Effect of epigenetic treatment on SST<sub>2</sub> expression in neuroendocrine tumour patients

Refardt, Julie; Klomp, Maria J.; Koetsveld, Peter M. van; Dogan, Fadime; Konijnenberg, Mark; Brabander, Tessa; Feelders, Richard A; Herder, Wouter W. de; Hofland, Leo J.; Hofland, Johannes

doi:10.1002/ctm2.957

Cited by 9 publications

(9 citation statements)

References 13 publications

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“…Several preclinical studies have demonstrated that epigenetic drugs can upregulate SST 2 expression in NET models ( 95 , 96 ). However, in a prospective clinical proof-of-concept trial involving 9 advanced NET patients with low SST expression, we were unable to show that epigenetic treatment with the histone deacetylase inhibitor valproic acid and the DNA methyltransferase inhibitor hydralazine increased the tumor-uptake of 68 Ga-DOTATATE, thereby contradicting the in vitro data ( 97 ).…”

Section: Prrt—the Next Levelmentioning

confidence: 76%

Peptide Receptor Radionuclide Therapy

Hofland

Brabander

Verburg

et al. 2022

The Journal of Clinical Endocrinology &Amp; Metabolism

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The concept of using a targeting molecule labeled with a diagnostic radionuclide for using PET or SPECT imaging with the potential to demonstrate that tumoricidal radiation can be delivered to tumoral sites by administration of the same or a similar targeting molecule labeled with a therapeutic radionuclide is named “theranostics”. Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs (SSAs) is a well-established second/third-line theranostic treatment for somatostatin receptor-positive well-differentiated (neuro-)endocrine neoplasms (NENs). PRRT with 177Lu-DOTATATE was approved by the regulatory authorities in 2017 & 2018 for selected patients with low-grade well-differentiated gastroenteropancreatic (GEP) NENs. It improves progression-free survival as well as quality of life of GEP NEN patients. Favorable symptomatic and biochemical responses using PRRT with 177Lu-DOTATATE have also been reported in patients with functioning metastatic GEP NENs like metastatic insulinomas, VIPomas, glucagonomas, gastrinomas and patients with carcinoid syndrome. This therapy might also become a valuable therapeutic option for inoperable low grade bronchopulmonary (BP) NENs, inoperable, or progressive pheochromocytomas and paragangliomas and medullary thyroid carcinomas. First-line PRRT with 177Lu-DOTATATE and combinations of this therapy with cytotoxic drugs are currently under investigation. New radiolabeled somatostatin receptor ligands include SSAs coupled with alpha radiation emitting radionuclides and somatostatin receptor antagonists coupled with radionuclides.

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Section: Prrt—the Next Levelmentioning

confidence: 76%

Peptide Receptor Radionuclide Therapy

Hofland

Brabander

Verburg

et al. 2022

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…This HDAC inhibitor, however, is not the most efficacious epigenetic drug to induce [ 68 Ga]Ga-DOTA-TATE or [ 68 Ga]Ga-DOTA-TOC uptake 17 , 25 . Short‐term epigenetic treatment with VPA and the DNMT inhibitor hydralazine had no stimulating effect on [ 68 Ga]Ga‐DOTA-TATE uptake in nine patients with well‐differentiated neuroendocrine tumors with low baseline expression of SSTRs 69 . These studies demonstrate that further investigations are required to fully appreciate and optimize the clinical potential for epigenetic drugs in improving PRRT.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic drugs in somatostatin type 2 receptor radionuclide theranostics and radiation transcriptomics in mouse pheochromocytoma models

Ullrich¹,

Richter²,

Liers³

et al. 2023

Theranostics

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Pheochromocytomas and paragangliomas (PCCs/PGLs) are catecholamine-producing tumors. In inoperable and metastatic cases, somatostatin type 2 receptor (SSTR2) expression allows for peptide receptor radionuclide therapy with [ 177 Lu]Lu-DOTA-TATE. Insufficient receptor levels, however, limit treatment efficacy. This study evaluates whether the epigenetic drugs valproic acid (VPA) and 5-Aza-2'-deoxycytidine (DAC) modulate SSTR2 levels and sensitivity to [ 177 Lu]Lu-DOTA-TATE in two mouse PCC models (MPC and MTT). Methods: Drug-effects on Sstr2/SSTR2 were investigated in terms of promoter methylation, mRNA and protein levels, and radiotracer binding. Radiotracer uptake was measured in subcutaneous allografts in mice using PET and SPECT imaging. Tumor growth and gene expression (RNAseq) were characterized after drug treatments. Results: DAC alone and in combination with VPA increased SSTR2 levels along with radiotracer uptake in vitro in MPC (high-SSTR2) and MTT cells (low-SSTR2). MTT but not MPC allografts responded to DAC and VPA combination with significantly elevated radiotracer uptake, although activity concentrations remained far below those in MPC tumors. In both models, combination of DAC, VPA and [ 177 Lu]Lu-DOTA-TATE was associated with additive effects on tumor growth delay and specific transcriptional responses in gene sets involved in cancer and treatment resistance. Effects of epigenetic drugs were unrelated to CpG island methylation of the Sstr2 promoter. Conclusion:This study demonstrates that SSTR2 induction in mouse pheochromocytoma models has some therapeutic benefit that occurs via yet unknown mechanisms. Transcriptional changes in tumor allografts associated with epigenetic treatment and [ 177 Lu]Lu-DOTA-TATE provide first insights into genetic responses of PCCs/PGLs, potentially useful for developing additional strategies to prevent tumor recurrence.

