Theratechnologies Inc T.TH

RE:RE:RE:Article from the Swedish Sortilin Researchers

[jfm1330]

Impossible. Anyways, binding to sotilin leads to endocytosis. The interesting experiment would be to have a slow release formulation of TH19P01, or call it a long acting release of TH19P01. That would allow to constantly induce the internalization of sortilin through endocytosis.

Up to now, Thera only tested single I.V. injection of TH19P01 and found it had no anti cancer effect, but a single injection is not enough. You would need long term circulating dose of TH19P01 to see if it would have an anti-cancer effect. Again, look a the example of Lutathera and long acting octreotide (Sandostatin LAR). Sandostatin LAR allows slow release of therapeutic level of octreotide in the bloodstream for 28 days. So to use the peptide alone, you need constant presence in the bloodstream, on the long term, at a therapeutic level. Thera never did such an experiment with TH19P01 on  mice. They would need a long acting formulation to try it, since I doubt constant I.V. infusuion on mice is possible for a long period of time.

jeffm34 wrote:

I wonder if Thera's peptide can be modified to bind irreversibley to Sortilin effectively blocking progranulin from exerting its effect. 

 

scarlet1967 wrote:

 

“Clinically, high tumor co-expression of progranulin and its receptor sortilin were recently shown to identify a highly malignant subgroup of breast cancer patients with significantly worse prognosis compared to variable and lower expression of progranulin and sortilin, supporting sortilin as a biological target in cancer. In cancers, sortilin appears to be important for tumor progression by promoting invasion and cell adhesion through epithelial–mesenchymal transition and activation of Akt and focal adhesion kinase (FAK)-Frc signaling.

Sortilin is overexpressed in various cancer types compared to normal tissues, including breast, lung, ovarian, and thyroid cancers.(36,37) Down-modulation of sortilin could be a beneficial targeted therapy for most cancers, as researchers have reported that sortilin knockdown in ovarian carcinoma reduces proliferation and induces apoptosis, and in chronic lymphocytic leukemia (CLL), anti-sortilin antibodies have been shown to induce apoptosis in CLL cells.(38,39) Moreover, in pancreatic cancer, sortilin knockdown or inhibition by a small molecule targeting sortilin (AF38469) inhibits cell invasion.(36) Sortilin has also been identified as a potential drug target for other disorders,(40) including frontotemporal lobar degeneration,(41) autism,(42) Alzheimer’s disease,(43) and atherosclerosis.(44,45) In cancer, sortilin is linked to poor prognosis and treatment resistance in several cancer types, indicating a potential therapeutic opportunity for targeting sortilin.

The aims of the current study were to determine the potencies of these compounds for down-modulation of sortilin in breast cancer cells and to determine whether they could influence progranulin-induced mammosphere formation for their potential use in breast cancer drug therapy.

We have identified potent CADA molecules that down-modulate sortilin protein expression and block progranulin-induced mammosphere formation in breast cancer cells. The most potent compounds for down-modulating sortilin in HEK293T cells were found to be 2 (VGD071), 3 (VGD020), and 5 (TL020), and from our analysis on breast cancer cells, we conclude that these compounds also have potent effects on sortilin protein expression and breast cancer stem cell activity.”

 

The article is really talking about the inhibiting role of CADA (Cyclotriazadisulfonamide which is a compound combining two molecules one with diuretic and antihypertensive effects and the other one antibacterial effects) on sortilin by  disruption of normal cell formation leading to cancer, fibrosis etc.

What he was referring to using peptides as sortilin inhibitors. Looking into it further there seems to be some synthetic peptide interfering with sortillin not only in cancer but various other conditions.

 

SPCEO1 wrote: Spartrap posted this over on Stocktwits and it may be of interest to our science team:

https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00943