jfm1330 wrote: I read the article and I came out unconvinced about a clear new mechanism of action to explain inhibition of vasculogenic mimicry (VM), which is real. This is pretty advanced biochemistry, and maybe I missed something. So don't take what I will write as the truth. It is just me guessing.
In fact, my questions after reading the article are pretty simple and were not answered by the article. The first unanswered question is why TH1902 and TH1904 are inhibiting VM, and that the unconjugated peptide (TH19P01) had no effect? This difference is not answered and to me it is a fundamental question. Again, maybe I missed something, but my understanding is that TH19P01 should bind to sortilin and initiate the endocytosis process, the same for the conjugated version TH1902 and TH1904. So these three molecules should trigger the endocytosis process and remove the sortilin receptor from the cell membrane. The same as gene silencing with siRNA is inhibiting the expression of sortilin on the cell membrane, or the monoclonal antibody against the extracellular part of sortilin is neutralizing it. Of these five ways to affect sortilin, TH19P01 is the only one that does not lead to VM inhibition. Why? This question is not answered and pretty fundamental. Maybe there is a simple explaination that I missed, but otherwise, it is a basic question that should be answered. Maybe TH19P01 alone is not triggering endocytosis. Maybe that alone it is very quickly recycled back on the cell membrane, so not affecting its role. I don't know, but at this point it seems that the simple endocytosis process of sortilin is not the explaination for the inhibition of VM. It seems to be related to the cytotoxic effect of doxorubicin or docetaxel, or to the effect of conjugation that would allow a stronger interaction of the conjugated peptide with sortilin and a slower recycling process of the receptor to the membrane, which would lead to a similar effect as gene silencing through siRNA.
The "why." You ask in the middle is the million dollar question. But it's not necessary to understand the "why?" In order to think this is good evidence for a 2nd MOA. The 2nd MOA is not fully explained but they are pretty clear this is not arising from the dumping of a chemo in the cell (that would be the 1st MOA). So a little like Wino's earlier logic around efficacy having closed down the possibility of some potential explanation then it must be another one. You have to start from 'believing' the observations. If TH19P01 doesn't stop VM and the PDCs does. And if the chemos alone don't stop VM but the PDCs do then the logic seems to me that when you bring the peptide and the chemo together as a PDC it must give this new molecule a property that the two molecule apart don't possess.
If you go back to the cancer KOL event you hear Beliveau answer a Q. I asked why the VM inhibition happened for the PDCs (the very Q JFM is asking). His answer (at least in part) was to speculate that the unique property of the PDCs is not just to engage with the SORT1 but to also deliver the chemo in a unique distribution around the cell. It's very easy to think of a cell as a kind of blob (with a few blobs inside it) but it's actually a very complex structure and I buy the idea that if you deliver chemo in a very unique and specific way to different parts of the cell then you have the potential to effect functions of the cell in different and unique ways. All that is speculation it would require more expts to begin to prove that (or alternative ideas).
The point I was making earlier was that I thought one specific way this new delivery of chemo might produce unique effects is if it not only hijacked the endosomal trafficking system to get in the cell but once it got released from the endosome it also disrupted the trafficking syste. Again that's huge speculation, it would require expts to prove that (or the better ideas the experts have). I thought the various things that are shown in this paper can be explained by disrupting the cells trafficking system, some of the things in the discussion that I'm reading as speculation/hints would also fit with disrupted trafficking. From what little I understand about cell transition to a migratory phenotype would rely on trafficking and the changes to the ECM of the cell to make VM would also be achieved through intracellular trafficking. It fits with my limited understanding of all this but I'm happy to be totally wrong.
I would go back and listen to Beliveau in the cancer KOL, in his answer to a Q is seems to believe in the ability of these unique molecules to have their own unique MOA, that aren't just silencing SORT1 and aren't just chemo delivery systems, but have something else. If they knew exactly what that something else was they'd have put it in this paper so there isn't a very satisfactory answer to the "why?" yet.
The basic point I'm making (and it is very basic) is you don't really need to know the "why?" To see they have something new even if you don't know exactly what the new is.
All that being said, there is also another, and much simpler explaination. We know that advanced cancer are genetically very heterogenous. In simpler terms, it means that in a same tumor there are a variety a cancer cells types expressing different genes and with different gene mutations. So a therapy that can work on a specific cancer cell type in the tumor won't work on other ones because they are not the same genetically or they are not expressing their genes in the same way, leading to different receptors on the membrane and also other proteins inside the cancer cells affecting signalling cascades.
In the article, they prove the necessity of sortilin expression on the cell membrane to have VM. On the other hand, we know that TH1902 and TH1904 are interacting only with cells that express sortilin on their membranes. So TH1902 and TH1904 would only kill cancer cells expressing sortilin, and if you are able to eliminate these cells, or part of them, the results would be no cells or much less cells with sortilin, and without sortilin, no VM. So the effect of TH1902 and TH1904 in inhibiting VM would only be the result of selectively killing cancer cells expressing the sortilin receptor. By reducing the number of cells in the tumor bearing the sortilin recptor, you reduce the tumor ability to generate VM.
That's the simple explaination of the end effect. That does not mean that there are no pathways for VM that could be inhibited by other drugs. But in the case of the SORT1+ technology, the explaination seems to be that the door to access the cancer cell is also necessary for VM. So using this door to bring in a deadly weapon inside the cell leads to selective reduction of these cancer cells in the tumor, but also to the reduction of one of their features which is VM. So the simple explaination is a Trojan horse effect working only on one type of door, sortilin. That being said, the double effect would be real. Not only you would selectively kill sortilin expressing cancer cells, but it would also dismantle to some extent the supply lines of the tumor, affecting other cancer cells type that are not expressing sortilin.