RE:Same with the paragraphs I had in it I'm not too excited about what results in cell lines in the lab tell us. Ultimately it's what they see in their enrolled patients that will be the only thing that matters.
Like you say where this lands is guess work atm, we all have to wait for the data.
I can tell you what I'd like. I'm dragged in two opposite directions. I'd love strong data that showed a relationship between Sortilin expression and response rates as this would prove out many things about the drug. At the same time I'd love them to maintain the broadest possible utility for this drug/technology and that might come from actually not having a strong relationship and maintaining efficacy in both high and low expressors. That might not shed too much light on the role Sortilin is playing but keep the highest possible number in the treatment population. So I'm for either getting to the bottom of the Sortilin/efficacy relationship and not getting to the bottom, if that makes sense.
First things first they need to show th3 drug works. Then let's assume they can get an approval in an unscreened population. After approval there are going to be mor3 clinical trials and large numbers of treated patients. You can work out the Sortilin level/response rate relationship post-approval on much larger population numbers than will be generated in the initial approval process. If the ORR justifies going forward without screening then this seems like a reasonable path to take. That's a very positive path where you don't actually get to the bottom of the role of Sortilin expression levels and you keep the broadest utility. There are obviously many different permutations of all this, the patient data is going to be what focuses us in on the eventual outcome.
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/