Abstract 2914: Phosphoproteomic and transcriptional biomarkers predict response to SAR302503, a JAK2 inhibitor, in human acute myeloid leukemia preclinical models
Notice bibliographique
Résumé
Abstract Research to develop new anti-cancer treatments has recently shifted focus to identifying and targeting molecules and pathways essential for cancer stem cell survival. However, preclinical models that rely on cell lines for drug testing do not capture the heterogeneity of response typically seen in the clinic that likely reflects the underlying genetic and functional heterogeneity of the tumors. Moreover, the use of cell lines makes it difficult to develop companion biomarker tools for patient stratification. We have taken a novel approach that combines drug testing of a large cohort of patient samples in xenograft assays, with multiplexed phosphoflow cytometric and RNA-Seq analysis of each patient sample to develop biomarkers that predict drug response. We applied this approach to study the efficacy of SAR302503 (Sanofi), a small molecule inhibitor of JAK2, against leukemia stem cells (LSCs) in acute myeloid leukemia (AML). JAK2 inhibitors have demonstrated efficacy in clinical trials for treatment of myeloproliferative disorders. Activated JAK2 signaling has been reported in AML, however it is not clear whether JAK2 inhibitors are effective in this disease, particularly against the disease-sustaining LSCs. SAR302503 treatment reduced leukemic engraftment in 22 of 34 (65%) AML patient samples of multiple subtypes with heterogeneous cytogenetic and molecular abnormalities. Phosphoflow analysis showed that AML samples that were sensitive to JAK2 inhibition in xenotransplantation assays exhibited high basal levels of pSTAT5 that were rapidly decreased by SAR302503 treatment in vitro, whereas non-responding samples showed low levels of pSTAT5, indicating that pSTAT5 is a useful drug response biomarker. This biomarker has now been validated in an independent cohort of AML patient samples. Phosphoflow cytometric profiling also enabled the rational design and testing of a novel drug combination regimen (SAR302503+Dasatinib) with efficacy against LSCs. Additionally, RNA-Seq analysis of paired vehicle- and drug-treated patient samples revealed that samples that were responsive to JAK2 inhibition in vivo had distinct transcriptional profiles compared to those that were not, suggesting that a molecular signature predictive of response to JAK2 inhibition can be identified. Overall, our approach, involving large-scale analysis of patient samples using state-of-the-art xenograft assays, captures the heterogeneity of response typically seen in the clinic that likely reflects the underlying genetic and functional heterogeneity of the tumors and offers a new paradigm for development of both novel agents that effectively target LSCs and biomarker tools to identify the patients most likely to benefit from targeted treatment. Citation Format: Weihsu Claire Chen, Julie S. Yuan, Nathan Mbong, Andreea C. Popescu, Yan Xing, Gitte Gerhard, Wei Zhang, Yussanne Ma, Richard Moore, Marco Marra, Mark D. Minden, Donna E. Hogge, Cynthia Guidos, John E. Dick, Jean C.Y. Wang. Phosphoproteomic and transcriptional biomarkers predict response to SAR302503, a JAK2 inhibitor, in human acute myeloid leukemia preclinical models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2914. doi:10.1158/1538-7445.AM2014-2914
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 | 0,001 |
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 ».