Neuroendocrine Tumor | Transcriptional effects of 177Lu-octreotate therapy using a priming treatment schedule on GOT1 tumor in nude mice | springermedicine.com

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Open Access 01-12-2019 | Neuroendocrine Tumor | Original research

Transcriptional effects of ¹⁷⁷Lu-octreotate therapy using a priming treatment schedule on GOT1 tumor in nude mice

Authors: Johan Spetz, Britta Langen, Nils-Petter Rudqvist, Toshima Z. Parris, Emman Shubbar, Johanna Dalmo, Bo Wängberg, Ola Nilsson, Khalil Helou, Eva Forssell-Aronsson

Published in: EJNMMI Research | Issue 1/2019

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Abstract

Background

¹⁷⁷Lu-octreotate is used for therapy of somatostatin receptor expressing neuroendocrine tumors with promising results, although complete tumor remission is rarely seen. Previous studies on nude mice bearing the human small intestine neuroendocrine tumor, GOT1, have shown that a priming injection of ¹⁷⁷Lu-octreotate 24 h before the main injection of ¹⁷⁷Lu-octreotate resulted in higher ¹⁷⁷Lu concentration in tumor, resulting in increased absorbed dose, volume reduction, and time to regrowth. To our knowledge, the cellular effects of a priming treatment schedule have not yet been studied. The aim of this study was to identify transcriptional changes contributing to the enhanced therapeutic response of GOT1 tumors in nude mice to ¹⁷⁷Lu-octreotate therapy with priming, compared with non-curative monotherapy.

Results

RNA microarray analysis was performed on tumor samples from GOT1-bearing BALB/c nude mice treated with a 5 MBq priming injection of ¹⁷⁷Lu-octreotate followed by a second injection of 10 MBq of ¹⁷⁷Lu-octreotate after 24 h and killed after 1, 3, 7, and 41 days after the last injection. Administered activity amounts were chosen to be non-curative, in order to facilitate the study of tumor regression and regrowth. Differentially regulated transcripts (RNA samples from treated vs. untreated animals) were identified (change ≥ 1.5-fold; adjusted p value < 0.01) using Nexus Expression 3.0. Analysis of the biological effects of transcriptional regulation was performed using the Gene Ontology database and Ingenuity Pathway Analysis. Transcriptional analysis of the tumors revealed two stages of pathway regulation for the priming schedule (up to 1 week and around 1 month) which differed distinctly from cellular responses observed after monotherapy. Induction of cell cycle arrest and apoptotic pathways (intrinsic and extrinsic) was found at early time points after treatment start, while downregulation of pro-proliferative genes were found at a late time point.

Conclusions

The present study indicates increased cellular stress responses in the tumors treated with a priming treatment schedule compared with those seen after conventional ¹⁷⁷Lu-octreotate monotherapy, resulting in a more profound initiation of cell cycle arrest followed by apoptosis, as well as effects on PI3K/AKT-signaling and unfolded protein response.

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Title: Transcriptional effects of 177Lu-octreotate therapy using a priming treatment schedule on GOT1 tumor in nude mice
Authors: Johan Spetz
Britta Langen
Nils-Petter Rudqvist
Toshima Z. Parris
Emman Shubbar
Johanna Dalmo
Bo Wängberg
Ola Nilsson
Khalil Helou
Eva Forssell-Aronsson
Publication date: 01-12-2019
Publisher: Springer Berlin Heidelberg
Keyword: Neuroendocrine Tumor
Published in: EJNMMI Research / Issue 1/2019
Electronic ISSN: 2191-219X
DOI: https://doi.org/10.1186/s13550-019-0500-2

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