Theratechnologies Inc T.TH

New PR aroundVM

[Wino115]

If you're not on the PR list, announced published article around Sort1 and VM.

MONTREAL, Oct. 22, 2021 (GLOBE NEWSWIRE) -- Theratechnologies Inc. (Theratechnologies, or Company) (TSX: TH) (NASDAQ: THTX), a biopharmaceutical company focused on the development and commercialization of innovative therapies, is pleased to announce the publication of a peer-reviewed article demonstrating that the Company’s novel investigational peptide-drug conjugates (PDCs) TH1902 and TH1904, derived from its SORT1+ Technology™, are effective in inhibiting vasculogenic mimicry (VM) in in vitro ovarian and triple negative breast cancer (TNBC) models.

The article was published in the science journal Frontiers in Oncology and is titled “New Peptide-Drug Conjugates for Precise Targeting of SORT1-Mediated Vasculogenic Mimicry in the Tumor Microenvironment of TNBC-Derived MDA-MB-231 Breast and Ovarian ES-2 Clear Cell Carcinoma Cells.”

“The results published in Frontiers in Oncology showcase for the first time that the sortilin receptor plays a role in the formation of VM, which is associated with cancer progression and resistance. By targeting SORT1, TH1902 and TH1904 have the potential to inhibit VM and cancer cell growth,” said Dr. Christian Marsolais, Senior Vice President and Chief Medical Officer at Theratechnologies. “This recognition by our scientific peers highlights the great potential of our PDCs as a unique and effective vehicle for the potential treatment of many types of cancers in which SORT1 receptors are overexpressed and provides additional evidence that SORT1 plays a major role in the generation of VM, particularly in TNBC and ovarian cancer.”

[stephanedodier]

I am a bit surprised that the volume is that low after this morning news...   Any comment ?

[SPCEO1]

Nobody is listening to what TH says. The few analysts still following the company got badly burned by by overly optimisitc Trogarzo and Egrifta sales expectations and have lost confidence in the company. The company's is currently targeting investors that really cannot invest in it much because of the sub-$5 stock price and small market cap. So, TH needs a better strategy if it wants to get

[palinc2000]

The PR states the following   “The results published in Frontiers in Oncology showcase for the first time that the sortilin receptor plays a role in the formation of VM, which is associated with cancer progression and resistance. By targeting SORT1, TH1902 and TH1904 have the potential to inhibit VM and cancer cell growth,” said Dr. Christian Marsolais, Senior Vice President and Chief

[SPCEO1]

Ome very practical problem for the non-reaction on the trading volume may be that Bloomberg only put the headline of the press release out there and there is therefore no way for the trading algos that chase such announcements to read the actual press release.  It seems to me that there is some very important info in that article. But I will again defer to the science experts. One thing I

[scarlet1967]

My take is what they found out is that only Sort1 positive cancer cells can form VM and Sort1 is a key player involved in VM formation. Other drugs’ success in disturbing the VM have been temporary due to low absorption, fast metabolism, low stability and penetration among others versus their PDCs which are interfering with extracellular domains of Sort1 and rapidly internalizing into cancer

[jeffm34]

A good comparison slide of how it works https://www.frontiersin.org/files/Articles/760787/fonc-11-760787-HTML-r1/image_m/fonc-11-760787-g005.jpg

[qwerty22]

"These new findings also indicate that both peptide-drug conjugates, in addition to their reported cytotoxicity, could possibly inhibit VM in SORT1-positive TNBC and ovarian cancer patients."   Seems to me that's a clear statement they are putting forward a second MOA for the drug that is distinct from the cytotoxicity of the chemo drug attached. They are now clearly linking

[qwerty22]

From the discussion "Therefore, it is inferred that SORT1 and its partners may exert paracrine regulation through exosome transfer and control of the tumor microenvironment.SORT1-positive extracellular vesicules have in fact been detected in our cells by immunofluorescence using anti-SORT1 Ab (not shown) and would understandably require further heavy investigation to potentially complement

