RE:RE:RE:RE:CSCs and VM - 2011 paper shows they are likely connected Just to be crystal clear. There are no weakest links in th1902 atm. It has essentially done everything THTX has asked of it. It has yet to deliver clear investable efficacy data but it has yet to be fully tested on that. It was a secondary consideration in 1a and until the company is more transparent about the 1a details we won't know just how far they could push that aspect. There will be no dodging efficacy in 1b, front and centre from now on. When it comes to everything else, again based on less than full transparency, it has passed the tests. Decent RP2D, tolerable profile, stability in blood.
qwerty22 wrote:
There are so many things right about TH1902 it's not worth listing them but it ends with proven efficacy signals in patients.
Even Beliveau doesn't exactly know where the anti-VM effect comes from, I know I asked. It's completely meaningless to say Doc is the weakest link, no data to support that. First two sentences are unscientific, ill-educated speculation.
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/