Abstract 1079: Anti-cancer efficacy of TH1902, a SORT1 docetaxel peptide-drug conjugate, against ovarian and endometrial cancers xenografts alone or in combination with carboplatin
Bibliographic record
Abstract
Abstract Effective, safe chemotherapy treatments for gynecological cancers remain a daunting challenge. One strategy to achieve greater selectivity and better anticancer drug delivery into cancer cells is to conjugate cytotoxic agents to specific peptide ligands that selectively target receptors abundantly expressed on these cells. Increased expression of sortilin (SORT1), a scavenging receptor, has been shown to be highly expressed in many cancers, including ovarian and endometrial cancers. The peptide-drug conjugate TH1902 (a peptide which targets SORT1 and is bis-linked to two docetaxel molecules) was investigated to determine whether it could be efficacious against SORT1-positive ovarian (ES-2, A-2780 and SKOV-3) and endometrial (AN3-CA) cancer models. The Alexa488-fluorescent peptide used to generate TH1902 was transported into ES-2 and SKOV-3 cells by a process requiring clathrin-coated vesicles, and which was strongly diminished by siRNA-mediated SORT1 silencing or by competition with SORT1 ligands. In vitro, TH1902 enabled an increase in apoptosis of over 2-fold compared to that of unconjugated docetaxel. The effects of TH1902 administration were also examined in multiple subcutaneous xenograft tumor models (ES-2, SKOV-3, A-2780 or AN3-CA cells). Following two weeks treatment at equivalent docetaxel doses, the ES-2 xenograft sizes in mice treated with vehicle or with docetaxel were statistically indistinguishable but there was a significant decrease in tumor size by 78% for mice treated with TH1902. In SKOV-3 xenografts, treatment with either drug both stopped tumor growth and induced similar tumor regressions. In AN3-CA xenografts, treatments administered at equivalent docetaxel maximum tolerated dose (MTD) induced similar initial tumor regressions. However, TH1902-treated mice showed prolonged tumors regression whereas tumors started to regrow upon docetaxel treatment interruption. At one quarter of the docetaxel MTD, TH1902 significantly inhibited AN3-CA tumor growth whereas docetaxel had minimal effect (-73% vs -11%, respectively). Mice bearing A-2780 xenograft tumors were treated with TH1902, paclitaxel or docetaxel alone, as well as with each in combination with carboplatin. Comparison of the tumor sizes between the various treatments showed that TH1902 alone caused stronger A-2780 tumor growth inhibition than did either of the unconjugated taxanes or carboplatin. Moreover, TH1902 combined with carboplatin also demonstrated better efficacy than did either of the taxane-carboplatin combinations. Overall, the results indicate that TH1902 possesses an in vivo efficacy superior to those of docetaxel against ovarian and endometrial cancers in the animal models tested, and that TH1902 could be safely combined with carboplatin to reach optimal inhibition of tumor growth. Citation Format: Christian Marsolais, Michel Demeule, Cyndia Charfi, Jean-Christophe Currie, Alain Larocque, Alain Zgheib, Richard Béliveau, Borhane Annabi. Anti-cancer efficacy of TH1902, a SORT1 docetaxel peptide-drug conjugate, against ovarian and endometrial cancers xenografts alone or in combination with carboplatin [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 1079.
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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".