Abstract 932: Predictive markers of the <i>in vitro</i> anticancer effect of the pan class I PI3K inhibitor BKM120 in primary B-CLL lymphocytes.
Notice bibliographique
Résumé
Abstract B-chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5+ B-lymphocytes that are long-lived in-vivo but die quickly by apoptosis when cultured in-vitro. The phosphatidylinositol-3 kinase (PI3K) cascade which is a critical component of survival signaling has increased activity in CLL lymphocytes as compared to normal B lymphocytes. There are three classes of PI3Ks of which class I is the most clearly implicated in human cancer. The PI3K-δ inhibitor, CAL-101, promotes apoptosis and abrogated protection from spontaneous apoptosis induced by CD40 in primary CLL lymphocytes in-vitro. Thus the PI3K pathway appears to play a critical role in B-CLL cell survival. BKM120 is a pan class I PI3K inhibitor developed by Novartis. Phase I trials demonstrated that plasma concentrations (Cmax) of 5 μM can be obtained. In view of the critical role of PI3K in CLL homeostasis, the activity of BKM120 was examined in CLL lymphocytes in-vitro. BKM120 was cytotoxic in the 3 CLL cell lines and in 78% of the primary B-CLL lymphocytes samples isolated from 65 B-CLL patients, including patients with del11 and del17. Interestingly, 60% of the B-CLL samples tested in our study have an IC50 below the Cmax. Furthermore, BKM120 cytotoxicity correlated with the basal expression of proteins involved in the PI3K/Akt pathway (Akt, rictor, raptor, p70S6K and 4E-BP1) but not with PTEN, mTor, IgVH or CD38 expression in these primary B-CLL lymphocytes. Further analysis of these different markers demonstrated that only patients very sensitive to BKM120 (IC50 ≤3 μM) expressed low basal levels of mTor, raptor and p70S6K simultaneously. Inhibition of PI3K was demonstrated by detection of phosphorylated Akt (S473) after BKM120 treatment in the cell lines. Molecular biomarkers such as p70S6K and 4E-BP1 have been used as indicators of PI3K pathway inhibition in-vivo. We also have demonstrated that BKM120 decreased the phosphorylation status of 4E-BP1 and p70S6K in the primary B-CLL lymphocytes tested. As detected by AnnexinV/propidium iodine staining and analysis of caspase-3 cleavage, BKM120 induced apoptosis in primary B-CLL cells culture in the presence and absence of stromal cell support. Taken together, our results demonstrated that the class I PI3K inhibitor BKM120 may be useful as a single agent in CLL patients independently of their IgVh mutational status, CD38 expression or genomic deletions (del11 and del17). Furthermore, a combination of different biomarkers (expression of mTor, raptor, and p70S6K) may predict the response to BKM120 treatment. Also, BKM120 abolished the protection against apoptosis and drug resistance conferred by the microenvironment to the primary B-CLL lymphocytes in-vitro. Our preclinical study demonstrated that BKM120, a molecule with acceptable clinical toxicity, may be useful in the treatment for CLL. Citation Format: Lilian Amrein, May Shawi, Jeremy Grenier, Raquel Aloys, Lawrence Panasci. Predictive markers of the in vitro anticancer effect of the pan class I PI3K inhibitor BKM120 in primary B-CLL lymphocytes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 932. doi:10.1158/1538-7445.AM2013-932
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 | 0,001 | 0,001 |
| 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) | 0,005 | 0,002 |
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 ».