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Theratechnologies Inc T.TH

Alternate Symbol(s):  THTX

Theratechnologies Inc. is a Canada-based clinical-stage biopharmaceutical company. The Company is focused on the development and commercialization of therapies addressing unmet medical needs. It markets prescription products for people with human immunodeficiency viruses (HIV) in the United States. The Company's research pipeline focuses on specialized therapies addressing unmet medical needs in HIV, nonalcoholic steatohepatitis (NASH) and oncology. Its medicines include Trogarzo and EGRIFTA SV (tesamorelin for injection). Trogarzo (ibalizumab-uiyk) injection is a long-acting monoclonal antibody which binds to domain 2 of the CD4 T cell receptors. EGRIFTA SV (tesamorelin for injection) is approved in the United States for the reduction of excess abdominal fat in people with HIV who have lipodystrophy. Its portfolio includes Phase I clinical trial of sudocetaxel zendusortide (TH1902), a novel peptide-drug conjugate (PDC), in patients with advanced ovarian cancer.


TSX:TH - Post by User

Comment by jfm1330on Apr 17, 2022 12:21am
114 Views
Post# 34608096

RE:RE:RE:RE:Sortilin info

RE:RE:RE:RE:Sortilin infoAbout the 90/10 sortilin distribution, I was aking the question to know if the ratio is the same in cancer cells, or in cancer cells at different stages of cancer evolution. I am not sure they have a straightforward way to test for that. Maybe some studies can give a rule of thumb to apply to healthy cells, early cancer cells and advanced cancer cells. By the way, damaged cells and cancer cells are they the same for you or are talking about two different things. A cell can be damaged and not cancerous. One thing is sure, is that the more we scratch, the more complex this sortilin thing is. Remember that sortilin on the cell membrane can also be cleaved to release what they call soluble sortilin.


Wino115 wrote:

For JFM to clarify the data I mentioned, it was that in a normal healthy cell only 10% was on the cell surface and 90% within the cell.  That helped with the fact that off-tumor take-up would be fairly low.  The paper then stated non-healthy tumor cells see far more go to the surface and the worse off the tumor, the more gets sent to the surface.  They postulated why a damaged cell sent more to the surface.  I will go dig out the paper again as it is a brand new one written by a new group of scientists.  

I think this is scientific benefit of Sortilin as a target, not the opposite as you are surmising.  Healthy tissue does not send it to the surface so gets much less chemo internalized, but tumor cells send a whole lot to the surface and recycle it constantly back to the surface. The difference between healthy and tumor was very large.  Also, one of the breast cancer studies had something like 500 plus samples they had taken over the years of healthy and tumor tissue from live humans and they also found the large Sortilin expression difference.  

 

jeffm34 wrote: This article has some insight into its distribution on the cell membrane

https://www.hindawi.com/journals/grp/2017/6456257/ 

Whereas the mitogenic effects of NTS were mediated through NTSR1, the role of the third NTS receptor, NTSR3, is less clearly defined. NTSR3 is not a G-protein-coupled receptor but appears to be a sortilin receptor. They were found not only predominantly in endoplasmic reticulum-Golgi compartments but also in the cell membrane of colonic cancer cells [
40]. NTSR1 and NTSR3 exist as a heterodimer on the cell surface of HT29 human colon cancer cells.
 

 

jfm1330 wrote: If you look closely you will see they use two types of antibodies for immunostaining, one where the antigen is a recombinant proteic sequence of sortilin, and the other is a peptide with no further details. The antibody made out of the recombinant sequence detect more sortilin. Correllation between immunostaining and quantification mRNA of sortilin (which shows level of sortilin expression) is not always good. The other thing, is that they claim the the main location of sortilin in the cell is in the Golgi appartus, the cytosol, and in third place, the celle membrane. It is in line with what Wino reported that 90% of sortilin is intracellular and 10% in the membrane.  

That raises a lot of questions. Do Thera know if the 90/10 sortilin distribution is always the same? Is the ratio different in cancer cells and does this ratio change in advanced cancer. Also, the data given for overall sortilin expression vary depending on the antibody used, and we have no idea of the stage of the cancer they tested. According to Thera, expression level goes up with the stage of the cancer.

I don't understand how immunostaining can allow the detection of intracellular sortilin on a very thin layer of dead tissue that has been frozen. It is important to recall that immunostaining id done on biopsies samples, not a tissue that is still alive. So I wonder if what is seen in immunostaining is true reflection of what exists in tumors and cancer cells that are still alive in the body. That's why I repeat myself with TH19P01-DOTA-Ga68. This tool would allow to see the level of sortilin on the membrane that really binds TH19P01 in vivo in humans. That would be the ultimate tool to really understand what is going on with a PDC based on TH19P01. It would likely not be exacly the same behavior os TH1902, since the load on TH19P01 would not be the same, but it would be as close as possible.

The more I read about sortilin expression, the more I think this is a weak spot of the whole concept. The whole thing is predicated on sortilin overexpession on the membranes, not in the Golgi and not in the cytosol, so it would be critical to have a reliable way to detect the level of sortilin on cancer cells membranes to select patients. With the "all comers" inclusion criteria in phase Ia, it is likely to be a good part of the problem, and as far as I can see, immunostaining of biopsie tissues for phase Ib will not be very reliable to show the real level of sortilin on the membranes of cancer cells. The would really need an in vivo imagaing tool to see where their peptide binds in vivo in humans. Again, as soon as they have a proof of concept they should start the development work on that.


jeffm34 wrote: Lots of information on sortilin available here

https://www.proteinatlas.org/ENSG00000134243-SORT1/pathology

 

 




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