jfm1330 wrote: In the last and recent article about TH1902 I focussed a lot on the fact that for the first they were disclosing the sequence of TH19P01 and the fact that the linker in TH1902 was the succinyl linker. After that I went quickly over the rest of the article thinking they were just recapitulating everything that was previously published. By doing so I missed something important that we never discussed here. Today I went back to the article looking at any new information that I could have missed in my previous fast reading.
In this slow reading, paying attention to everything, I noticed that the authors are making a very important claim that I never saw before. I went back to read previous articles or abstracts to see if I missed it before, and I did not find it presented the way it is in the recent article. What I am talking about here is the fact that Thera, through the authors of the article, is claiming that TH1902 is acting through a different mechanism of action thant docetaxel alone. They already made a similar claim with articles about vasculogenic mimicry, But in the last article they don't talk about vasulogenic mimicry, which is a bit odd, but what they talk about are the known mechanisms of action of docetaxel, which are stabilization of the microtubules invovlved in the cell division process, and the inhibition of the protein Bcl-xL which is a protein preventing apoptosis (cell death). So the higher the level of the protein Bcl-xL is, the more it will play its role in preventing cell death.
In the recent article, there is a description of an experiment that was made on a TNBC MDA-MB-231 commercial cell line that was treated with 100 nanomolar solution of docetaxel and 50 nanomolar solution of TH1902. Since there is two molecules of docetaxel in every molecule of TH1902, these concentrations are identical on a docetaxel basis. So, they treated these cells with equivalent quantities of docetaxel, either free, or within TH1902. The result shows that the Bcl-xL protein level was much lower (around 50% lower) in the TH1902 treated cells than it was in the free docetaxel treated cells. So, for an unexplained reason, TH1902 is inhibiting the expression of Bcl-xL a lot more than docetaxel alone. This leads the authors to write the following:
The expression of Bcl-xL was assessed by immunoblotting (Figure 8B) and was found to be more reduced in TH1902-treated cells than in docetaxel-treated cells (Figure 8C). This differential effect confirms that TH1902 acts through a distinct mechanism of action than the unconjugated docetaxel drug in apoptotic cell death-inducing events. This, to me is a very important piece of evidence in favor of TH1902 potential because with that experiment result we are, maybe, in a new territory no longer related to capacity of TH1902 to increase the intracellular concentration of docetaxel. That being said, the article is not clear for somebody that is not actively working in a biochemistry lab and working on cancer cell culture. I wondered if this result could be because of the MDR resistance mechanism in the cancer cells that they used (TNBC cell line MDA-MB-231). So I searched about that commercial cell line, and it seems it is not MDR. You need to induces the resistance in the lab to have it MDR (see link)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725499/
So, all that to say that it seems that TH1902 has a much higher inhibition activity of Bcl-xL protein expression on non MDR TNBC cells than docetaxel alone. So it would not be related to higher intracellular docetaxel concentration allowed by TH1902. I say it seems, but the authors clearly claim a distinct mechanism of action for TH1902 over docetaxel related to Bcl-xL expression, but they cannot explain it. That's probably why, in the last KOL presentation, Marsolais said that they are working to better understand the mechanism of action of TH1902 inside the cancer cells. But at this point, TH1902 seems to have three anti-cancer mechanisms of action. First, allowing higher concentrations of docetaxel inside cancer cells to achieve higher stabilzation of microtubules involved in cell division. Second, vasulogenic mimicry (unexplained). Third, higher inhibition of the protein involved in preventing cell death (Bcl-xL), than docetaxel alone (unexplained). So, in theory, there are three axis on which TH1902 is working to kill cancer cells, and you can add to that the bypassing of the MDR resistance to docetaxel in cancers expressing it.
https://onlinelibrary.wiley.com/doi/10.1111/cas.15086