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.
journal_name
Endocr Relat Cancerjournal_title
Endocrine-related cancerauthors
Hofving T,Sandblom V,Arvidsson Y,Shubbar E,Altiparmak G,Swanpalmer J,Almobarak B,Elf AK,Johanson V,Elias E,Kristiansson E,Forssell-Aronsson E,Nilsson Odoi
10.1530/ERC-18-0509subject
Has Abstractpub_date
2019-04-01 00:00:00pages
437-449issue
4eissn
1351-0088issn
1479-6821pii
ERC-18-0509journal_volume
26pub_type
杂志文章abstract::Bone metastases are common in advanced prostate cancer patients, but mechanisms by which specific pro-metastatic skeletal niches are formed before tumor cell homing are unclear. We aimed to analyze the effects of proteins secreted by primary prostate tumors on the bone microenvironment before the settlement and propag...
journal_title:Endocrine-related cancer
pub_type: 杂志文章
doi:10.1530/ERC-20-0116
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abstract::The androgen receptor (AR) is well known to play a central role in the pathogenesis of prostate cancer (PCa). In several studies, AR was overexpressed in castration-resistant PCa (CRPC). However, the mechanism of AR overexpression in CRPC is not fully elucidated. Y-box binding protein-1 (YB-1) is a pleiotropic transcr...
journal_title:Endocrine-related cancer
pub_type: 杂志文章
doi:10.1530/ERC-11-0017
更新日期:2011-07-11 00:00:00
abstract::Mouse models of prostate cancer (PCa) are critical for understanding the biology of PCa initiation, progression, and treatment modalities. Here, we summarize recent advances in PCa mouse models that led to new insights into specific gene functions in PCa. For example, the study of transgenic mice with TMPRSS2/ERG, an ...
journal_title:Endocrine-related cancer
pub_type: 杂志文章,评审
doi:10.1530/ERC-12-0285
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abstract::Pancreatic endocrine tumors (PET) represent a heterogenous group of neoplasms. Although surgical resection is considered a safe and effective treatment for many PET, therapeutic options for inoperable and progressive PET are limited. The expression of heat-shock protein (HSP) 90 was investigated in 120 clinically and ...
journal_title:Endocrine-related cancer
pub_type: 杂志文章
doi:10.1530/ERC-11-0227
更新日期:2012-05-03 00:00:00
abstract::Metastatic tumor cells can interfere directly with the function of bone cells involved in normal bone remodeling or indirectly by influencing the behavior of hematopoietic, stromal and other cells in bone marrow that interact with bone cells. Recent studies of metastatic cancer have revealed that tumor cells interact ...
journal_title:Endocrine-related cancer
pub_type: 杂志文章,评审
doi:10.1677/erc.0.0060333
更新日期:1999-09-01 00:00:00
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journal_title:Endocrine-related cancer
pub_type: 杂志文章
doi:10.1677/ERC-09-0134
更新日期:2010-02-18 00:00:00
abstract::Thyroid cancer is the most frequent endocrine tumor with a growing incidence worldwide. However, common diagnostic strategy for thyroid cancer classification is hardly to make a proper diagnosis in some cases. To assist classical approach, this study used metabolomics to screen and validate biomarkers from serum and u...
journal_title:Endocrine-related cancer
pub_type: 杂志文章
doi:10.1530/ERC-19-0344
更新日期:2019-12-01 00:00:00
abstract::Selection of novel molecular markers is an important goal of cancer genomics studies. The aim of our analysis was to apply the multivariate bioinformatical tools to rank the genes - potential markers of papillary thyroid cancer (PTC) according to their diagnostic usefulness. We also assessed the accuracy of benign/mal...
journal_title:Endocrine-related cancer
pub_type: 杂志文章
doi:10.1677/ERC-06-0048
更新日期:2007-09-01 00:00:00
abstract::Non-functioning pituitary adenomas, recently alternatively termed pituitary neuroendocrine tumours (NFpitNETs), are mostly benign neoplasms that are not associated with a hormonal hypersecretory syndrome. The clinical spectrum of NFpitNETs varies from completely asymptomatic to the development of panhypopituitarism an...
