Abstract 1830: E7386, a selective inhibitor of the interaction between β-catenin and CREB-binding protein (CBP), in combination with lenvatinib (LEN), exerts antitumor activity in preclinical tumor models with prior immune checkpoint inhibitor (ICI)-based combination treatment
Notice bibliographique
Résumé
Abstract Introduction: Combination anti-CTLA-4 antibody (Ab) + anti-PD-1 Ab is approved in multiple cancer types and has improved clinical outcomes. In addition, atezolizumab + bevacizumab combination therapy is approved for unresectable hepatocellular carcinoma. Given the rapid changes in the therapeutic landscape, it is important to investigate effective treatments for people with prior ICI-based combination therapy. E7386 modulates Wnt/β-catenin signaling, and a phase 1 study in combination with LEN (a receptor tyrosine kinase inhibitor that mainly targets both VEGFR and FGFR), in people with solid tumors (NCT04008797) is ongoing. In this study, we examined the antitumor activity of the combination of E7386 + LEN, with either prior anti-CTLA-4 Ab + anti-PD-1 Ab or anti-PD-1 Ab + aflibercept (a soluble decoy receptor against VEGF), in the mouse lung tumor KLN 205 model. Methods: Antitumor activity of E7386 (25 or 50 mg/kg), LEN (3 mg/kg), and the combination, was evaluated in the KLN 205 model (orally, once daily x 14 days), with or without prior treatments of either anti-CTLA-4 Ab (0.2 mg/head, weekly x 3, intraperitoneally [ip]) + anti-PD-1 Ab (0.2 mg/head, weekly x 3, ip)─ie, CTLA-4 + PD-1; or aflibercept (5 mg/kg) + anti-PD-1 Ab (0.2 mg/head, twice a week x 2, ip)─ie, AFL + PD-1. Mice with relatively rapid-growing tumors and prior treatments were given E7386, LEN, and their combination. RNA-seq analyses were conducted by using tumor tissues collected from mice one day after the prior treatment period or without treatment to analyze gene-expression alterations with prior treatments. Results: In the mouse model without prior treatments, LEN had clear antitumor activity. E7386 had limited antitumor activity as a monotreatment. E7386 + LEN had superior antitumor activity vs LEN in a dose-dependent manner. In addition, E7386 + LEN had superior antitumor activity to each single treatment despite either prior CTLA-4 + PD-1 or AFL + PD-1. E7386 + LEN with prior CTLA-4 + PD-1 had equivalent antitumor activity to LEN without prior treatments. Conversely, E7386 + LEN with prior AFL + PD-1 had strong antitumor activity, including marked tumor regression, compared to both LEN alone and E7386 + LEN without prior treatments. RNA-seq analyses showed that intratumoral Axin2, a target gene in the canonical Wnt-signaling pathway, was upregulated with prior AFL + PD-1—suggesting a potential activation of the Wnt-signaling pathway. Conclusion: E7386 + LEN combination shows antitumor activity in the mouse KLN 205 lung tumor model when there is prior ICI-based (CTLA-4 + PD-1 or AFL + PD-1) combination treatment. Further, E7386 + LEN shows enhanced antitumor activity with prior AFL + PD-1; possibly due to activation of Wnt-signaling pathway during prior treatments. Citation Format: Satoshi Kawano, Yusuke Adachi, Megumi Kuronishi, Kohta Toshimitsu, Kotaro Kodama, Takayuki Kimura, Masahiko Kume, Jialing Shen, Saori Watanabe Miyano, Akira Yokoi, Junji Matsui, Yu Kato, Yasuhiro Funahashi. E7386, a selective inhibitor of the interaction between β-catenin and CREB-binding protein (CBP), in combination with lenvatinib (LEN), exerts antitumor activity in preclinical tumor models with prior immune checkpoint inhibitor (ICI)-based combination treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1830.
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 machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 0,001 |
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 source (Gemma direct ou Codex distillé), 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 ».