Development and validation of a biology-based novel therapeutic agent targeting the LIN28/ <i>let-7</i> pathway in cancer.
Notice bibliographique
Résumé
3114 Background: Currently, brain tumors that are diagnosed in infants and young children carry an exceptionally high risk for treatment resistance and toxicities. The LIN28 family of RNA-binding proteins regulate stem cell biology and pluripotency. In addition to embryonic development, they have also been implicated in oncogenesis through interaction with the tumor suppressor micro-RNA (miRNA), let-7 . In cancer, LIN28 expression leads to let-7 loss-of-function, oncogenic activation, and tumorigenesis. Importantly, LIN28 expression has been associated with stemness and subsequent tumor aggressiveness and poor survival in early childhood brain tumors. Thus, LIN28 may offer an effective therapeutic strategy to prevent relapse by specifically targeting cancer stem cells. In this study, we describe a novel therapeutic inhibitor of LIN28 in cancer. Methods: Using an in silico approach, we designed and synthesized a panel of novel compounds predicted to bind and inhibit the critical molecular interaction between LIN28 and let-7 . Cytotoxicity was evaluated by alamar blue viability assay in a panel of LIN28-positive cancer cell lines derived from atypical teratoid rhabdoid tumor (ATRT), embryonal tumor with multilayered rosettes (ETMR), and germ cell tumor. LIN28-negative cells were used as control. LIN28 protein expression and let-7 miRNA levels were determined by immunoblot and reverse transcription quantitative polymerase chain reaction (RT-qPCR), respectively. Self-renewal capacity was analyzed by sphere formation assay. Mice carrying xenografts were treated to investigate LIN28 inhibition in vivo . Results: Preliminary screening of small molecule inhibitors identified a lead compound, designated THNB-3, that induces cell death at micromolar concentrations in LIN28-positive cell lines established from various tumors, without affecting LIN28-negative controls. Treatment with THNB-3 increased the level of let-7 tumor suppressor, confirming effective inhibition of LIN28. In addition to cytotoxicity, THNB-3 significantly inhibited sphere formation in brain tumor cells, reducing self-renewal and multipotency of cancer stem cells. Lastly, the anticancer activity of THNB-3 was validated in vivo against LIN28-positive xenografts and the drug also demonstrated systemic tolerability in mice. Conclusions: Our studies provide the first evidence for an effective, targeted therapeutic agent against the LIN28/ let-7 pathway for the treatment of cancer in the future. THNB-3 selectively induces cytotoxicity in LIN28-positive cancers by restoring let-7 miRNA, confirming effective target modulation. Further, LIN28 inhibition by THNB-3 may reduce self-renewal and multipotency of cancer stem cells. Together, our preclinical data supports further development of THNB-3 for the treatment of high-risk LIN28-positive tumors.
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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 | 0,004 | 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 | 0,001 |
| 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 ».