Anti-tumor effects of rigosertib in high-risk neuroblastoma

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• High-risk neuroblastoma presents a significant therapeutic challenge with poor patient outcomes.
• There is a critical need for novel treatment strategies to improve survival rates.

Purpose of the Study:

• To evaluate the efficacy of rigosertib (ON-01910.Na) in preclinical models of high-risk neuroblastoma.
• To investigate the molecular mechanisms underlying neuroblastoma's response to rigosertib.
• To explore potential drug combinations involving rigosertib.

Main Methods:

• Screening of numerous cancer cell lines to identify sensitivity to rigosertib.
• Treatment of MYCN-amplified neuroblastoma organoids and patient-derived xenograft (PDX) models.
• Assessment of cell viability, apoptosis, cell cycle progression, and protein phosphorylation (AKT, ERK1/2).
• Evaluation of tumor growth delay and survival in mouse models.

Main Results:

• Neuroblastoma exhibited the highest sensitivity to rigosertib among 24 tumor types screened.
• Rigosertib induced organoid disintegration, reduced cell viability, and increased apoptosis in neuroblastoma models.
• Treatment led to G2M cell cycle arrest and decreased phosphorylation of AKT and ERK1/2.
• Rigosertib significantly delayed tumor growth and prolonged survival in mice with MYCN-amplified neuroblastoma PDX tumors.
• Vincristine and rigosertib combination therapy was identified as a promising approach.

Conclusions:

• Rigosertib demonstrates significant preclinical efficacy against MYCN-amplified neuroblastomas.
• The drug's mechanism involves cell cycle arrest and modulation of key signaling pathways.
• Rigosertib holds potential as a therapeutic agent for high-risk neuroblastoma, especially when combined with existing treatments.