Efficacy and safety study of a novel alpha-fetoprotein (AFP)-maytansine conjugate in an ovarian xenograft model.
Notice bibliographique
Résumé
e14570 Background: AFP receptor is an oncofetal antigen and a novel target for cancer therapeutics. It is highly expressed on the surfaces of many cancers and Myeloid Derived Suppressor Cells (MDSCs) but absent on normal tissues. By conjugating maytansine toxin to a recombinant human AFP, we selectively deliver toxin to cancer cells and MDSCs while sparing normal cells, enabling a combination of targeted and immune activating approaches. We previously reported high efficacy of AFP-maytansine conjugate in a xenograft model of colorectal cancer. Here we report the effect of this conjugate in an ovarian xenograft model and in 2 independent patient-derived 3D ovarian organoids, supporting the wider utility of this approach. Methods: Four dose regimens of AFP-maytansine conjugate were compared to control in a mouse A2780 ovarian xenograft model. The conjugate was administered IV 10 days after implantation, when tumor volumes reached ≈150 mm 3 . Mice were randomized into 4 treatment and 1 control group (10 mice/group, table below). Tumor growth, survival and clinical observations were assessed for 62 days post implantation. In addition, organoids were cultured from primary reprogrammed tumor cells from 2 separate patients with high-grade serous ovarian carcinoma. Conjugate, staurosporine, thapsigargin or DMSO (control) were added to the media. Cytotoxicity was assessed by staining for AnnexinV and TMRE. Results: A statistically significant dose-dependent reduction in tumor volume (p<0.001) and increase in survival (p<0.002) were seen in all treatment groups relative to control. All animals in Groups 1,3 and 4 survived to the end of the study and 6 of 10 mice survived in the lowest dose group. 100% of mice in Group 1, highest dose group had complete tumor regression with no regrowth seen by day 62. In the other treatment groups majority of animals had complete tumor regression with no regrowth. All control animals were dead by day 38 due to excessive tumor burden. No signs of toxicity, such as ocular toxicity or vascular scarring of the tail were seen. All mice gained weight during the study. Gross pathology at the time of sacrifice was unremarkable. In addition, in the 2 ovarian organoids the AFP-maytansine conjugate demonstrated a cytotoxic effect over 72 hours exposure similar to that of thapsigargin and staurosporine given at known effective concentrations. Conclusions: This ovarian xenograft study confirms high activity without obvious toxicity of the novel AFP-maytansine conjugate in a 2nd tumor type. The targeted cytotoxic activity is further confirmed by the effect of the conjugate in 2 different ovarian cancer organoids. These results support advancing this novel conjugate toward clinical use with a dose-dense regimen. [Table: see text]
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».