177 Lu-octreotate therapy for neuroendocrine tumours is enhanced by Hsp90 inhibition
Artikel i vetenskaplig tidskrift, 2019

Lu-177-octreotate is an FDA-approved radionuclide therapy for patients with gastroenteropancreatic neuroendocrine tumours (NETs) expressing somatostatin receptors. The Lu-177-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 Lu-177-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 1224 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 x 10(-11)). The potential for Hsp90 inhibitor ganetespib to enhance the anti-tumour effect of Lu-177-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 Lu-177-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 Lu-177-octreotate therapy synergistically in SINET tumour models and suggest that this potentially promising combination should be further evaluated.

peptide receptor radionuclide therapy

ganetespib

Hsp90 inhibitor

Lu-177-octreotate therapy

neuroendocrine tumours

Författare

Tobias Hofving

Göteborgs universitet

Viktor Sandblom

Göteborgs universitet

Yvonne Arvidsson

Göteborgs universitet

Emman Shubbar

Göteborgs universitet

Gulay Altiparmak

Göteborgs universitet

John Swanpalmer

Göteborgs universitet

Bilal Almobarak

Göteborgs universitet

Anna-Karin Elf

Göteborgs universitet

Viktor Johanson

Göteborgs universitet

Erik Elias

Göteborgs universitet

Erik Kristiansson

Chalmers, Matematiska vetenskaper, Tillämpad matematik och statistik

Eva Forssell-Aronsson

Göteborgs universitet

Ola Nilsson

Göteborgs universitet

Endocrine-Related Cancer

1351-0088 (ISSN)

Vol. 26 4 437-449

Ämneskategorier

Hematologi

Urologi och njurmedicin

Cancer och onkologi

DOI

10.1530/ERC-18-0509

PubMed

30730850

Mer information

Senast uppdaterat

2019-03-27