Cell death ELISAs in the phase I clinical evaluation of AEG35156 (XIAP antisense) administered as an intravenous infusion over 7-days, 3-days, and 2-hours.
Notice bibliographique
Résumé
C163 The X-linked inhibitor of apoptosis protein (XIAP) is a potent anti-apoptotic protein and is widely up-regulated in a variety of cancer cell lines. AEG35156 (Aegera Therapeutics Inc) is a second generation antisense oligonucleotide targeting human XIAP and pre-clinical studies indicate that AEG35156 will induce tumour cell death both as a single agent and in combination with radiotherapy or chemotherapy. AEG35156 has been administered as a 7-day or 3-day continuous infusion every 3 weeks, and as a weekly 2-hour infusion (ongoing). The primary objectives of these Phase I trials were to establish the Maximum Tolerated Dose (MTD) and toxicity profile. Secondary objectives included the evaluation of three potential plasma pharmacodynamic biomarkers of apoptosis, which may be used in conjuction with measurements of the direct impact of AEG35156 on XIAP mRNA and protein, to identify optimal biological doses and schedules of AEG35156 for future studies. 1) An M30 ELISA detects a caspase-cleaved fragment of the epithelial cell protein cytokeratin 18 (CK18) as a selective marker of apoptosis 2) An M65 ELISA detects both intact and caspase-cleaved CK18 as markers of apoptotic and non-apoptotic cell death; and 3) An ELISA assay for the quantification of circulating nucleosomal DNA (nDNA). Plasma samples were collected from treated patients, initially with epithelial tumours and subsequently from all types of advanced refractory cancer, at multiple time points during treatment. Samples have been analysed from 24 patients in the 7-day infusion protocol, 16 patients in the 3-day protocol, and 20 patients in the 2-hour protocol. The biomarker profiles showed a temporal association with drug infusion; a significant rise in biomarker value from baseline typically occurred before day 4 of treatment. Generally there was a good correlation between M30, M65 and nDNA results, with the best agreement between M65 & nDNA. Some patients have a biomarker signature suggestive of disease progression. The most commonly occurring drug-related toxicities were reversible transaminitis and thrombocytopenia. . Longitudinal plots of liver transaminases and M65 antigen levels revealed that patients who had an elevation in liver transaminases also had a significant temporally associated rise in M65 antigen levels. Such increases in circulating M65 antigen levels during or following treatment in patients with non-epithelial, non-CK18 expressing tissues suggest that ELISAs may also detect non-tumour tissue toxicity. In conclusion, these emerging results from the XIAP trials suggest three pharmacodynamic biomarkers of apoptosis may have clinical potential as indicators of pathological progression, and can also yield information on both tumour and non-tumour response to AEG35156. Further studies are required to assess the correlation with clinical outcome.
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 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 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 ».