Targeting Oncogenic Polyamines in Refractory Pediatric Leukemias Using the Anti-Protozoan Drug Α-Difluoromethylornithine (DFMO) in Combination with GC7 and Aurothioglucose
Notice bibliographique
Résumé
Abstract Introduction: Polyamines (PAs) are cationic metabolites that enhance pro-tumorigenic cellular processes including the stimulation of cell division and proliferation, pro-survival gene expression, DNA and protein synthesis, regulation of apoptosis, oxidative stress and angiogenesis. Spermidine is a particularly important polyamine because it acts as an essential substrate of hypusine biosynthesis. Hypusination is required for the post-transcriptional activation of eukaryotic initiation factor 5A (eIF5A) which is critical to cell growth and protein synthesis. Spermidine production is highly regulated through the rate-limiting enzyme ornithine decarboxylase (ODC). Polyamines and eIF5A have been shown to be critical growth promoters in various pediatric cancers. Thus, targeted inhibition of ODC has therapeutic potential for this unique group of currently incurable pediatric malignancies. The anti-protozoan drug α-difluoromethylornithine (DFMO) is a suicide inhibitor of ODC and its effect may be potentiated by GC7 and Aurothioglucose. Previous mechanism based studies indicate that DFMO effectively reduces polyamine levels in neuroblastoma (NB) and provides rationale for ongoing Phase I and II clinical trials. To our knowledge, the effects of DFMO, GC7 and aurothioglucose have not yet been tested in pediatric leukemias. In this report, we evaluate the effectiveness of these therapeutic agents as a novel treatment of refractory hematological malignancies in the pediatric population. Methods: The recently published TARGET 2018 dataset was analyzed to determine the relationship between ODC expression and patient survival. Demographic data from this study was used to identify patients populations who may benefit from an ODC targeted therapy. Western blot analyses were then used to screen a comprehensive panel of pediatric cancer cell lines for ODC expression. Infant and pediatric leukemia cell lines were selected to represent the various subtypes including AML (TIB202, KASUMI) as well as B ALL (SUP-B15, MV411, RS4-11, CCRF-SB ) and T ALL (CEM/C1, MOLT-3). These cells were derived from children with relapsed disease and have varying degrees of resistance to conventional chemotherapy. Drug combination studies were used to define drug candidates having potential synergistic activity when combined with DFMO. Results: A Kaplan-Meier evaluation determined that high expression of ODC was associated with significantly lower patient survival and this finding was confirmed via cox regression analysis. The demographic analysis determined that females were significantly overrepresented in the high expression group whereas no variation was seen between race and ethnicity groups. Furthermore, a correlation was observed between high expression of eIF5A and younger diagnosis, indicating that ODC targeted therapy may be more effective in infant populations. DFMO-induced cytotoxicity was detected in many of the tumor cells including infant AML (TIB202) at an approximate physiologically achievable IC50 value of 200 uM. This was representative of values previously published for neuroblastoma. In infant AML, a western blot analysis determined that DFMO increased the abundance of cleaved PARP, cleaved caspase 3 and cleaved caspase 7 which serve as mechanistic markers of apoptosis. Probing for caspase 8 and caspase 9 showed no difference between treated cells and control. A combination screen of over 80 biologically active compounds was conducted to identify potential synergistic treatment partners of DFMO where GC7 and aurothioglucose (AuTG) ranked among the most promising. Further experimentation determined that doses of GC7 and AuTG, which were not effective as a singular treatment, were able to enhance the ability of DFMO to kill tumor cells. Discussion: The preclinical studies discussed here offer the first proof-of-concept data on a novel treatment approach for refractory leukemia in children. We provide mechanistic evidence to show the ability of DFMO to effectively kill polyamine-dependent tumor cells at physiologically attainable concentrations. In addition, effective drug combinations have been identified to further enhance their clinical utility. Our findings provide key preclinical information on the utility of these drugs as treatment for refractory hematological malignancies in the pediatric population. Disclosures No relevant conflicts of interest to declare.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| 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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 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 tête enseignante, 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 ».