An evaluation in vitro of the efficacy of nutlin-3 and topotecan in combination with 177Lu-DOTATATE for the treatment of neuroblastoma
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Mathias Tesson1, Richa Vasan1, Andreas Hock2, Colin Nixon2, Colin Rae1, Mark Gaze3 and Robert Mairs1
1Radiation Oncology, Institute of Cancer Sciences, Wolfson Wohl Translational Cancer Research Centre, University of Glasgow, Bearsden, Glasgow, UK
2Cancer Research UK Beatson Institute, Bearsden, Glasgow, UK
3Department of Oncology, University College London Hospitals NHS Foundation Trust, London, UK
Mathias Tesson, email: [email protected]
Keywords: DOTATATE; neuroblastoma; radiosensitisation; topotecan; nutlin-3
Received: August 09, 2017 Accepted: May 28, 2018 Published: June 26, 2018
Targeted radiotherapy of metastatic neuroblastoma using the somatostatin receptor (SSTR)-targeted octreotide analogue DOTATATE radiolabelled with lutetium-177 (177Lu-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 177Lu-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 177Lu-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 177Lu-DOTATATE. The efficacy of the combination treatments was p53-dependent. These results indicate that targeted radiotherapy of high risk neuroblastoma with 177Lu-DOTATATE may be improved by combination with the radiosensitising drugs nutlin-3 and topotecan.
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