RE:RE:RE:RE:RE:RE:New PR aroundVMI 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.
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.