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

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

Hofving, Tobias, 1989 (author): Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center,Institutionen för biomedicin,Institute of Biomedicine

Sandblom, Viktor, 1987 (author): Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för radiofysik,Sahlgrenska Cancer Center,Institute of Clinical Sciences, Department of Radiation Physics

Arvidsson, Yvonne, 1960 (author): Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center,Institutionen för biomedicin,Institute of Biomedicine

Shubbar, Emman, 1974 (author): Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för radiofysik,Sahlgrenska Cancer Center,Institute of Clinical Sciences, Department of Radiation Physics

Altiparmak, Gülay (author): Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center,Institutionen för biomedicin,Institute of Biomedicine

Swanpalmer, John, 1958 (author): Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för radiofysik,Sahlgrenska Cancer Center,Institute of Clinical Sciences, Department of Radiation Physics

Almobarak, Bilal (author): Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center,Institutionen för biomedicin,Institute of Biomedicine

Elf, Anna-Karin (author): Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery

Johanson, Viktor, 1958 (author): Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery

Elias, Erik, 1979 (author): Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery

Kristiansson, Erik, 1978 (author): Chalmers tekniska högskola,Chalmers University of Technology

Forssell-Aronsson, Eva, 1961 (author): Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för radiofysik,Sahlgrenska Cancer Center,Institute of Clinical Sciences, Department of Radiation Physics

Nilsson, Ola, 1957 (author): Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center,Institutionen för biomedicin,Institute of Biomedicine

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2019
2019
English.
In: Endocrine-Related Cancer. - 1479-6821 .- 1351-0088. ; 26:4, s. 437-449

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Journal article (peer-reviewed)

Abstract Subject headings

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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Urologi och njurmedicin (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Urology and Nephrology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Radiologi och bildbehandling (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Radiology, Nuclear Medicine and Medical Imaging (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Keyword

neuroendocrine tumours
Lu-177-octreotate therapy
peptide receptor radionuclide therapy
ganetespib
Hsp90 inhibitor

Publication and Content Type

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Hematology

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Urology and Neph ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Cancer and Oncol ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Radiology Nuclea ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

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