journal_title:Endocrine-related cancer
pub_type: 杂志文章,评审
doi:10.1530/ERC-20-0136
更新日期:2020-10-01 00:00:00
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journal_title:Endocrine-related cancer
pub_type: 杂志文章,评审
doi:10.1677/erc.0.0060271
更新日期:1999-06-01 00:00:00
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journal_title:Endocrine-related cancer
pub_type: 杂志文章,评审
doi:10.1530/ERC-12-0067
更新日期:2012-09-05 00:00:00
abstract::Pancreatic neuroendocrine neoplasms (PNENs) constitute a rare tumour entity, and prognosis and treatment options depend on tumour-mediating hallmarks such as angiogenesis, proliferation rate and resistance to apoptosis. The molecular pathways that determine the malignant phenotype are still insufficiently understood a...
journal_title:Endocrine-related cancer
pub_type: 杂志文章
doi:10.1530/ERC-14-0152
更新日期:2014-01-01 00:00:00
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journal_title:Endocrine-related cancer
pub_type: 杂志文章
doi:10.1530/ERC-14-0537
更新日期:2015-04-01 00:00:00
abstract::Imatinib mesylate (IM), a small molecule that is a selective inhibitor of the ABL, platelet derived growth factor receptor (PDGFR-R) and stem cell ligand receptor (c-kit) tyrosine kinases (TK). IM was also found to inhibit the TK activity of BCR/ABL fusion protein produced in chronic myelogenous leukemia, with marked ...
journal_title:Endocrine-related cancer
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1677/erc.1.01124
更新日期:2006-06-01 00:00:00
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journal_title:Endocrine-related cancer
pub_type: 杂志文章
doi:10.1530/ERC-19-0129
更新日期:2019-07-01 00:00:00
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journal_title:Endocrine-related cancer
pub_type: 杂志文章
doi:10.1530/ERC-18-0314
更新日期:2019-03-01 00:00:00
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journal_title:Endocrine-related cancer
pub_type: 杂志文章
doi:10.1677/ERC-08-0059
更新日期:2009-03-01 00:00:00
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journal_title:Endocrine-related cancer
pub_type: 杂志文章
doi:10.1530/ERC-14-0454
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journal_title:Endocrine-related cancer
pub_type: 杂志文章
doi:10.1530/ERC-14-0032
更新日期:2014-05-06 00:00:00
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journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
pub_type: 杂志文章
doi:10.1677/erc.1.00808
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journal_title:Endocrine-related cancer
pub_type: 杂志文章,评审
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journal_title:Endocrine-related cancer
pub_type: 杂志文章,评审
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journal_title:Endocrine-related cancer
pub_type: 杂志文章
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journal_title:Endocrine-related cancer
pub_type: 杂志文章,评审
doi:10.1677/erc.1.01290
更新日期:2006-12-01 00:00:00
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journal_title:Endocrine-related cancer
pub_type: 杂志文章
doi:10.1530/ERC-17-0196
更新日期:2017-08-01 00:00:00
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journal_title:Endocrine-related cancer
pub_type: 杂志文章,评审
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更新日期:2017-07-01 00:00:00
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journal_title:Endocrine-related cancer
pub_type: 杂志文章,评审
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journal_title:Endocrine-related cancer
pub_type: 杂志文章
doi:10.1677/ERC-09-0308
更新日期:2010-11-30 00:00:00
abstract::The clinical course of medullary thyroid carcinoma (MTC) associated with the MEN2A syndrome as well as of sporadic MTC shows considerable heterogeneity. The disease picture varies not only between the same RET proto-oncogene mutation carriers but also among sporadic MTC patients with no RET germinal mutations, which s...
journal_title:Endocrine-related cancer
pub_type: 杂志文章
doi:10.1530/ERC-17-0452
更新日期:2018-04-01 00:00:00