Abstract A015: Biochemical and preclinical anti-tumor activity of a bi-steric mTORC1-selective inhibitor in fusion positive rhabdomyosarcoma
Notice bibliographique
Résumé
Abstract Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Although FOXO1 fusions portend a dismal prognosis for patients with both localized (5-year survival 65%) and metastatic (19%) disease, current therapy is largely agnostic to fusion status. The allosteric mTORC1 inhibitor temsirolimus delays disease progression in relapsed RMS but does not improve survival. We hypothesized that this incomplete response is due to inadequate suppression of critical downstream effectors of the mTORC1 complex. Recently described bi-steric mTORC1-selective inhibitors combine allosteric and catalytic modes of kinase inhibition, and have shown promise in diverse preclinical cancer models with early evidence of clinical activity. We therefore set out to compare the activity of the bi-steric mTORC1-selective inhibitor RMC-6272 to the allosteric mTOR inhibitor rapamycin in cell line and xenograft models of fusion positive RMS. Methods: We compared the in vitro anti-proliferative activity of RMC-6272 and rapamycin in FOXO1 fusion positive RMS cell lines at 72 and 144 hours. We assessed the ability of these inhibitors to suppress mTORC1 outputs, using immunoblot to quantify phosphorylation of p70S6K, RPS6, and 4EBP1, and m7-GTP pulldowns to assess repression of cap-dependent translation. In vivo studies were conducted in patient-derived xenograft (PDX) models subcutaneously implanted in NSG mice. We tested preclinical anti-tumor activity of RMC-6272 at two doses and used immunoblots and m7-GTP assays in tumors harvested from treated mice to assess target engagement. Results: We observed superior anti-proliferative effects of RMC-6272 when compared to rapamycin in vitro, with the latter having only modest effect. Biochemically, treatment of RMS cell lines with either RMC-6272 or rapamycin diminished phosphorylation of p70S6K and RPS6. However, RMC-6272 blocked 4EBP1 phosphorylation and cap-dependent translation much more potently than rapamycin. Based on these findings, we conducted in vivo studies using weekly intraperitoneal injections of RMC-6272 in PDX-harboring mice. Both doses were associated with tumor regressions in two fusion positive RMS PDX models: 2 CR and 1 PR at 8 mg/kg, and 3 CR, 1 PR, 1 SD, and 2 PD at 6 mg/kg. NSG mice treated at 8 mg/kg demonstrated more weight loss than those at 6 mg/kg, suggesting strain-specific determinants of tolerability. We confirmed in vivo suppression of p70S6K phosphorylation and cap-dependent translation in tumors. Conclusions: The mTORC1 inhibitor RMC-6272 exhibits greater anti-tumor activity than the allosteric inhibitor rapamycin in vitro, and is capable of inducing complete remissions as monotherapy in FOXO1 fusion positive RMS PDX. Increased anti-tumor activity was associated with suppression of cap-dependent translation as assessed by m7-GTP assays, nominating dephosphorylation of 4EBP1 as a potential response biomarker. Preclinical studies are ongoing to assess mechanism-informed combination therapeutic strategies incorporating this highly active agent in FOXO1 fusion positive RMS. Citation Format: Jacqueline Morales, Kristen Kwong, W. Clay Gustafson, Amit J. Sabnis. Biochemical and preclinical anti-tumor activity of a bi-steric mTORC1-selective inhibitor in fusion positive rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A015.
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) | 0,002 | 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 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 ».