RE:RE:Same with the paragraphs I had in it It's a one horse race. Docetaxel gets us across the line or we fail. You're going to have to raise your opinion of docetaxel or walk away because all the other fantasy molecules will never exist if docetaxel fails.
THTX will MAKE DOCETAXEL GREAT AGAIN! Lol
jfm1330 wrote: This 57 % sortilin positive cell on hypoxic cultured selected cancer cells does not mean much as a value that can be related to real tumors in real patients. We already knew that sortilin expression could vary a lot depending on a lot of factors in cancer cells. That is why it is so frustrating that Thera did not provide anything on the sortilin expression status of the three patients in phase Ia that showed some signs of efficacy. It is clear that the key to all the CSC and VM part of TH1902 is related to sortilin expression levels. I am quite sure that docetaxel is not the best cytotoxic drug to be attached to TH19P01. Also, the idea of uneven sortilin expression within cancer cells in a tumor is one more reason to think that ultimately radioisotopes could be a warhead of choice since it is not only killing cells it can get into, but radiations allow to kill or damage many layers of neighboring cells. Again. At this point the key is to get the freakin proof of concept. If Thera can have that, there will be many other possiblities based on the TH19P01/Sortilin couple. Docetaxel is just the basic model.
Wino115 wrote: Sorry -easier to read. BTW, the 57% is on the paragraph right after Fig 2 charts.
In the past, we've asked the question about getting a quantitative measure of just how many cells in a tumor express Sort1. I think I found a small answer that pushes our understanding along a bit for ER+ and ER- breast cancer tumors. I know just enough to be dangerous, so take that as a warning.
I was reading the Univ Gothenburg paper that shows how Sort1 is associated with cancer stem cell proliferation and metastases in breast cancer and that if you "turn off" Sort1, the spread of the tumor slows. In it, they did a study for just Sort1 positive tumor cells and ran a gene expression study on 60 samples. It was for one specific breast cancer line called MCF7.
For 60 sample MCF7 breast cancer tumor cells, they found that 57% of the cells expressed Sort1. Given ER Breast cancer is one that is considered Sort1 "overexpressed" in 90% or so of the cases, maybe we can roughly conclude that the High-Expression group shown with the staining process in various THTX journal charts means around 60% or higher of the tumor cells express Sort1. I seem to recall they've said they think it will be very effective for those in the "very high" and "high" categories, so maybe that would mean where your tumor has cells where 50%+ show express Sort1. Both THTX and I are just guessing and at some point they will roughly find that number for each different cancer type as I'm sure it won't be the same for each. But maybe that's a good starting estimate. It could work with lower numbers too for all I know.
It's known that Sort1 is a prerequisite for cancer stem cell propagation. As a reminder, The UnivGothem guys overall conclusion was this:
"The fact that we could show that progranulin mediates sortilin activation resulting in CSC propagation suggests that sortilin is a key molecule that genuinely affects tumour progression and metastatic properties. Further studies are needed in order to define the exact role for sortilin in this context, but our results clearly support an important role for sortilin in CSC propagation."
This impact on cancer stem cells, VM and the like via engaging sortilin somehow just may be the unique MOA that propels this platform for us. The paper is here:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245804/