Abstract 1853: TH1902, a SORT1 docetaxel peptide-drug conjugate, inhibits tumor growth of human cancer stem-like cells (CD133+) from both triple-negative breast cancers and ovarian cancers
Bibliographic record
Abstract
Abstract Cancer stem cells (CSC), typically associated with CD133 expression, represent a small proportion of cells residing within most tumors and which have high metastatic potential and enhanced drug resistance capacities. In cancer indications such as breast and ovarian cancers, CSC have been shown to be involved in vasculogenic mimicry (VM) and to express the receptor protein sortilin (SORT1). The newly developed SORT1-targeted peptide-docetaxel conjugate (TH1902) has been reported to inhibit both the growth of xenograft tumors in mice and the formation of VM. This work now examines the efficacy of TH1902 against CSC and its potential to circumvent some of the known drug resistance phenotype associated with this population of cells. The effects of TH1902 on human triple-negative breast cancer or ovarian CSC (hTNBCSC and hOvCSC respectively) were explored using two commercial CD133-positive cell lines which are highly resistant to docetaxel and doxorubicin, and which express SORT1 along with the drug efflux pump P-gp and other CSC markers such as CD44, Oct4, Nanog and Sox2. The cellular uptake of the fluorescent Alexa488-peptide from TH1902 was inhibited by SORT1 ligands and in cells where SORT1 expression was repressed using siRNA. In contrast to docetaxel, the addition of TH1902 in vitro induced a marked increase in cell apoptosis and produced cell cycle arrest in the G2/M phase. Interestingly, TH1902-mediated cell cycle arrest was unaffected by the presence of the P-gp inhibitors cyclosporine A or PSC-833. However, the cell cycle which was unaffected by docetaxel was arrested in the G2/M phase in the presence of P-gp inhibitors to levels similar to those of TH1902 alone. These results suggest that TH1902 bypasses the P-gp drug efflux pump. Also, in contrast to docetaxel, exposure to TH1902 inhibited in vitro migration of the hTNBCSC in a wound-healing assay. In vivo, in both CSC models, TH1902 significantly inhibited the growth of CSC-tumor xenografts when administered weekly as intravenous bolus for three cycles at a dose equivalent to the maximal tolerated dose of docetaxel (15 mg/kg) and TH1902-treated mice showed an increased tolerability when compared to those treated with docetaxel. A decrease of approximately 80% of hTNBCSC or hOvCSC tumor growth was observed in TH1902-treated animals while tumor volumes were diminished by about 35% in docetaxel-treated mice. Overall, these results demonstrate that TH1902 exerts superior anticancer activity than the unconjugated docetaxel in two CD133-positive CSC animal models. Furthermore, these results show that TH1902 can circumvent the chemoresistance phenotype of CSC through use of a SORT1-mediated internalization process and therefore could possibly reduce the potential recurrence of cancers associated with CSC. Citation Format: Christian Marsolais, Cyndia Charfi, Michel Demeule, Jean-Christophe Currie, Alain Zgheib, Alain Larocque, Richard Béliveau, Borhane Annabi. TH1902, a SORT1 docetaxel peptide-drug conjugate, inhibits tumor growth of human cancer stem-like cells (CD133+) from both triple-negative breast cancers and ovarian cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1853.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".