The Potent STAT3/5 Inhibitor, BP-1-102 Demonstrates Significant Anti-Tumor Activity Against Waldenstrom Macroglobulinemia
Notice bibliographique
Résumé
Abstract Abstract 5101 STAT3 is a cytoplasmic transcription factor, transiently activated in response to external stimuli such as growth factors and cytokines. As a transcription factor, STAT3 induces the expression of genes known to be involved in tumorigenesis, implicating STAT3 dysregulation in a number of hallmark oncogenic processes including tumor cell survival, proliferation, angiogenesis, metastasis, and drug resistance. Aberrant STAT3 signaling is prevalent in hematologic malignancies including Waldenstrom Macroglobulinemia (WM), a rare form of B cell non-Hodgkin lymphoma that is characterized by hyper-monoclonal IgM secretion in the peripheral blood. Despite the development of novel therapies and combinatorial treatment regimes, WM remains uniformly fatal, and as the limits of current chemotherapies have been reached, new approaches to treatment are urgently needed to improve patient outcome. Analysis of the gene and protein expression profiles of WM patients suggests that activation of STAT3 signaling plays a critical role in WM, providing rationale for the therapeutic use of STAT3 inhibitors. We have demonstrated pre-clinical efficacy of a novel, highly specific and potent small molecule STAT3/5 inhibitor, BP-1-102, in both hyper-IgM secreting B cell lymphoma cell lines (Mec-1 and RL) as well as two WM cell lines (MWCL-1 and BCWM-1). BP-1-102 directly targets STAT proteins by specifically blocking the SH2 domain that is a required for the phosphorylation, dimerization and nuclear localization of STAT3, ultimately resulting in inhibition of STAT3 transcriptional activation of target genes. We have shown that BP-1-102 directly interacts with STAT3's SH2 domain and is one of the most effective disruptors of STAT3 activity described to date. Treatment of cell lines with low μM doses of BP-1-102 induced dose-dependent decreases in constitutive and IL10-induced STAT3 phosphorylation (pSTAT3) as well as pSTAT3 nuclear localization. We further evaluated the potency of BP-1-102 against STAT1 and 5 compared to STAT3 using phosphor-flow cytometry to measure STAT phosphorylation status. BP-1-102 effectively inhibited GM-CSF induced STAT5 phosphorylation in AML2 cells at low dose concentrations (< 12.5uM) but only weakly inhibited IFNγ induced STAT1 phosphorylation in U937 leukemic cells at similar dose concentrations confirming the selectivity of BP-1-102 for STAT 3 and 5. Using a STAT3 dependent luciferase reporter construct, we confirmed repression of STAT3 transcriptional activity which correlated with a dose-dependent decrease in expression of STAT3 target genes (Mcl-1, Bcl-XL, Survivin and c-Myc). Inhibition of pSTAT3 resulted in decreased cell viability as assessed by MTT assay after 72 hours of in vitro exposure, with IC50 values ranging from 6uM to 10uM. In addition, treatment of cells with BP-1-102 resulted in caspase-dependent apoptosis which correlated with the activation of caspase-3 and PARP cleavage. Interestingly, co-culture of Mec-1 and RL with bone marrow stroma cells reduced the cytotoxicity of BP-1-102 suggesting stroma-conferred resistance, while MWCL-1 were equally sensitive to the cytotoxic effects of BP-1-102 regardless of either culture condition. Preliminary investigation suggests that the efflux system, used by cells to extrude toxic substances and linked to drug resistance in cancer, may be responsible for conferring stroma-mediate resistance to BP-1-102 in Mec-1 and RL cells. Finally, xenograft experiments to determine in vivo efficacy and safety are planned and will be presented. Collectively, these findings demonstrate a critical role for STAT3 signaling in WM pathology and provide the rationale for further development of STAT3 inhibitors for the treatment of WM. Disclosures: No relevant conflicts of interest to declare.
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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) | 0,001 | 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 ».