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177Lu-octreotate therapy for neuroendocrine tumours is enhanced by Hsp90 inhibition

Journal article
Authors Tobias Hofving
Viktor Sandblom
Yvonne Arvidsson
Emman Shubbar
Gülay Altiparmak
John Swanpalmer
Bilal Almobarak
Anna-Karin Elf
Viktor Johanson
Erik Elias
Erik Kristiansson
Eva Forssell-Aronsson
Ola Nilsson
Published in Endocrine-Related Cancer
Volume 26
Issue 4
Pages 437-449
ISSN 1351-0088
Publication year 2019
Published at Institute of Clinical Sciences, Department of Radiation Physics
Institute of Clinical Sciences, Department of Surgery
Sahlgrenska Cancer Center
Institute of Biomedicine, Department of Pathology
Pages 437-449
Language en
Links dx.doi.org/10.1530/ERC-18-0509
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Molecular biology, Radiation biology, Radiological physics, Cancer and Oncology

Abstract

177Lu-octreotate is an FDA-approved radionuclide therapy for patients with gastroenteropancreatic neuroendocrine tumours (NETs) expressing somatostatin receptors. The 177Lu-octreotate therapy has shown promising results in clinical trials by prolonging progression-free survival, but complete responses are still uncommon. The aim of this study was to improve the 177Lu-octreotate therapy by means of combination therapy. To identify radiosensitising inhibitors, two cell lines, GOT1 and P-STS, derived from small intestinal neuroendocrine tumours (SINETs), were screened with 1,224 inhibitors alone or in combination with external radiation. The screening revealed that inhibitors of Hsp90 can potentiate the tumour cell-killing effect of radiation in a synergistic fashion (GOT1; false discovery rate <3.2×10-11). The potential for Hsp90 inhibitor ganetespib to enhance the anti-tumour effect of 177Lu-octreotate in an in vivo setting was studied in the somatostatin receptor-expressing GOT1 xenograft model. The combination led to a larger decrease in tumour volume relative to monotherapies and the tumour-reducing effect was shown to be synergistic. Using patient-derived tumour cells from eight metastatic SINETs, we could show that ganetespib enhanced the effect of 177Lu-octreotate therapy for all investigated patient tumours. Levels of Hsp90 protein expression were evaluated in 767 SINETs from 379 patients. We found that Hsp90 expression was upregulated in tumour cells relative to tumour stroma in the vast majority of SINETs. We conclude that Hsp90 inhibitors enhance the tumour-killing effect of 177Lu-octreotate therapy synergistically in SINET tumour models and suggest that this potentially promising combination should be further evaluated.

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