An evaluation in vitro of the efficacy of nutlin-3 and topotecan in combination with 177 Lu-DOTATATE for the treatment of neuroblastoma

Tesson, M., Vasan, R. , Hock, A., Nixon, C., Rae, C. , Gaze, M. and Mairs, R. (2018) An evaluation in vitro of the efficacy of nutlin-3 and topotecan in combination with 177 Lu-DOTATATE for the treatment of neuroblastoma. Oncotarget, 9(49), pp. 29082-29096. (doi: 10.18632/oncotarget.25607) (PMID:30018737) (PMCID:PMC6044389)

Abstract

Targeted radiotherapy of metastatic neuroblastoma using the somatostatin receptor (SSTR)-targeted octreotide analogue DOTATATE radiolabelled with lutetium-177 (177 Lu-DOTATATE) is a promising strategy. This study evaluates whether its effectiveness may be enhanced by combination with radiosensitising drugs. The growth rate of multicellular tumour spheroids, derived from the neuroblastoma cell lines SK-N-BE(2c), CHLA-15 and CHLA-20, was evaluated following treatment with 177 Lu-DOTATATE, nutlin-3 and topotecan alone or in combination. Immunoblotting, immunostaining and flow cytometric analyses were used to determine activation of p53 signalling and cell death. Exposure to 177 Lu-DOTATATE resulted in a significant growth delay in CHLA-15 and CHLA-20 spheroids, but not in SK-N-BE(2c) spheroids. Nutlin-3 enhanced the spheroid growth delay induced by topotecan in CHLA-15 and CHLA-20 spheroids, but not in SK-N-BE(2c) spheroids. Importantly, the combination of nutlin-3 with topotecan enhanced the spheroid growth delay induced by X-irradiation or by exposure to 177 Lu-DOTATATE. The efficacy of the combination treatments was p53-dependent. These results indicate that targeted radiotherapy of high risk neuroblastoma with 177 Lu-DOTATATE may be improved by combination with the radiosensitising drugs nutlin-3 and topotecan.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Nixon, Mr Colin and Rae, Dr Colin and Hock, Dr Andreas and Mairs, Professor Robert and Vasan, Dr Richa and Tesson, Dr Mathias
• Authors: Tesson, M., Vasan, R., Hock, A., Nixon, C., Rae, C., Gaze, M., and Mairs, R.
• Subjects: R Medicine > RM Therapeutics. Pharmacology
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Oncotarget
• Publisher: Impact Journals
• ISSN: 1949-2553
• ISSN (Online): 1949-2553
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in Oncotarget 9(49):29082-29096
• Publisher Policy: Reproduced under a Creative Commons License