TY - JOUR
T1 - Anti-relapse effect of trametinib on a local minimal residual disease neuroblastoma mouse model
AU - Togashi, Yuichi
AU - Tanaka, Tomoko
AU - Takemoto, Masakazu
AU - Takeuchi, Yuki
AU - Higashi, Mayumi
AU - Fumino, Shigehisa
AU - Tajiri, Tatsuro
N1 - Funding Information:
This work was supported by Grant-in-Aid for Exploratory Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT KAKENHI grant number 19H03719) and by the Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development, AMED (grant number 19ck0106332h0003). The English used in this manuscript was reviewed by Brian Quinn (Editor-in-Chief, Japan Medical Communication).
Publisher Copyright:
© 2021
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
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U2 - 10.1016/j.jpedsurg.2021.03.031
DO - 10.1016/j.jpedsurg.2021.03.031
M3 - Article
C2 - 33863557
AN - SCOPUS:85104140842
VL - 56
SP - 1233
EP - 1239
JO - Journal of Pediatric Surgery
JF - Journal of Pediatric Surgery
SN - 0022-3468
IS - 7
ER -