RE:RE:RE:RE:RE:RE:RE:RE:Trodelvy's most direct competitor in TNBC Ph 1 data released What seems to stand out in cancers is that the SORT1 is directed to the outer membrane. In many tissues it seems SORT1 sits mostly on internal membranes and does it's "sorting" job of shifting components to various compartments of the cell. I think in brain neutrons it's also externally expressed but from what little I remember about its role in liver it's as an internal "sorter". So overall gene expression tells you something but it doesn't tell you where the SORT1 ends up in the cell. For our purposes the only SORT1 that matters is SORT1 that finds its way to the external membrane. The RKPM is only of limited use. It may be that it works as a differentiator between high/low expressing cancers, it certainly has more of a chance of being quantative than IHC. Maybe ultimately they can show a relationship between SORT1 mRNA expression and tumour response.
jfm1330 wrote: I found the relative expression of sortilin in different tissues of the human body. The level of expression is given in "RKPM", which stands for "reads per kilobase million". Honestly, I don't understand exactly the meaning of RKPM, but it relates to RNA sequencing, and RNA is the direct result of gene expression and peptide and proteins are made by decoding RNA. At least I understand that the higher the RKPM value is, the higher the gene expression for a given protein.
All that being said, I would like to know what is the range of values for RKPM of sortilin RNA in cancer cells, from what is considered low expression and what is considered high and very high expression. If this analysis can be done on healthy organ tissues, It could surely be done on cancer biopsies samples. If proof of concept is established in phase Ia, having the range of possible RKPM values for different cancer types would be a powerful tool to help understand the power of sortilin as an entry target into cancer cells. So please Thera, do that or release the data if you have it.
https://www.ncbi.nlm.nih.gov/gene/6272
https://www.arrayserver.com/wiki/index.php?title=RPKM
Wino115 wrote: Interesting stains. I toyed around with this too, getting nowhere. But one thing that seemed to be true as I compared other targets is that it appears sortilin is in fairly low levels normally and has some concentration in the brain and a few other organs. It doesn't appear to be in concentration in many places in the body.
Secondly, it seems the differential becomes extremely large around the tumor environment, especially in those advanced cases they are targeting. This may help it stay fairly "on target" and have fewer side effects. But I can't say I know how either of those compares to other targets used. It may be similar, it may be uniquely good for the purpose. My guess is those traits are no worse than any others being used for solid tumors, and for the advanced cases where the unmet need is, it may be better given the large overexpression the tumor environment causes. But I'm ok just thinking it's similar to others at worst, until someone can be more definitive around it.
jfm1330 wrote: One thing Thera did not explain, and I made some research about that on the net to find some answers, is how sortilin expression compare to other receptors expression that are targets for other PDCs and ADCs. I did not find any data where you would be able to compare the levels of receptors expression.The only thing I found is a visual comparison from histological staining of sortilin expression in breast cancers from two levels of low expression (1 and 2) and two levels of high expression (3 and 4). One thing is sure, just within the possible sortilin expression levels, the differences of expression are huge. If you have level 4 of sortilin expression, it is hard to imagine how TH1902 would not be much more efficacious, if you put aside other possible factors like docetaxel resistance.
https://bmccancer.biomedcentral.com/articles/10.1186/s12885-021-07854-0/figures/1