RE:RE:RE:RE:RE:CSCs and VM - 2011 paper shows they are likely connected Except that Th1902 IC50 conc. is close to 2000X lower than the IC50 of Th1904. And if you took into account the molecular weight of each chemo then the concentration of TH19P01 required by the docetaxel construct would be even lower. If TH19P01 was the main protagonist here I don't believe you would see such a large difference in IC50. It's likely that SORT1 engagement plays a specific part in this but based on these two constructs docetaxel is supercharging this process (in scientific terms there's some strong synergy going on between the peptide and docetaxel). You can't ignore that TH19P01 can't do any of these things alone, it's more than just receptor/ligand dependant.
It still remains wholely wrong to call docetaxel the weak link.
What they talk about in the discussion is a bunch of oncogene cell processes being up regulated by SORT1 and the cells 'transport' system (exosomes) potentially playing a part in this. It's very easy to see how SORT1 blocking/engagement/saturation by the peptide would disrupt VM and CSC. But it's also very easy to speculate on why the docetaxel construct is so much more effective given that docetaxel specifically disrupts the structures that the cells transport system runs on, namely microtubules. Most of the focus on microtubules when it comes to docetaxel is in regard to their role in cell division but micotubules also play a huge role in cell plasticity, cell migration and cell communication with the tumour micro environment. My hope (dream) is that HOW/WHERE SORT1 delivers docetaxel in the cell is leading to greater disruption of these processes, my memory is that is what Beliveau hinted at. It's easy to think of cells a just blobs with a few smaller blobs inside them but they have a very complex structure. It might be that SORT1, through the endosome/lysosome system is delivering docetaxel to some very important parts of the cell. SORT1 tech might be about quantitative delivery (how much chemo gets in) but also qualitative delivery (where the chemo ends up).
What this paper shows is you get greatest anti-VM activity when you combine TH19P01 with docetaxel. It's telling that TH19 P01 can't do any of these things alone. Why would you describe your strongest construct as having a weakest link? Why would you potentially give up such strong synergy just because you feel docetaxel is not up to it?
There are some people on this board, JFM is not alone, who think they must move on to something better because docetaxel being an old molecule can't be very effective. It's a powerful cytotoxic, if you overcome some of it's weaknesses (which SORT1 tech is hypothesized to do) then you make it even better. It's given in many forms to very large numbers of patients. There's really nothing wrong with it. From a regulatory perspective it's very unlikely to throw up any surprises, that will be super important once they prove out it's efficacy. We are on to a potential winner with this molecule. Other payloads may offer something different but that does make what docetaxel offer bad.
I like the idea of an siRNA construct, I actually don't hate a radioligand or SN38 or many others. There's just absolutely no reason to run down a docetaxel construct while considering the potential of these others.
jfm1330 wrote: They made that proof many times in vitro and in vivo in xenograft animal models. VM is related to sortilin expression, and VM is also correlated with cancer stem cells (CSC). So all that is linked. Here is just one if these articles. Obviously a cytotoxic agent is needed, but it also works with doxorubicin. Si it's not specific to docetaxel, but the action all originates from the sortilin and the ligand TH19P01. So it's receptor/ligand dependant, then efficacy need a cytotoxic agent, but it is not specific to docetaxel. And docetaxel alone has no effect on VM and CSC.
https://www.frontiersin.org/articles/10.3389/fonc.2021.760787/full
Wino115 wrote: To understand your idea better, I guess I'm wondering how receptor affinity effects VM if sort1 is recycled back to the surface? Also, what data has lead you to that conclusion? Thanks for us non-scientists.
jfm1330 wrote: VM inhibition and reducing the speed of matastatic spread is all related to TH19P01/Sortilin ligand/receptor affinity. Docetaxel remains the weak link in this PDC. I don't say TH1902 will be a failure because it has docetaxel as the cytotoxic agent. I just say that TH19P01/Sortilin could allow to concentrate a more potent cytoxic agent into cancerous cells. Then the therapeutic window would be narrower. In that sense, docetaxel is a good first step because its toxicity is well known.
Wino115 wrote: If you want something more updated, here's a 2019 article that took those findings and applied it just to TNBC. They found the same thing and reached the same conclusion --
"...
In conclusion, CSCs lined VM channels directly. Additionally, CSCs provide more VM-related molecules to synergize VM formation. The signaling pathways that control CSC differentiation may also be potential therapeutic targets for TNBC." THTX, and the whole sortilin platform, may just be the first and best hope for tackling this CSC-VM relationship in cancers. If so, it's going to be very powerful....and very valuable.
(Just a note, odd how it's Chinese Univ that are doing all this CSC/VM work. Perhaps they will understand the science over there and value it a whole lot more than N.Am is at this point!)
Cancer stem-like cells directly participate in vasculogenic mimicry channels in triple-negative breast cancer https://www.cancerbiomed.org/content/16/2/299
Wino115 wrote: I think this axis of CSCs and VM is of critical importance and the fact TH1902 has, in the lab, shown to both disrupt VM (recall the "loop" slides showing a vastly different picture after TH1902) and the survival and proliferation of cancer stem cells is a very positive conclusion they published. It really could be one of the key attributes that sets the platform apart from competitors.
It could be we have the ability to deliver a large toxin dose, safely into the tumor cell AND to disrupt both VM and CSCs from doing their thing. How this is done, they will look to find out and no one really knows at this point except that we see the derived pre-clinical results --much lower metastices, far fewer VM loops, and the CSC markers like CD133 being negatively affected.
In 2011, these researchers started to put the pieces together and suggested it was an area to focus new therapies on. This article reviewed a number of individual conclusions to portray a fuller picture of what could be happening based on the previous findings. This was a decade ago, and the science is all still very new. Here's their conclusion and the article:
"VM-TARGETED THERAPEUTIC STRATEGY: NEW PERSPECTIVES
CSCs are considered as the root of tumor initiation, metastasis, and reoccurrence. If CSCs are proven to be critical for VM formation, there will be significant implications in the design of novel anti-tumor therapies. As discussed earlier, VM is the dominant blood supply pattern in the early stage of tumor formation and CSCs are capable of differentiating/transdifferentiating and lining up to form branching lumens and tubes, a process resembling the formation of VM. ....... Furthermore, the unique structure of VM channels, in which tumor cells line up the inner surface, directly exposes tumor cells to blood vessel and facilitates the metastasis of tumor cells. VM frequently is seen in the regions between the tumor and surrounding normal tissues, and associated with poor prognosis in clinical patients. Therefore, VM-targeted therapies may destroy the niche that maintains CSCs, block the metastasis passage of tumor cells, and reduce the recurrence of cancer."
Contribution of cancer stem cells to tumor vasculogenic mimicry
https://pubmed.ncbi.nlm.nih.gov/21533771/