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Anti-relapse effect of trametinib on a local minimal residual disease neuroblastoma mouse model
Yuichi Togashi1, Tomoko Tanaka1, Masakazu Takemoto1
1Department of Pediatric Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
Purpose:
We reported the in vitro and in vivo anti-tumor effects of trametinib, an MEK inhibitor, on neuroblastoma. However, long-term trametinib administration for bulky tumors failed to prevent local relapse. In this study, we established a local minimal residual disease (L-MRD) model to develop an optimal clinical protocol.
Methods:
We prepared an l-MRD model by implanting neuroblastoma cells (SK-N-AS) into the renal capsule of nude mice with total tumorectomy or sham operation 14 days later. These mice received post-operative administration of trametinib or vehicle for eight weeks. Relapse was measured once weekly. Flow cytometry was performed with SK-N-AS cells treated by trametinib.
Results:
Tumorectomy+trametinib dramatically suppressed relapse, and all mice survived during trametinib administration, while other treatments failed to suppress relapse. The survival rates for other groups were 20% in sham+trametinib, 17% in tumorectomy+vehicle, and 0% in sham+vehicle. Relapse occurred in the tumorectomy+trametinib group after withdrawal of trametinib administration. Flow cytometry revealed G1 arrest in SK-N-AS cells treated with trametinib.
Conclusion:
These findings suggested that trametinib was able to suppress relapse from minimal residual tumor cells. Therefore, we propose that trametinib be administered as an option for maintenance therapy after surgical and chemotherapeutic treatments for neuroblastoma in future clinical protocols.
Insights
Trametinib, a MEK inhibitor, effectively suppressed neuroblastoma relapse in a minimal residual disease model. Further research is needed to optimize its use in clinical settings for preventing tumor recurrence.
Area of Science:
- Oncology
- Pharmacology
- Cancer Research
Background:
- Neuroblastoma is a pediatric cancer with a high risk of relapse.
- Trametinib, a MEK inhibitor, shows in vitro and in vivo anti-tumor effects but failed to prevent local relapse in bulky tumors.
- A local minimal residual disease (L-MRD) model is crucial for developing effective clinical protocols.
Purpose of the Study:
- To establish a local minimal residual disease (L-MRD) model for neuroblastoma.
- To evaluate the efficacy of trametinib in preventing relapse in a post-surgical setting.
- To develop an optimal clinical protocol for neuroblastoma treatment.
Main Methods:
- An L-MRD model was created using SK-N-AS neuroblastoma cells in nude mice.
- Mice underwent tumorectomy or sham operation, followed by trametinib or vehicle administration for eight weeks.
- Relapse was monitored weekly, and flow cytometry analyzed SK-N-AS cells treated with trametinib.
Main Results:
- Tumorectomy combined with trametinib significantly suppressed relapse and improved survival rates.
- Other treatment groups showed high relapse rates and lower survival (20% sham+trametinib, 17% tumorectomy+vehicle, 0% sham+vehicle).
- Trametinib induced G1 arrest in SK-N-AS cells, suggesting a mechanism for relapse suppression.
Conclusions:
- Trametinib effectively suppresses relapse from minimal residual neuroblastoma cells.
- Trametinib is a potential maintenance therapy option after surgery and chemotherapy for neuroblastoma.
- Further clinical studies are warranted to confirm trametinib's role in neuroblastoma treatment protocols.
