RE:RE:RE:RE:RE:RE:RE:RE:RE:New PR aroundVMYou know my view on the essential thing in all that story, hard facts on humans. We don't have that at this time. So all this discussion is theoretical when it comes to how it would apply to human use on real patients with real big tumors. So my baseline view has not changed. That being said, any discussion to have here assume that it could work on humans, otherwise there is no point. So, assuming it will translate positively to humans, obviously the most important piece is sortilin because everything then results from that. They were able to design TH19P01 out of knowing sortilin sequence and structure. Then you needed TH19P01 to be able to carry a massive payload and still bind to sortilin. And as I discussed in depth here, the linker is also critical, because without selective cleavage inside the cancer cell, the whole concept will not work.
All that being said, obviously sortilin is the most important part. In theory it is close to an ideal target. A receptor whose main role is to selectively import/export molecules, often macromolecules like protein in and out of the cell. A receptor overexpressed in many cancers, and with higher overexpression the more a cancer is at an advanced stage. And from the last article, cancer cells expressing sortilin are necessary for a resistance mechanism called vasculogenic mimicry (VM). So if you kill the cancer cells bearing sortilin, you also inhibit or destroy VM. And also from the last article, it seems that sortilin is often express on cells that are also bearing on their membrane the glycoprotein CD133, that is a marker for CSC (cancer stem cells). So sortilin would often be expressed on those CSC that are invovlved in cancer resistance because they have the potentiality to differentiate in many cancer cell types.
So again, in theory with what we know from in vitro and xenograft experiments with selected commercial cancer cell lines, yes, sortilin seems to be a target that would allow multiple beneficial effects against tumors containing cancer cells expressing it. But again, at this point we have zero efficacy results on real human cancer cells. All we know is that the PDC allows to inject relatively much higher doses of docetaxel, but with a very different pharmacokinetic profile. The only hints of possible efficacy we have is through the behavior and communications of the company since the phase Ia has entered in the theoretical therapeutic dose area, so since the KOL presentation last June. At this point, it's a bit like circumstantial evidence in a murder case. No direct proof. Not enough to go to trial. It is still a guessing game. But we know the testing results are coming soon to shed some light on the whole thing. Will it be enough to know for sure? Will it be a defenitive proof of concept? I don't know. But we will finally know more. In vitro and animal data are great. The company acts like it is working on humans to some extent, but it is still speculative.
Wino115 wrote: Interesting. So what you are really saying is they hit the jackpot by being the first to focus on Sortilin. Sortilin just happens to be associated with two parts of cancer progression. Sortilin is THE key and targeting it helps in at least two ways...
jfm1330 wrote: I would add that we need to remember that the experiments made by Thera are on selected cancer cells on which they already proved that docetaxel and doxorubicin alone had little effect because of resistance mechanisms like MDR1 efflux pump and dose limitations due to toxicity. So the mechanism of action of both PDCs is not the same as the mechanism of action of the free chemo drugs given alone. We already knew that. The whole point of the PDC strategy is to have a different delivery system of the chemo drugs that would allow them to be efficacious, contrary to when they are given alone. So in the context of PDC treatment, the MOA is enhanced delivery and concentration of the drug inside the cells + the effect of the chemo drug itself. There is nothing new there. This is the basis of the whole strategy that is to bring the chemo drug inside the cell where it can be effective and at a sufficient concentration to be effective.
All that being said, it brings us back to the question of a second or third mechanism of action. I think that at this point there is no clear proof of that. I am not saying it does not exist. But the idea that it all comes from the same MOA is possible. The PDC allows to bring enough chemo drugs inside the cell in the right places by avoiding resistance mechanisms like MDR1, this allow to selectively kill cancer cells expressing sortilin, and by eliminating these sortilin bearing cells, it inhibits or destroy vasculogenic mimicry (VM) because cancer cells expressing sortilin are essential for VM to occur.
Another interesting point in the article is that VM is correlated with sortilin expression and also correlated to the glycoprotein CD133 which is described as a cancerous stem cell marker. CD133 role is believed to be an organizer of cell membrane topology. So if cell membrane topology change, it can have an impact on intercells organization. Also, we know that stem cells have the potential to become different types of cells. So there is a plasticity there that is in line with VM development. So if sortilin expression is linked to CD133 expression, it means VM is likely linked to cancerous stem cells. If you can kill these cells or a part of them, it will without a doubt affect tumor structure and organisation which VM is obviously a part of.
So again, selectively killing sortilin expressing cells can also lead to selectively killing some of the cancerous stem cells in advanced stage tumors. All that can happen through a single mode of action, which is selective chemotoxic action of TH1902 or TH1904 on sortilin expressing cells which are linked to some extent to cancerous stem cells. At this point, it is impossible to distinguish the killing of cancer cells and the VM inhibition. Both happen at the same time and clearly killing sortilin expressing cells will have the secondary effect of inhibiting VM. All we know about a second possible mechanism of action out of Thera experiments, is that removing sortilin from the cancer cell membrane through si RNA gene silencing inhibits VM, but we don't know if TH1902 or TH1904 have such an effect of removing sortilin from the membrane. We know that the sortilin ligand alone, TH19P01, has no effect on VM. At this point, the important thing is that there is clearly a dual effect, cancer cell killing and VM inhibition. Also, maybe there is selective killing of cancerous stem cell, which would be very important since these are the cells that allows cancers to adapt and resist. I would like another KOL with Dr. Beliveau. He surely has a clearer picture of the whole thing and his educated guesses would be better than mine. Also, back in June, at the time of the KIOL presentation, he was already aware of these results. Maybe it can help explain why he was smiling so easily...
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.
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.