RE:RE:RE:RE:TH1902 effects on Progranulin The question of whether the short half-life of the PDC might impair activity on VM for sure has merits.
However, an important keyword here is *half*. HL is the time it takes for the drug concentration to be half of the original. If you remember the poster, the TH-1902 effect on VM is comparable to that of a 10,000 times higher docetaxel concentration. I'm too lazy to figure out how far beyond normal therapeutic dose levels that particular docetaxel concentration is, but assuming e.g. that a concentration of even just a 1000th of th-1902's standard therapeutic dose still has a very significant effect on VM, then we are looking at 10 cycles+ of half-life, which could very well translate to several days of inhibition, not unlike the standard treatment cycles of some inhibitors.
Besides, the effect of accumulating docetaxel in precisely the sortilin-expressing cells that are responsible for cancer stemness (e.g. those that would dedifferenciate to CSCs or build a CSC promoting micro TME important for VM), as the works from University of Gothenburg seem to show, the effect of such an accumulation aren't to be overlooked.
There is often this gross simplification of saying that docetaxel "kills" the cancer cells. But that is not at all what it does. What it does is promote microtubule polymerisation in such a way that the cell's cytoskeleton loses all plasticity and can't build the mitotic network needed for cell division. So the cell can't divide, and this often triggers a cascade of catastrophic reactions leading to cell death (in the MAPK pathway, with added BCL-2 phosphorylation). But the point of the matter is the cell can't divide, can't revert to CSC, or can't otherwise continue any work that requires cell plasticity, and I'd suspect VM is very much one of those.
qwerty22 wrote: There seems to be some type of sortilin effect in the in vitro VM assay when the cells remain 'bathed' in the drug for the period of the experiment. I agree that might be transient in nature in an actual patient, it could though be more prolonged than the amount of time the PDC stays in the blood depending on the exact nature of the MOA of anti-sortilin activity of the drug. The question would be is the potential anti-sortilin effect transient (only happening while there is free drug available to continue to give the effect) or is the effect more permanent and therefore doesn't require free drug in the blood to continue to work. I don't think that question has been answered yet.
Here is the VM poster
https://media.sparx-ip.net/AACR2020EPd/685.pdf
Something that hadn't stuck in my mind from when I first read it is the result in column 4 with sisortilin. What that result shows is that simply silencing sortilin has these dramatic structural impacts on cancer cells completely separate from the presence of docetaxel. And column 5 suggests it happens at extremely low concentrations of the PDC. And the suggestion is silencing sortilin does more than just impact VM formation, given the markers they use, it seems to impact some of the basic 'plasticity' processes seen in cancer cells. The processes behind EMT etc.
Some of these processes are extremely important to the cancer cells survival and aggressiveness I don't think you should rush to say the drug may be too transient to impact all this until that is actually proven to be the case but it is a good point you make.
(If we were making a hypothetical list of pros and cons of PDC versus ADC then this might go in the cons column for PDCs, it's short half life. On the other hand rapid clearance might also be a pro. It could be that by not lingering for days you get much less potential off target toxicity (assuming that it can do the necessary job in the tumour in the hours that it does stick around).)
jfm1330 wrote: The competitive effect of TH1902 on sortilin receptors, versus progranulin is too short in my view to have any meaningful effect on cancer proliferation. Half-life of TH1902 is relatively short, few hours, so soon as it is no longer in the bloodstream, progranulin is free to bind sortilin again. This MOA would possibly work only with long acting formulation of the peptide (without docetaxel) or with daily injections. We are far from that at this point. Let's see proof of concept of the PDC first, if so, it will open alot of possibilities.
Wino115 wrote: I think you've stumbled upon one of the possible methods of action that both Spartrap and Qwerty are hoping is one of the 3 MOAs for TH1902. It may also be part of the disruption of vascular mimicry that they have seen in vitro. That is one of the more intriguing possibilities of the peptide and whole platform. If they can uncover that it does work beneficially in three different ways, it's not just a home run, it's a grand slam....or for our hockey-heads, a hat-trick!
jeffm34 wrote: If Th1902 can target and kill cancer cells that have Sortilin, it should also have positive effects on cancer progression by inhibiting Progranulin.
"Progranulin is involved in biological processes such as wound healing, inflammation and cancer progression. Progranulin and its receptor sortilin are known to be highly expressed in subgroups of breast cancer and are further associated with a clinically aggressive phenotype."