Abstract B003: Expanding therapeutic horizons: Unleashing the untapped potential of MEK inhibitor treatment in pediatric cancers
Notice bibliographique
Résumé
Abstract The Australian Zero Childhood Cancer (ZERO) program and German INFORM registry - the largest precision medicine initiatives for childhood cancers - conduct comprehensive tumour molecular characterisation and ex vivo drug sensitivity profiling (DSP) to support clinical treatment decision-making. Both programs have identified frequent alterations in the mitogen-activated protein kinase (MAPK) pathway, leading to the recommendation of treatment with a mitogen-activated protein kinase kinase (MEK) inhibitor. Interestingly, ex vivo DSP indicates that tumors without MAPK aberrations can also respond to MEK inhibition, revealing potential broader therapy applications. Although promising, clinical responses to single MEK inhibitor treatment guided by predictive MAPK alterations have been disappointing, highlighting the need for effective combination strategies to overcome resistance. Here, we compare vertical blockade of the MAPK pathway with horizontal inhibition of the MAPK and phosphatidylinositol-3 kinase (PI3K) pathways to enhance the efficacy of MEK inhibitors for childhood cancers.Ex vivo testing was conducted on 68 samples from high-risk pediatric cancer patients enrolled in ZERO, representing all major cancer types. Tumor samples were treated with the MEK inhibitors trametinib and/or pimasertib, the rapidly accelerated fibrosarcoma (RAF) inhibitor tovorafenib, and the PI3K inhibitor paxalisib, either alone or in combination. Efficacy was integrated with matched molecular profiling data. Vertical blockade of the MAPK pathway by combined MEK and RAF inhibition demonstrated strong synergy (highest Loewe synergy score >20) at clinically relevant concentrations in 23 out of 58 samples, resulting in at least a 75% reduction in cell viability in 17 of these 23 samples. Western blot analysis confirmed MAPK pathway reactivation upon single-agent MEK inhibitor treatment. Synergy was particularly notable in sarcoma samples with homozygous loss of function (LoF) of the neurofibromin 1 (NF1) gene, consistent with observations for another sarcoma sample with NF1 LoF derived from a patient enrolled in the INFORM registry. Among 17 diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG) samples, 12 exhibited strong synergy and high efficacy in the absence of MAPK alterations. These included two cases with PI3K pathway-activating mutations in PIK3R1, a gene previously associated with activated MAPK signalling. No synergism was observed between horizontal inhibition of the MAPK and PI3K pathways in these two cases. Combined MAPK and PI3K pathway inhibition was only strongly synergistic in one rhabdomyosarcoma sample without alterations in either pathway. Our findings indicate that vertical blockade of the MAPK pathway is a promising strategy to enhance the efficacy of MEK inhibitors for brain tumor and sarcoma subgroups, which otherwise face dismal outcomes. If validated in vivo, combined MEK and RAF inhibition will be included as an arm in the recently opened OPTIMISE trial. Citation Format: Gabor Tax, Jie Mao, Roxanne Cadiz, Tamar Barhen, Jinhan Xie, Jessica Harris, Mirae Bae, Lauren M. Brown, Karina Pazaky, Andrew J. Gifford, Chelsea Mayoh, Marion K. Mateos, Heike Peterziel, Ina Oehme, David S. Ziegler, Maria Tsoli, Ben Rayner, Paul G. Ekert, M. Emmy M. Dolman. Expanding therapeutic horizons: Unleashing the untapped potential of MEK inhibitor treatment in pediatric cancers [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 B003.
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 | 0,001 | 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 | 0,001 | 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 ».