Priming increases the anti-tumor effect and therapeutic window of 177Lu-octreotate in nude mice bearing human small intestine neuroendocrine tumor GOT1

Johanna Dalmo; Johan Spetz; Mikael Montelius; Britta Langen; Yvonne Arvidsson; Henrik Johansson; Toshima Z Parris; Khalil Helou; Bo Wängberg; Ola Nilsson; Maria Ljungberg; Eva Forssell-Aronsson

doi:10.1186/s13550-016-0247-y

Priming increases the anti-tumor effect and therapeutic window of ¹⁷⁷Lu-octreotate in nude mice bearing human small intestine neuroendocrine tumor GOT1

EJNMMI Res. 2017 Dec;7(1):6. doi: 10.1186/s13550-016-0247-y. Epub 2017 Jan 5.

Authors

Affiliations

¹ Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, SE-413 45, Gothenburg, Sweden. johanna.dalmo@vgregion.se.
² Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, SE-413 45, Gothenburg, Sweden.
³ Department of Pathology, Institute of Biomedicine, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, SE-413 45, Gothenburg, Sweden.
⁴ Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, SE-413 45, Gothenburg, Sweden.
⁵ Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, SE-413 45, Gothenburg, Sweden.

Abstract

Background: ¹⁷⁷Lu-[DOTA⁰, Tyr³]-octreotate (¹⁷⁷Lu-octreotate) is used for treatment of patients with somatostatin receptor (SSTR) expressing neuroendocrine tumors. However, complete tumor remission is rarely seen, and optimization of treatment protocols is needed. In vitro studies have shown that irradiation can up-regulate the expression of SSTR1, 2 and 5, and increase ¹⁷⁷Lu-octreotate uptake. The aim of the present study was to examine the anti-tumor effect of a ¹⁷⁷Lu-octreotate priming dose followed 24 h later by a second injection of ¹⁷⁷Lu-octreotate compared to a single administration of ¹⁷⁷Lu-octreotate, performed on the human small intestine neuroendocrine tumor cell line, GOT1, transplanted to nude mice.

Results: Priming resulted in a 1.9 times higher mean absorbed dose to the tumor tissue per administered activity, together with a reduced mean absorbed dose for kidneys. Priming gave the best overall anti-tumor effects. Magnetic resonance imaging showed no statistically significant difference in tumor response between treatment with and without priming. Gene expression analysis demonstrated effects on cell cycle regulation. Biological processes associated with apoptotic cell death were highly affected in the biodistribution and dosimetry study, via differential regulation of, e.g., APOE, BAX, CDKN1A, and GADD45A.

Conclusions: Priming had the best overall anti-tumor effects and also resulted in an increased therapeutic window. Results indicate that potential biomarkers for tumor regrowth may be found in the p53 or JNK signaling pathways. Priming administration is an interesting optimization strategy for ¹⁷⁷Lu-octreotate therapy of neuroendocrine tumors, and further studies should be performed to determine the mechanisms responsible for the reported effects.

Keywords: 177Lu-DOTATATE; Fractionated radionuclide therapy; Gene expression; MRI; Neuroendocrine tumor; Radiation biology; Somatostatin receptors; Xenograft model.