Mechanisms of actionThis phase Ia is so long that I forgot some of the stuff that I wrote here before (see links)
We know that TH1902 is exerting two visible effects on cancer cells overexpressing sortilin, apoptosis (cell death) and inhibition of vasculogenic mimicry. To achieve that, we know one mechanism of action for sure, which is concentration of docetaxel within cancer cells overexpressing sortilin. This concentration is possible because using sortilin to enter cells allows to bypass resistance exerted through the action of the MDR1 efflux pump. So higher docetaxel inside the cancer cells, and probably at different places within the cells, allow for a greater cytotoxic effect of docetaxel, hence, of TH1902.
We also know that TH1902, compared with docetaxel alone at the same concentration, is reducing by 50% the expression of the mitochondrial protein Bcl-xL which has an anti apoptic effect, in other words, Bcl-xL help preventing cell death, so if you reduce its expression by 50%, you are favoring cell death. This Bcl-xL inhibition was tested in a non MDR cell line, so the better activity of TH1902 over docertaxel alone is not related to this resistance mechanism. This experiment shows that there would likely be a second mechanism of action at play with the use of TH1902. The strange thing, is that Thera never made a big announcement about that. It was in the middle of a long and dry scientific article and you needed to read through it with some scientific knowledge to know about it. It is out of a single experiment and they did not make a big noise about it, so at this point it needs to be taken carefully, but they published it.
The other thing we know is that TH1902 is also inhibiting valsculogenic mimicry (VM). There is no explaination provided by Thera for this effect. The best I can see at this point with published data, is that VM inhibition would be a secondary effect of killing cancer cells in general that are overexpressing sortilin, but in particular, killing cancer stem cells (CSC). We know that VM is correlated to sortilin expression, but also to the expression of glycoprotein CD133, and CD133 is a marker of CSC. So, VM would be correlated to CSC. If you kill CSCs, you inhibit VM. So the capacity of TH1902 to kill cancer stem cells would explain in good part the inhibition of vasculogenic mimicry.
So as we can see, it seems to be secondary cytotoxic effects of TH1902 and it seems that entering the cancer cells into an endocytosis vesicule could change the pathway of TH1902 and ultimately of free docetaxel, allowing the cytotoxic drug to go to places inside the cells that it cannot go to when it diffuses into the cell passively under the free form. Inhibition of mitochondrial protein Bcl-xL is a sign of that. Maybe endocytosis vesicules containing TH1902 can fuse with mitochondria or other organelles membranes allowing docetaxel to go to places inside the cell that is cannot when entering free. It also seems that when it starts killing cells, especially CSCs, it can lead to a cascade effect of toxicity, like disrupting VM structures that allow to feed the tumor, and by inhibiting VM, it leads to even more deaths of cancer cells than can no longer get oxygen and nutrients.
The only thing we know for sure is the primary cytotoxic effect of free docetaxel on tubulin. But as I just tried to show here, it seems to be more behind the added effect of doceraxel entering cancer cells through the endocytosis of sortilin and TH1902. I am sure that Marsolais and Beliveau know more about that and could give a much clearer picture, even though, some would still be at the hypothesis stage. I guess they never went into more details publicly because a lot of their explainations would still be based on deductions made out of incomplete data. It is hard to clearly understand the complete action and fate of a molecule at the cell level. I guess that if they have the proof of concept in humans in the next six months, they will be able to share more of their ideas. What you have here are my non expert best guesses from the outside with the very limited data we have. It seems very positive, but I still long for efficacy data in humans strongly hinting at a proof of concept.
https://stockhouse.com/companies/bullboard?symbol=t.th&postid=33724326
https://stockhouse.com/companies/bullboard?symbol=t.th&postid=34040967
https://onlinelibrary.wiley.com/doi/10.1111/cas.15086
https://www.frontiersin.org/articles/10.3389/fonc.2021.760787/full