Abstract A063 Selective targeting of BET family epigenetic regulators in metastatic alveolar rhabdomyosarcoma
Notice bibliographique
Résumé
Abstract Objective: Alveolar rhabdomyosarcoma (ARMS) is a soft tissue cancer driven by a PAX3/7-FOXO1 (P3F) fusion and is the most aggressive pediatric RMS subtype. P3F transcriptional activity is dependent on the bromodomain-containing protein 4 (BRD4) epigenetic protein. Given that >70% of high-risk patients develop resistance to chemotherapy, we focus on novel BET-inhibitors (BETi) as a therapeutic option for metastatic ARMS. Methods: To establish metastatic models of the axilla/lymph node (AX), liver (LV) and retroperitoneum (RP), NSG mice (n=10) were injected with human ARMS cells expressing luciferase (Luc) and the tumor-bearing hindlimb was amputated. Metastases (mets) were detected using bioluminescent imaging (BLI) followed by necropsy. Histology was evaluated by pathologist Dr. Brendan Dickson, and P3F fusion was assessed using RT-PCR. The parent cell lines and cells derived from metastatic models (n=3; LV, AX, RP) were treated with BETi (n=2) using a 12-point concentration (2.6nM-10µM). Half maximal inhibitory concentrations (IC50) were calculated after an ATPlite assay. Caspase-3 apoptotic marker was assessed via flow cytometry. On-target efficacy was confirmed with IncuCyte after siRNA-depletion of BETi targets BRD2/3/4. ARMS cells expressing Luc controlled by a constitutively active or P3F dependent reporter were treated with BETi (1nM-1µM) and relative Luc activity was detected. An ex vivo pulmonary lung metastasis assay (PuMA) was established by injecting GFP expressing ARMS cells into the mouse tail vein (n=4), followed by euthanasia. The lungs were insufflated with an agarose mix and allowed to solidify. Lung slices were placed on gelatin sponges and incubated in media. PuMA sections were treated with IC50 values of BETi and lung metastatic burden was detected over time with confocal fluorescent microscopy and analyzed via ImageJ. Results: Mets in surgical models occurred at sites relevant to human disease (AX, LV, RP). AX mets, one of the most aggressive sites in humans, occurred in 90% of models. Mets displayed ARMS histopathology and the P3F fusion present in parent cells was preserved. BLI detected AX mets with high sensitivity ∼1.5 weeks prior to palpability. The in vitro IC50 of BETi compounds was in the micromolar range in both the parent and met-derived cell lines, and increased apoptosis >3-fold compared to vehicle. Depletion of BRD4 hindered cell proliferation, ensuring target specificity of the BETi. BETi selectively suppressed the activity of the P3F dependent reporter, indicating an impairment of P3F activity. Given that lungs are the most common metastatic site, we developed an ARMS PuMA model which showed significant increase in metastatic burden over time (p<0.01). Treatment of PuMA sections with IC50 doses of BETi reduced lung metastatic burden (p<0.01). Conclusion: Our metastatic models demonstrate clinical relevance and BETi sensitivity. Next, we aim to compare the transcriptomes of these models with patient data and test the BETi compounds in our surgical models in vivo. Citation Format: Anna Mandel, Yael Babichev, Claire Wunker, Jennifer Dorsey, Abha A. Gupta, Elizabeth Demicco, Richard Marcellus, Brendan Dickson, Rebecca Gladdy. Selective targeting of BET family epigenetic regulators in metastatic alveolar rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A063.
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 ».