[qwerty22]

Four observations from the result that I want to consider together. 1) "When SORT1 expression was repressed through specific siRNA-mediated gene silencing (Figure 4A), MMP-9 was also decreased (Figure 4B). SORT1 silencing lead to decreased 3D structures when compared to scrambled siRNA in ES-2 ovarian cancer cells (Figure 4C) and in MDA-MB-231 TNBC cells" 2) "After

[Wino115]

I think this is the clearest indication and wording around there being a second MOA (maybe a third too?) which you have desired to see all along.  It clearly states in the text there are potentially two MOAs. from a business perspective, what I see is that you may be able to sell a somewhat low dose version  that you start at the 2L level when you start whatever therapy you choose

[jfm1330]

I read the article and I came out unconvinced about a clear new mechanism of action to explain inhibition of vasculogenic mimicry (VM), which is real. This is pretty advanced biochemistry, and maybe I missed something. So don't take what I will write as the truth. It is just me guessing. In fact, my questions after reading the article are pretty simple and were not answered by the article

[qwerty22]

 

[Wino115]

Helpful analysis from you all and way above my head! I vaguely remember the doctor saying something about the mysterious ways of his creation. As long as it does what it does, we don't need the "why?" at this point in the process. I'm sure the lab folks are experimenting like crazy around some of this to try to get reasonable answers.  Will go back and listen to that KOL Q

[jfm1330]

I would add that we need to remember that the experiments made by Thera are on selected cancer cells on which they already proved that docetaxel and doxorubicin alone had little effect because of resistance mechanisms like MDR1 efflux pump and dose limitations due to toxicity. So the mechanism of action of both PDCs is not the same as the mechanism of action of the free chemo drugs given alone. We

[scarlet1967]

This is from the global patent application with the subject, METHODS AND COMPOUNDS FOR TARGETING SORTILIN RECEPTORS AND INHIBITING VASCULOGENIC MIMICRY   From the description; “Vasculogenic mimicry plays a significant role in tumour growth (42) and it has also been characterized in carcinomas of ovary, breast, lung, liver, colorectal, prostate, bladder, kidney, sarcomas and

[Wino115]

Interesting.  So what you are really saying is they hit the jackpot by being the first to focus on Sortilin.  Sortilin just happens to be associated with two parts of cancer progression.  Sortilin is THE key and targeting it helps in at least two ways...

[jfm1330]

You know my view on the essential thing in all that story, hard facts on humans. We don't have that at this time. So all this discussion is theoretical when it comes to how it would apply to human use on real patients with real big tumors. So my baseline view has not changed. That being said, any discussion to have here assume that it could work on humans, otherwise there is no point. So

[qwerty22]

From the present paper. "The TH1902 IC50 value for the number of total loops was ~30 pM as compared to 10 nM for unconjugated Docetaxel" From the recent preclinical paper https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.15086 IC50 for cell proliferation (the cytotoxic effect) 0.66nM for docetaxel  0.24nM for th1902 So just to note the preclinical paper is

[qwerty22]

I'm just going to go back to one of the things I highlighted as exciting for me. The part in the discussion about exosomes. "Therefore, it is inferred that SORT1 and its partners may exert paracrine regulation through exosome transfer and control of the tumor microenvironment. SORT1-positive extracellular vesicules have in fact been detected in our cells by immunofluorescence using

[Wino115]

So for my layman's brain, extracellular vesicules are exosomes?  Is the thought around exosomes that they are secreted from the cancer cell anc communicate the deadly instructions or plan of what to do for the outside cell that picks it up?  So that is part of how a tumor spreads?  And what they've detected is that those exosomes they saw actually have SORT1+ on them, as

[SPCEO1]

I sincerely hope that TH will find some way to speak to the various issues our science team has brought up and make clear to all exactly what they see as a result of this research and what the business opportunities might be because of it. Our science team on this board is impressive and had raised all kinds of interesting points - now we need TH to have some sort of call to clarify as much as

