in cancer cells, blocking its activity, which will disrupt the regulation of the ERK signaling pathway to the point where the cancer cells will die. But eIF4F is also important in cells for other processes important for survival, so the question is whether we can even achieve blocking it in tumour cells without bothering normal cells.
But you've already tried to block it as part of your research, haven't you?
We've used some compounds known to target it. Some of them show anti-cancer activity under in vitro conditions, some appear to be able to kill cancer cells even in vivo. But since there is no approved drug that targets eIF4F, it is not yet possible to say that this is the way to treat patients. For example, we don't know if there would be any major side effects. However, we are showing new biology and regulation that is crucial for cancer cells that was not known before. And the question is whether a drug that takes advantage of this will be found. There are teams around the world looking for eIF4F inhibitors, and we are trying to do it ourselves. (smiles)
Why does excessive activation of the ERK signaling pathway bother cancer cells so much?
We don't know. The pathway has many targets and is a topic for further exploration...
If over-activation leads to cancer cell death, can we expect a complete silencing effect of the pathway?
That's what the current drugs do, they block the pathway. But the problem is that at some point resistance develops and the drugs stop working. The tumor comes back. And now the only other way is to increase the activity extremely. There's every indication that the unifying element in all of this is increased eIF4F activity. That's why we looked into it. Because it's been shown that eIF4F is somehow involved in this resistance.
Thus, the destruction of cells through excessive activation of this signaling pathway could serve as a boost to existing therapies? Or, the cancer cells would first be suppressed, then killed?
It is thought that if eIF4F were inhibited, resistance might not develop at all using existing drugs. The eIF4F complex gives the cells some chance of escaping the treatment. But by blocking it, we could ensure that cells that would otherwise be resistant would not survive at all. The patient would be cured. But this has so far only been demonstrated in vitro.
Specifically, you have dealt with BRAF and NRAS gene mutations, which are among the most prevalent in melanoma. Is it possible to generalise how large a segment of melanoma your research covers?
The BRAF mutation is present in about 50% of melanomas and NRAS in about 30%. The other mechanisms that lead to the disease are already statistically relatively insignificant, so we can say that our research covers the vast majority of melanomas. And we don't yet know if the regulation of the ERK pathway that we have described is important in other types of tumors as well. Or, rather, it is to be expected, and our results suggest that there are many types of tumors that control the ERK pathway by the same or similar mechanisms. How many and which ones, we intend to address in the future.
Where should research in this direction go from here? When we were talking two years ago, you mentioned that in the United States, a company had already advanced to clinical testing of a substance that would affect eIF4F...
Well, that company went bankrupt less than six months ago. Unfortunately, it failed clinical testing. Not an anti-eIF4F drug, but an MNK kinase drug that was thought to help lung cancer patients. But it hasn't worked, they've spent about $300 million, and they haven't gotten around to further proving the effect of the eIF4F inhibitor yet, and they may not. There are some patents on the molecules they're testing that belong to someone, and that someone is going to be wondering if it's worth continuing to fund the research, and if it's going to succeed at all. From my point of view, it makes sense, but it is always about weighing up the chances of whether the compound can be turned into a drug.
So, going back to the question of where your research should go next, who might bounce off of it...
I think our results support the importance of the eIF4F complex, at least in malignant melanoma. That could perhaps motivate pharmaceutical companies to pay more attention to it.
Two years ago, we talked about your project on a cell-based system for efficient screening of chemical compound libraries to help identify new drugs that target important proteins in the cancer cell. How are the two researches linked?
Significantly. The current paper has been several years in the making just to get far enough with testing. And now that we have tested a large chemical library, and have candidate molecules, we can let loose on how our discovery could make new eIF4F inhibitors relatively easy to identify.
In the context of today's ubiquitous artificial intelligence, there is talk of how it could help the pharmaceutical industry in particular to identify suitable molecules. Do you use AI in your research in any way?
Not myself, because I'm not a chemist and I don't have much experience in designing molecules. But our collaborators are using them. And it's quite possible that at some stage, in collaboration with chemists who know how to use modern drug design tools, we will try to improve the molecules we have identified as potential drug candidates targeting eIF4F. Because there are only a limited number of molecules in existing libraries, if we can model a variant that fits the target protein - in our case eIF4F - better than the molecule we discovered in our testing, then it makes sense to have it synthesized and work with it further. But that's not what we do or can do. There are other experts in the faculty and university for that.
NÚVR: Překonat odolnost nádorových buněk k léčbě
Scientists from the Faculty of Medicine of Masaryk University have discovered new mechanisms controlling the division of cancer cells while studying skin melanomas. Their findings represent an important stepping stone for future drug development.
