So, this “subpopulation” of cancer stem cells responsible for tumor growth and highly resistance to chemotherapeutic agents have been a reason for cancer recurrence. As per the article the cancer stem cells are also contributing to expression of proteins responsible for MDR efflux. (Transponders)
The idea is to target these cancer stem cells therefore in vitro they did some experiments such as clearing the cells, exposure to Docetaxel and TH1902 and the result showed the region were repopulated by the cancer stem cells 24 hours later in Docetaxel’s case but not TH1902 so the PDC had an anti-migratory effect! Next, they compared the apoptosis effect of both Docetaxel and TH1902 on cancer stem cells again TH1902 produced cytotoxic effects (it seems TH1902 effected the distribution/increase /decrease of certain chromosomes) and Docetaxel did not. Then they looked at MDR proteins' efflux effect (cancer stem cells) where TH1902 again bypassed that versus Docetaxel.
Then they did some experiments on Mice, they implanted both ovarian and TNBC stem cells xenografts and exposed the subject to both Docetaxel and Th1902 same dosage again TH1902 had a greater tumor inhibitory effect than Docetaxel and at higher dosage of TH1902 (equivalent to 1.5 of docetaxel alone) they still produce same results but interestingly no weight lost versus Docetaxel causing 10 percent weight lost (better tolerability).
They also looked at combination of carboplatin (chemo drug) with Docetaxel, TH1902 or paclitaxel and the taxanes alone(hOvCSC xenografts) results showed TH1902 had much better tumor inhibitory effect than other taxanes alone or with Carboplatin and TH1902 with carboplatin had slightly better efficacy than TH1902 alone. They also showed similar VM effect on cancer stem cells exposed to TH1902.
“The development of resistance against adjuvant chemotherapies is one of the greatest hurdles to successful cancer treatment, and much of this resistance phenotype has been recently attributed to the presence of cancer stem cells (CSC) residing within the tumors [SC are a subpopulation of slow-growing cells within the tumor mass that are self-renewing, undifferentiated and which can regenerate tumors from which they were derived. The overexpression of multi-drug resistance (MDR) proteins such as those from the permeability glycoprotein (P-gp) members ATP-binding cassette sub-family B member 1 (ABCB1) and 5 (ABCB5) within CSC is one of the major mechanisms by which these cells can survive chemotherapeutic treatment. Consequently, a broad variety of unrelated pharmacological agents, including docetaxel, are prevented from reaching a concentration at which they would be effective by being rapidly extruded from the cell by those membrane efflux pumps.”
Conclusion:
“Our study reports the first comprehensive evidence indicating the potential therapeutic impact of TH1902 would offer against the CSC sub-population known to reside within ovarian cancer and TNBC. Given the current molecular demonstration that exploiting SORT1 function to internalize TH1902 within these CSC further enables to circumvent their chemoresistance phenotype provides the rationale that such therapy may also impact on the tumor microenvironment of the CSC niche. Finally, the future of anti-CSC therapy with TH1902 appears promising, both in experimental settings and in clinical trials, against cancer cells showing plasticity, metastatic potential, and resistance against anti-cancer treatment.”
https://mdpi-res.com/d_attachment/pharmaceutics/pharmaceutics-14-01910/article_deploy/pharmaceutics-14-01910.pdf?version=1662706520