RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:TH2101One thing we are not talking about right now, because it is way too early, even though I mentioned it before, is the possibility of combo therapies with different PDCs that SORT1+ is theoretically allowing for. Again, I know it is way too early, but still, on paper the possibility is there. To attack cancer cells with two or three PDCs at the same time, with different mechanism of actions. If the proof of concept is well established and the therapeutic window is very wide. It would allow such an approach with limited toxicity.
So I go a bit wild there with the possibility of combo therapies, but at the same time it just reinforces the idea of how critical is the step that Thera is in now with TH1902, which is clearly establishing the proof of concept. In my readings yesterday, searching about Sortina, I fell on this article about how animal xenograft models in cancer are not reproducing adequately a real human tumor in a rreal human body. We already knew that the jump from modified mice, with xenograft tumors, to real cancer patients, with real tumors, was a big one, but this article just point to this fact with even more emphasis. So as much as I am optimistic for TH1902, I also remember how difficult this jump is. Even though things look good at this point, and it seems that the SORT1+ approach will be validated in this phase Ia, I will be sure only after clearly positive results.
This message may look a bit schizophrenic to some, talking about possible stuff that is way ahead, and at the same time about the fact that nothing is sure at this point, but this is the reality of cancer research. It is just to say that I like to think about the future potential, but at the same time I am still not 100% sure that the basic principle behind all that will work. Again, at this point they should be over the MTD of docetaxel, and they know the level of free docetaxel TH1902 is generating in the bloodstream, so they should be able to extrapolate the toxicity, but it still need to happen for real.
https://iscaffpharma.com/wp-content/uploads/2020/05/article-200515.pdf
Wino115 wrote: It seems the UG labs found that relationship to certain late stage cancer expression of Sort1, specifically mTNBC, but probably also found that the UQAM labs had already built a peptide that latches on and were way, way ahead on that approach and went with the alternative -assuming Sort1 is necessary for tumor cell growth so trying to suppress it. It does sound a lot more challenging and will take some time in the lab first. Certainly a far riskier bet.
jfm1330 wrote: IL6 is interleukin-6, a protein in the family of what is called cytokines. Progranulin is also classified as a cytokine. We heard about cytokines related to the covid-19 infections. Covid is provoking in some patients what is called a cytokines storm, which is an inflamatory overreaction of the immune system because cytokines are involved in inflamatory processes.
But it seems that many cytokines are also involved in cancer progession, probably from modified expression in cancer cells. And all these cytokines are ligands to membrane receptors and part of signaling pathways that can affect gene expression. It is very complex stuff, not well understood, and their role always depend on the type of tissue they are coming from, or type of cells that are producing it, and with the receptors they are interacting with. Add to that possible cleavage of receptors to give soluble versions, like soluble sortilin. It is very complex.
For example we know that sortilin is present in the normal brain tissue, but much less elsewhere in healthy tissues, but sortilin expression in cancer cells is another ball game. In cancer cells, many genes have mutations, many signaling pathways are modified, and the result of that is modified signaling and utimately modified gene expression on other pathways. So to mute sortilin expression could have effect in some cancers, but also elswhere in the body.
That leads us back to the Sortina approach of inhibiting expression of sortilin, it looks to me as much more complicated avenue because it uses a small molecule that is not only targeted to cancer cells, or to sortilin expressing cells. In theory, like most small molecules, it will diffuse in all cells. So if you mute sortilin expression in healthy cells, what will be the consequence of that? Also, will it silence only sortilin expression, or also other genes or protein expressions? With SORT1+, the main effect is dependant on the nature of the cytotoxic agents carried by the peptide, and even though these agents are not good for slow dividing healthy cells, expressing low level of sortilin, it is unlikely to kill them. Also, we don't know if the silencing of sortilin expression will be enough to kill all cancer cells, or only some specific ones with particular mutations.
Wino115 wrote: Thank you for digging in. I do recall in the new presentation their new diagram specifically shows that the Sortilin is recycled and spit out the cell again to attach to the membrane. That was the first time I saw that. No doubt they understand the amount and timing of recycle are important factors to learn in trials. Very helpful and I think you found the UnivGotenburg papers that describe what they are aiming to do, which is very different from THTX. As you point out, they are specifically looking for an anti-Sortilin therapy and really focusing on stopping metasticism function more than anything else.
The Feb 2021 UGoth paper states: "Data suggest that co-expression of progranulin and its receptor sortilin is a novel prognostic biomarker combination identifying a highly malignant subgroup of breast cancer. Importantly, this subpopulation could potentially be targeted with anti-sortilin based therapy"
I also see they focus on IL6 which I have no clue what it is, but wonder if we will hear about that in the future.
" Sortilin is apart from being a receptor to progranulin also described to bind with high-affinity to the proinflammatory cytokines IL6. In breast cancer, IL6 is associated with increased tumor stage, lymph node infiltration, recurrence, and treatment resistance further signifying the role of sortilin in breast cancer progression.
Thanks for helping us get the Sortilin / stem cell connection. All good stuff and glad we are way ahead of them in moving to trials.