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Bullboard - Stock Discussion Forum 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... see more

TSX:TH - Post Discussion

Theratechnologies Inc > CSCs and VM - 2011 paper shows they are likely connected
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Post by Wino115 on Sep 16, 2022 4:17pm

CSCs and VM - 2011 paper shows they are likely connected

I think this axis of CSCs and VM is of critical importance and the fact TH1902 has, in the lab, shown to both disrupt VM (recall the "loop" slides showing a vastly different picture after TH1902) and the survival and proliferation of cancer stem cells is a very positive conclusion they published. It really could be one of the key attributes that sets the platform apart from competitors.

It could be we have the ability to deliver a large toxin dose, safely into the tumor cell AND to disrupt both VM and CSCs from doing their thing.  How this is done, they will look to find out and no one really knows at this point except that we see the derived pre-clinical results --much lower metastices, far fewer VM loops, and the CSC markers like CD133 being negatively affected.

In 2011, these researchers started to put the pieces together and suggested it was an area to focus new therapies on. This article reviewed a number of individual conclusions to portray a fuller picture of what could be happening based on the previous findings. This was a decade ago, and the science is all still very new.  Here's their conclusion and the article:

"VM-TARGETED THERAPEUTIC STRATEGY: NEW PERSPECTIVES

CSCs are considered as the root of tumor initiation, metastasis, and reoccurrence. If CSCs are proven to be critical for VM formation, there will be significant implications in the design of novel anti-tumor therapies. As discussed earlier, VM is the dominant blood supply pattern in the early stage of tumor formation and CSCs are capable of differentiating/transdifferentiating and lining up to form branching lumens and tubes, a process resembling the formation of VM. ....... Furthermore, the unique structure of VM channels, in which tumor cells line up the inner surface, directly exposes tumor cells to blood vessel and facilitates the metastasis of tumor cells. VM frequently is seen in the regions between the tumor and surrounding normal tissues, and associated with poor prognosis in clinical patients. Therefore, VM-targeted therapies may destroy the niche that maintains CSCs, block the metastasis passage of tumor cells, and reduce the recurrence of cancer."

 

Contribution of cancer stem cells to tumor vasculogenic mimicry
https://pubmed.ncbi.nlm.nih.gov/21533771/

 

Comment by Wino115 on Sep 16, 2022 4:26pm
If you want something more updated, here's a 2019 article that took those findings and applied it just to TNBC.  They found the same thing and reached the same conclusion -- "...In conclusion, CSCs lined VM channels directly. Additionally, CSCs provide more VM-related molecules to synergize VM formation. The signaling pathways that control CSC differentiation may also be ...more  
Comment by jfm1330 on Sep 16, 2022 4:51pm
VM inhibition and reducing the speed of matastatic spread is all related to TH19P01/Sortilin ligand/receptor affinity. Docetaxel remains the weak link in this PDC. I don't say TH1902 will be a failure because it has docetaxel as the cytotoxic agent. I just say that TH19P01/Sortilin could allow to concentrate a more potent cytoxic agent into cancerous cells. Then the therapeutic window would be ...more  
Comment by qwerty22 on Sep 16, 2022 5:12pm
There are so many things right about TH1902 it's not worth listing them but it ends with proven efficacy signals in patients. Even Beliveau doesn't exactly know where the anti-VM effect comes from, I know I asked. It's completely meaningless to say Doc is the weakest link, no data to support that. First two sentences are unscientific, ill-educated speculation.
Comment by qwerty22 on Sep 16, 2022 5:28pm
Just to be crystal clear. There are no weakest links in th1902 atm. It has essentially done everything THTX has asked of it. It has yet to deliver clear investable efficacy data but it has yet to be fully tested on that. It was a secondary consideration in 1a and until the company is more transparent about the 1a details we won't know just how far they could push that aspect. There will be no ...more  
Comment by Wino115 on Sep 16, 2022 6:58pm
To understand your idea better, I guess I'm wondering how receptor affinity effects VM if sort1 is recycled back to the surface?  Also, what data has lead you to that conclusion?  Thanks for us non-scientists.  
Comment by jeffm34 on Sep 16, 2022 9:32pm
Competitive inhibition of Neurotensin binding to sortilin may have positive effects but not sure if that affects VM  https://biosignaling.biomedcentral.com/articles/10.1186/s12964-020-00569-y
Comment by jfm1330 on Sep 17, 2022 4:30pm
They made that proof many times in vitro and in vivo in xenograft animal models. VM is related to sortilin expression, and VM is also correlated with cancer stem cells (CSC). So all that is linked. Here is just one if these articles. Obviously a cytotoxic agent is needed, but it also works with doxorubicin. Si it's not specific to docetaxel, but the action all originates from the sortilin and ...more  
Comment by qwerty22 on Sep 17, 2022 8:49pm
Except that Th1902 IC50 conc. is close to 2000X lower than the IC50 of Th1904. And if you took into account the molecular weight of each chemo then the concentration of TH19P01 required by the docetaxel construct would be even lower. If TH19P01 was the main protagonist here I don't believe you  would see such a large difference in IC50. It's likely that SORT1 engagement plays a ...more  
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