Theratechnologies Inc T.TH

RE:RE:RE:RE:RE:AACR abstracts

[qwerty22]

These are the likely cancers for the basket trial which could easily start as soon as they get proof of efficacy in the lead indication (if that comes)

realitycheck4u wrote: I agree, and it's too bad we will not know if they chase this opportunity down, because that would be very interesting to see it happen.
 

qwerty22 wrote:

Reality I think that this paper you highlight falls into the category of 'potential 2nd MOA' for the THTX PDC. There is another paper just out in colorectal cancer that shows a very similar role for sortilin in aggressiveness of the cancer.

https://onlinelibrary.wiley.com/doi/10.1111/jcmm.15752#jcmm15752-fig-0002

But this is speculative for now because the company would first need to show that the drug is disrupting or interring with the (ab)normal functioning of sortilin in these cancers, at the moment they are just piggybacking on sortilin to get in the cell we don't know yet that they are disputing it's function. I think potentially the vasculogenic mimicry effect is a hint that it might be doing that but the company would need to prove it with some more science. One potential route I'd be tempted by would be to see if they could setup (pay for) a collaboration with these researchers where they took these cancer models they've developed a threw in TH-1902 with all the right controls to see if the PDC had any impact on some of the effects these researchers are describing. A 2nd MOA would be a very valuable thing in my opinion.

 

realitycheck4u wrote:

 

this seems to suggest that you can target the correct cells

The membrane protein sortilin can be targeted to inhibit pancreatic cancer cell invasion

Fangfang Gao, Nathan Griffin, Sam Faulkner, Xiang Li, Simon J King, Phillip Jobling, Jim W Denham, Chen Chen Jiang, Hubert Hondermarck

The American Journal of Pathology, 2020

Pancreatic cancer has a dismal prognosis and there is no targeted therapy against this malignancy. The neuronal membrane protein sortilin is emerging as a regulator of cancer cell development, but its expression and impact in pancreatic cancer is unknown. In this study, we found that sortilin expression was higher in pancreatic cell lines vs normal pancreatic ductal epithelial cells, as demonstrated by Western blot and mass spectrometry. The increased sortilin level in pancreatic cancer cells was confirmed by immunohistochemistry in a series of 99 human pancreatic adenocarcinomas vs 48 normal pancreatic tissues (p=0.0014). Sortilin inhibition by siRNA and the pharmacological inhibitor AF38469 strongly reduced the adhesion and invasion of pancreatic cancer cells without affecting cell survival and viability. Sortilin inhibition also decreased the phosphorylation of the focal adhesion kinase (FAK) in Tyr925. Together, these data reveal that sortilin contributes to pancreatic cancer invasion and could eventually be targeted in therapy.

 

 

jfm1330 wrote: Something Thera did not talk a lot about to my knowledge, maybe I missed it, is the level of Sortilin receptors expression in healthy cells. This is important because their peptide-drug conjugate will also concentrate the cytotoxic drug in healthy cells bearing Sortilin receptors.

I know that for Lutathera clear overexpression of Somatostatin on cancer cells is the key to efficacy. You really need to have cancer cells that largely overexpress the receptors in comparison with healthy cells. If the difference in the level of expression is not large enough, it will not work. I think it would be a good thing to know what is the difference in level of expression they need and what is the average difference in patient they will target. To me the part is not clear. 

Again, maybe I missed something, but Sortilin receptor expression in healthy cells of an animal model means nothing. I can be very different from the level of expression in healthy human cells. Without an imaging technique, like PET Scan with Dotatate-Ga68 for Lutathera, it is almost impossible to have a clear view of the level of expression of receptors in all the different tissues in the body. They would need biopsies of all the different healthy tissues or they know that if they do it once it is good enough to extrapolate on all the patients??? To me, thinking about all that, it is the unclear part of the whole thing. Without an imaging technique allowing to visualize Sortilin receptors expression. How will they know exactly what they are doing?