Abstract 3012: A highly potent selective CDK9 inhibitor OBP-004 reduces metastatic tumor burden in bone, brain, lung and lymph nodes and decreases growth of triple-negative breast cancer cells in bone
Notice bibliographique
Résumé
Abstract CDK9 is a promising target in many cancers. Development of first generation CDK9 inhibitors has been stopped due to severe adverse effects, but next generation selective CDK9 inhibitors are considered safer and more effective. OBP-004 is a highly potent selective small-molecule inhibitor of CDK9 with favorable physicochemical properties, 17-20 h in vivo half-life and high tissue biodistribution in brain, lung, spleen and kidneys. Triple-negative breast cancer (TNBC) patients have limited treatment options together with high incidence of metastatic relapse. TNBC typically forms multi-organ metastases and has a high incidence of bone metastases. In this study, we demonstrate preclinical efficacy of OBP-004 on metastatic tumor burden, and more specifically on bone metastatic TNBC. For studying efficacy on metastatic disease, NMRI nude mice were inoculated intravenously with luciferase-labelled MV4-11 human acute monocytic leukemia cells. OBP-004 was given orally at a dose of 1.0 mg/kg three times a week (3-day on, 4-day off). The mice were randomized to groups based on body weight and bioluminescence imaging (BLI) signal at day 15, and tumor growth was monitored by BLI during the study. Treatment was started after the randomization at day 15 and continued until day 32. For studying efficacy on tumor growth in bone metastatic microenvironment in more detail, BALB/c mice were inoculated intratibially with aggressive luciferase-labelled 4T1 mouse TNBC cell line. OBP-004 was given orally at a dose of 0.8 mg/kg three times a week (Mon/Wed/Fri). The mice were randomized to groups based on body weight and BLI signal at day 4. Treatment was started after the randomization at day 4 and continued until day 21. During the study, tumor growth was monitored by BLI, cancer-induced bone changes by X-ray radiography, and bone pain by mechanical allodynia using Von Frey filaments. The 1.0 mg/kg dosing (3-day on, 4-day off) of OBP-004 in the MV4-11 study resulted in slight decrease of body weight without any clinical signs. The optimized dosing with 0.8 mg/kg (Mon/Wed/Fri) in the 4T1 study was well tolerated. In the MV4-11 model, OBP-004 showed strong decrease of bone, brain, lung and lymph node metastases. In the intratibial 4T1 model, OBP-004 decreased tumor growth in bone from day 10 forward, bone pain at day 14, and cancer-induced bone loss at day 21. We conclude that the highly potent selective CDK9 inhibitor OBP-004 reduces metastatic tumor growth in bone, brain, lung and lymph nodes and decreases metastatic growth of TNBC cells in bone microenvironment, bone pain and cancer-induced bone loss in an aggressive preclinical TNBC model. Citation Format: Tiina E. Kahkonen, Gergana Galabova, Ru Yang, Jie Wen, MIchael Thormann, Jussi M. Halleen. A highly potent selective CDK9 inhibitor OBP-004 reduces metastatic tumor burden in bone, brain, lung and lymph nodes and decreases growth of triple-negative breast cancer cells in bone. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3012.
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) | 0,000 | 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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 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 ».