RE:RE:RE:RE:RE:RE:RE:RE:RE:Sortilin infoIn Dr. Beauregard profile you can read this:
Another strategy we are studying is to pre-treat NET cells with molecules that can increase their somatostatin receptor expression, thereby promoting increased PRRT radiopharmaceutical accumulation within these cells This is not a near term thing for Thera, they need to establish a clear proof of concept first, but imagine finding a way to increase the expression of sortilin in cancer cells. That is science fiction at this point, but on paper this is a good idea.
jfm1330 wrote: It is sure that they don't disclose every research things that they try. Remember Marsolais said about a year ago that they would report results this year at AACR or ASCO about testing TH1902 on mice grafted with real patient tumors. We did not hear a word about that since. That being said, the use of radionuclides has nerver been mentionned anywhere yet in their communications, written or oral, either for imaging urpose or therapeutic.
If somebody at Thera monitors this board, they are aware of it for a while now. That being said, I am not sure they really monitor it since the guy doing it would have to read a lot of insane stuff just to get a few interesting nuggets here and there. Also, Marsolais said they hired a company to work on an immunostaining test. If I remember well, he said they were the best in that field. So if they invest in immunostaining of biopsies, I doubt they invest at the same time in in PET scan detection not requiring biopsies.
As I said before here, there are two very good hospitals in Quebec linked to two universities that are working with radionuclides and doing research on this subject, imaging with Ga68 is in Sherbrooke (university center CHUS) and therapeutic Lu177 in Quebec City (Hotel-Dieu hospital, also linked to an university center).
https://www.crchudequebec.ulaval.ca/en/research/researchers/jean-mathieu-beauregard/
https://www.researchgate.net/profile/Brigitte-Guerin
SPCEO1 wrote: I have commented in the past that company managements tend to tell the truth but not necessarily th whole truth. What do you think the chances are that TH has already done the testing you have been suggesting but has decided not to share the reesults with us, either because those results do not enhance their case withTH-1902 or because the results do enhance the case and they are just keeping them to be shared at a more propitious time, like near a fundraising?
jfm1330 wrote: After further readings, cells tested by immunostaining are permeabilized, meaning that the antibody can access the intracellular protein and stain them. So the staing score for protein expression is for all the sortilin in a cell type, intracellular and membrane. So it seems that this technique, or at least the data we can read on Protein Atlas, is for all sortilin expression by a cell type. Also, in Protein Atlas, their data for healthy tissue is from cancer biopsies. The score they give for healthy tissue is the score of non cancerous cells in a cancer biopsies. Strange way to do science. RNA testing also gives total sortilin expression, not sortilin on the membrane. That's why TH19P01-DOTA-Ga68 would be so useful for patients selection, because it would give you the internalization capacity of a tumor expressing sortilin with no biopsies needed. A simple IV injection, a waiting period, and a PET scan. It would also be an awesome tool to understand PDC distribution in the body. In time they woud be able to establish correlation between PET scan results and efficacy per cancer types, etc... This would be modern personalized medecine at its best.
Wino115 wrote: You're right --It is a complex issue and does seem highly novel as we keep learning about it with them. It is likely why the investigators were perfectly happy to drop down to the 300mg level as they probably surmised (or saw) it was enough to have a strong therapeutic effect, but not enough to cause serious issues with the sortilin not in the cancer cells. Marsolais and Belevieu have said numerous times that there's not a lot of sortilin expression in normal tissue compared to cancerous. How they quantify that other than the staining, I don't know. You are also right that what I meant by damaged cells was cancerous cells.
I guess my question would be is sortilin1, as a traget, any different than any other target used for an ADC or PDC? It seems many of the others (Nectin, Trop2, etc...) may not show as strong a relationship between severity and expression, but I'm just guessing from some of the statements Belevieu made. I guess what you're looking for the is difference between normal expression and high expression and the greater that difference, the more effective a targeting treatment can be. In other words, a target that at refractory levels of cancer is 6x more than normal would be a better target to use than one that is only 2x higher. Differences are important I think.
By the way, that paper I found isn't that helpful because it's talking about how unregulated hypertension is correlated with soluable sortilin in blood.
jfm1330 wrote: About 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.