Theratechnologies Inc T.TH

TH1902 effects on Progranulin

[jeffm34]

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."

[Wino115]

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

[jfm1330]

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

[jeffm34]

TH1902 doesn't have to competitively inhibit progranulin from binding to Sortilin. It kills the cells that have Sortilin leaving nothing for progranulin to bind to. 

[qwerty22]

Sure delivering the chemo bomb might be all that is needed to finish off the cancer (let's hope so). But it may not. So identifying other MOAs might be extremely important. I'm jumping way ahead here but being able to say your drug also shuts down plasticity mechanisms in the cancer cell (I'm suggesting VM is just one mechanism of many), the sort of basic mechanisms the cell uses to

[Wino115]

The bottom chart on column 3 seems to suggest that the 3D tubes "vascular" tubes created are loaded with sortilin too. Perhaps another reason they are hopeful. It sure will be fascinating to see how this all works in patients. Let's hope we hear of miraculous things happening in Gettysburg again. 

[jfm1330]

Yes, in an ideal world, but you won't get that, be sure of that.

[jeffm34]

so you're saying TH1902 won't kill any cancer cells that express Sortilin? 

[jfm1330]

You wrote: "It kills the cells that have Sortilin leaving nothing for progranulin to bind to." To me it meant all the cancer cells expressing the sortilin receptor would be killed by TH1902. If it's not the case, which is highly likely, progranulin will still have sortilin on cancer cells to bind to and to promote that pathway.  

[qwerty22]

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

[Spartrap]

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

[qwerty22]

I'd like to see them do some transcriptomics to see what effects the drug is having at the therapeutic doses and anti-VM levels. Could shed some light on all this. The thing that interests me is docetaxel doesn't just affect mitosis. Microtubules are the highways of the cell, they transport all sorts of things around the cell. The endosomes that Th1902 highjack to get in the cell run