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“…Based on our findings, we would expect epigenetic drugs targeting the DNA methylation profile to be more effective in upregulating SST 2 than drugs targeting the histone modifications. However, one trial involving nine patients with NETs from different origin and low baseline SST 2 expression showed no SST 2 upregulation upon epigenetic treatment with DNA methyltransferase inhibitor hydralazine combined with histone deacetylase (HDAC) inhibitor valproic acid ( 23 ). Meanwhile, another small clinical trial involving five well-differentiated SI-NET patients with sufficient SST 2 expression showed a minor but significant increase in radiolabelled somatostatin analogue uptake after treatment with the HDAC inhibitor vorinostat ( 24 ).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic regulation of SST2 expression in small intestinal neuroendocrine tumors

et al. 2023

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BackgroundSomatostatin receptor type 2 (SST2) expression is critical for the diagnosis and treatment of neuroendocrine tumors and is associated with improved patient survival. Recent data suggest that epigenetic changes such as DNA methylation and histone modifications play an important role in regulating SST2 expression and tumorigenesis of NETs. However, there are limited data on the association between epigenetic marks and SST2 expression in small intestinal neuroendocrine tumors (SI-NETs).MethodsTissue samples from 16 patients diagnosed with SI-NETs and undergoing surgical resection of the primary tumor at Erasmus MC Rotterdam were analysed for SST2 expression levels and epigenetic marks surrounding the SST2 promoter region, i.e. DNA methylation and histone modifications H3K27me3 and H3K9ac. As a control, 13 normal SI-tissue samples were included.ResultsThe SI-NET samples had high SST2 protein and mRNA expression levels; a median (IQR) of 80% (70-95) SST2-positive cells and 8.2 times elevated SST2 mRNA expression level compared to normal SI-tissue (p=0.0042). In comparison to normal SI-tissue, DNA methylation levels and H3K27me3 levels were significantly lower at five out of the eight targeted CpG positions and at two out of the three examined locations within the SST2 gene promoter region of the SI-NET samples, respectively. No differences in the level of activating histone mark H3K9ac were observed between matched samples. While no correlation was found between histone modification marks and SST2 expression, SST2 mRNA expression levels correlated negatively with DNA methylation within the SST2 promoter region in both normal SI-tissue and SI-NETs (p=0.006 and p=0.04, respectively).ConclusionSI-NETs have lower SST2 promoter methylation levels and lower H3K27me3 methylation levels compared to normal SI-tissue. Moreover, in contrast to the absence of a correlation with SST2 protein expression levels, significant negative correlations were found between SST2 mRNA expression level and the mean level of DNA methylation within the SST2 promoter region in both normal SI-tissue and SI-NET tissue. These results indicate that DNA methylation might be involved in regulating SST2 expression. However, the role of histone modifications in SI-NETs remains elusive.

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Effect of epigenetic treatment on SST₂ expression in neuroendocrine tumour patients

Cited by 9 publications

References 13 publications

Peptide Receptor Radionuclide Therapy

Peptide Receptor Radionuclide Therapy

Epigenetic drugs in somatostatin type 2 receptor radionuclide theranostics and radiation transcriptomics in mouse pheochromocytoma models

Epigenetic regulation of SST2 expression in small intestinal neuroendocrine tumors

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Effect of epigenetic treatment on SST2 expression in neuroendocrine tumour patients

Cited by 9 publications

References 13 publications

Peptide Receptor Radionuclide Therapy

Peptide Receptor Radionuclide Therapy

Epigenetic drugs in somatostatin type 2 receptor radionuclide theranostics and radiation transcriptomics in mouse pheochromocytoma models

Epigenetic regulation of SST2 expression in small intestinal neuroendocrine tumors

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Effect of epigenetic treatment on SST₂ expression in neuroendocrine tumour patients