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Augmented Antitumor Activity for Novel Dual PI3K/BDR4 Inhibitors, SF2523 and SF1126 in Ewing Sarcoma
Amanda N Goldin1,2, Alok Singh2, Shweta Joshi2
1Department of Orthopedic Surgery.
Abstract:
Ewing sarcoma (ES) is the second most common pediatric bone cancer. Despite recent advances in the treatment, patients with metastatic tumors have dismal prognosis and hence novel therapies are urgently needed to combat this cancer. A recent study has shown that phosphoinositide-3 kinase (PI3K) inhibitors can synergistically increase sensitivity to bromodomain and extraterminal domain inhibitors in ES cells and therefore combined inhibition of PI3K and bromodomain and extraterminal domain bromodomain proteins might provide benefit in this cancer. Herein, we have investigated the efficacy of dual PI3K/BRD4 inhibitors, SF2523 and SF1126, for their antitumor activity in ES cell lines. The effect of SF1126 and SF2523 on cell viability and PI3K signaling was assessed on a panel of human ES cell lines. To evaluate the antitumor activity of SF1126, A673 cells were injected intrafemorally into RAG-2-/- mice and treated with 50 mg/kg SF1126 6 days per week, for 30 days. Both SF1126 and SF2523 decreased cell survival and inhibited phosphorylation of AKT in human ES cell lines. In vivo, SF1126 showed a significant reduction in tumor volume. These results suggest that dual PI3K/BRD4 inhibitor, SF1126, has antitumor activity in ES models.
Insights
Dual PI3K/BRD4 inhibitors, SF1126 and SF2523, show promise against pediatric bone cancer. SF1126 demonstrated significant antitumor activity in Ewing sarcoma models, reducing tumor volume in mice.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Ewing sarcoma (ES) is a prevalent pediatric bone cancer with poor prognosis for metastatic cases.
- Current treatments are insufficient, highlighting the need for novel therapeutic strategies.
- Combined inhibition of phosphoinositide-3 kinase (PI3K) and bromodomain and extraterminal domain (BRD) proteins may offer synergistic benefits in ES.
Purpose of the Study:
- To investigate the antitumor efficacy of dual PI3K/BRD4 inhibitors, SF11253 and SF1126, in Ewing sarcoma.
- To assess the impact of these inhibitors on cell viability and PI3K signaling pathways in ES cell lines.
- To evaluate the in vivo antitumor activity of SF1126 in a preclinical model of ES.
Main Methods:
- Human ES cell lines were treated with SF1126 and SF2523 to assess cell viability and PI3K signaling.
- Western blotting was used to analyze the phosphorylation of AKT, a key component of the PI3K pathway.
- A673 ES cells were xenografted into RAG-2-/- mice, and tumor-bearing mice were treated with SF1126 to evaluate in vivo efficacy.
Main Results:
- Both SF1126 and SF2523 significantly reduced cell survival in human ES cell lines.
- Treatment with SF1126 and SF2523 inhibited AKT phosphorylation, indicating PI3K pathway suppression.
- In vivo administration of SF1126 resulted in a significant reduction in tumor volume in the mouse model.
Conclusions:
- Dual PI3K/BRD4 inhibition represents a potential therapeutic strategy for Ewing sarcoma.
- SF1126 exhibits significant preclinical antitumor activity in both in vitro and in vivo ES models.
- Further investigation of SF1126 as a novel therapy for pediatric bone cancer is warranted.