[jeffm34]

The potential business opportunities are endless. There are so many clinical studies they could do once the phase 1 trial is over and they have a proof of concept.  Different payloads targeting different cancers, different dosing schedules and cycles, combination therapy with other chemo drugs to take advantage of the disruption to VM formation that is occurring. Then there are other non

[scarlet1967]

Well that has to be communicated to the market so when they announce a second MOA for their PDC people understand it and it's scientific and financial potentials if proved in humans. Despite all the good efforts by scientific experts at THTX none of those encouraging findings have been translated to increasing SP. Of course when and if the human data verify all those potentials and financial

[Wino115]

That  is a reason to stay public and move your science around Sortilin mich further down the field to get maximum value for shareholders. Yes, Partner all around like SeaGen has done, but ramp it so if someone gets interested they pay us a full price, and I'm talking more than Immunomedics went for should POC show.  I'd hate to sell a $300 stock for $30.

[scarlet1967]

We haven't seen any meaningful efforts of any of those you mentioned less than two months before the results are out good or not they should prep the market in case of better than expected results now this "high risk high reward" company with " ridiculously low SP" should be less risk but same reward investment so why only few thousands of insider buying? When you claim

[palinc2000]

Scarlett  wrote ''We haven't seen any meaningful efforts of any of those you mentioned less than two months before the results are out good or not they should prep the market in case of better than expected results now this "high risk high reward" company with " ridiculously low SP" should be less risk but same reward investment so why only few thousands of

[jeffm34]

Is it possible Theras PDC could be used as an adjunct to other chemo drugs that have reduced efficacy due to VM.   https://scholar.google.ca/scholar?q=vascular+mimicry+effects+on+cancer+treatments&hl=en&as_sdt=0&as_vis=1&oi=scholart#d=gs_qabs&u=%23p%3DhYMFxg3j3CEJ

[JayjayUSA12007]

"Is it possible Theras PDC could be used as an adjunct to other chemo drugs that have reduced efficacy due to VM.   https://scholar.google.ca/scholar?q=vascular+mimicry+effects+on+cancer+treatments&hl=en&as_sdt=0&as_vis=1&oi=scholart#d=gs_qabs&u=%23p%3DhYMFxg3j3CEJ " Only when the neuroprotein sortilin are overexpressed on  cancerous tumors. 1/ Breast,

[jeffm34]

I guess the question is, how critical sortilin is to the formation of VM. Can VM occur in the absence of sortilin?  If not, then the applications for TH's cancer platform are staggering. 

[jfm1330]

Functional SORT1 Is Required for In Vitro Vasculogenic Mimicry The contribution of SORT1 in the formation of 3D capillary-like structures by ES-2 ovarian cancer cells and MDA-MB-231 TNBC cells was next assessed. When SORT1 expression was repressed through specific siRNA-mediated gene silencing (Figure 4A), MMP-9 was also decreased (Figure 4B). SORT1 silencing lead to

[qwerty22]

I think this isn't necessarily a process that kills tumour, I think by stopping VM you stop the production of new tumour material by limiting the ability of tumours to grow. Seems like a property you'd want for an adjunct drug. (Just to add the PDC also has the tumour killing property by delivering chemo)

[qwerty22]

Probably some good luck here in that they started looking for a chemo delivery system and have stumbled on a VM inhibiting drug. I'm starting to think of VM inhibition in two ways. The first is to think of VM as an importantstand alone process in the tumour that allows the tumour to grow and survive. In hibiting that has the potential to added to the anti-tumour properties of the drug

[qwerty22]

My last nerdy science comment (for now). The two things I want to know going forward that isn't in this paper is 1) Whether they can really show some effect on exosome production as they might be hinting in the discussion. 2) What happens to SORT1 expression at the surface of the cell. One way the PDC might mimic SORT1 silencing would be to cause the SORT1 on the surface to get internalized