Epigenetic potentiation of somatostatin-2 by guadecitabine in neuroendocrine neoplasias as a novel method to allow delivery of peptide receptor radiotherapy

Evans, Joanne; Beaumont, Jamie; Braga, Marta; Masrour, Nahal; Mauri, Francesco; Beckley, Alice; Butt, Shamus; Karali, Christina S.; Cawthorne, Christopher; Archibald, Stephen J.; Aboagye, Eric O.; Sharma, Rohini

doi:10.1016/j.ejca.2022.09.009

Cited by 11 publications

(17 citation statements)

References 36 publications

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“…Our current study only focused on SI-NETs, and it is therefore unknown if our findings would have been similar in NETs of other origins. In line with our results, a correlation was found between the level of DNA methylation in the SST 2 promoter and SST 2 expression levels in pancreatic NETs ( 26 ). In contrast, the direct role of histone marks in regulation SST 2 in pancreatic NETs remains unclear.…”

Section: Discussionsupporting

confidence: 91%

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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Section: Discussionsupporting

confidence: 91%

Epigenetic regulation of SST2 expression in small intestinal neuroendocrine tumors

et al. 2023

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“…The authors report increased cytotoxicity with combination therapy compared with [177Lu]Lu-DOTA-TATE alone 19. We extended these findings into a mouse model of NEN using BON-1 cells (low basal expression SSTR2) and QGP-1 cells (high basal expression SSTR2) using guadecitabine to illustrate a 70% increase in the SSTR2-directed radioligand, [ 18 F]-FET-βAG-TOCA in BON-1 tumour model 21 22. We therefore demonstrated that PET imaging can be used as a biomarker of demethylation of SSTR2 21.…”

Section: Introductionmentioning

confidence: 66%

Study protocol of LANTana: a phase Ib study to investigate epigenetic modification of somatostatin receptor-2 with ASTX727 to improve therapeutic outcome with [177Lu]Lu-DOTA-TATE in patients with metastatic neuroendocrine tumours, UK

Murphy,

Chander,

Martinez

et al. 2023

BMJ Open

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IntroductionSuitability for peptide receptor radionuclide therapy (PRRT) for neuroendocrine neoplasia (NENs) depends on presence of somatostatin receptor-2 (SSTR2) determined by [68Ga]Ga-DOTA-peptide-positron emission tomography (PET). Some patients have low or no uptake on [68Ga]Ga-DOTA-peptide-PET, precluding PRRT. The upstream promoter region of SSRT2 is methylated, with percentage of methylation correlating with SSTR2 expression. Demethylating agents increase uptake on PET imaging in vivo such that tumours previously negative on PET become positive, correlating with a dose dependent increase in tumorous SSTR2 expression. LANTana will determine whether treatment with the demethylating agent, ASTX727, results in re-expression of SSTR2 using [68Ga]Ga-DOTA-peptide-PET to image epigenetic modification of the SSTR2 locus, allowing subsequent PRRT.Methods and analysis27 participants with a histological diagnosis of NEN (Ki67<55%) with no or low uptake on baseline [68Ga]Ga-DOTA-TATE-PET/CT will be recruited. Patients will receive 5 days of ASTX727 (fixed dose 35 mg decitabine+100 mg cedazuridine). [68Ga]Ga-DOTA-peptide-PET/CT will be repeated day 8±2; where there is significant uptake greater than liver in most lesions, PRRT will be administered. Primary objective is to determine re-expression of SSTR2 on PET imaging. Tolerability, progression-free survival, overall response and quality of life will be assessed. Methylation in peripheral blood mononuclear cells and tumorous methylation will be evaluated.Ethics and disseminationLANTana has ethical approval from Leeds West Research Ethics Committee (REC Reference: 21/YH/0247).Sponsored by Imperial College London and funded by Advanced Accelerator Applications pharmaceuticals. Results will be presented at conferences and submitted to peer-reviewed journals for publication and will be available on ClinicalTrials.gov.Trial registration numbersEUDRACT number: 2020-003800-15,NCT05178693.

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“…(Ohki et al, 2014) Increased Somatostatin Receptor 2 (SSTR2) methylation was reported in 27 human PNET samples compared to non-NET tissue, and this was inversely correlated to SSTR2 expression by immunohistochemistry. (Evans et al, 2022a) Recently, DAXX was reported to be hypermethylated in almost all PNETs. (Yachida et al, 2022) Overall, half of these studies have investigated protein and/or mRNA expression with their relationships to promoter and enhancer methylation, and have reported a variable association between gene methylation and expression.…”

Section: Dna Methylation In Pnetsmentioning

confidence: 99%

“…(Yachida et al, 2022) Overall, half of these studies have investigated protein and/or mRNA expression with their relationships to promoter and enhancer methylation, and have reported a variable association between gene methylation and expression. (Wild et al, 2003, Malpeli et al, 2011, Schmitt et al, 2014, Ohki et al, 2014, Ushiku et al, 2016, Tirosh et al, 2019, Bartsch et al, 2000, Ban et al, 2022, Zhang et al, 2020, Marinoni et al, 2017, Cros et al, 2016, Dejeux et al, 2009, Yachida et al, 2022, Evans et al, 2022a Five of these studies have investigated DNA hypomethylation in PNETs, using long interspersed nuclear elements 1 (LINE-1) and Alu hypomethylation as a surrogate for global DNA methylation. (Marinoni et al, 2017, Choi et al, 2007, Stefanoli et al, 2014, Yachida et al, 2022, Stricker et al, 2012 LINE-1, the most abundant LINE, is located non-randomly in GC-poor regions of DNA, approximately 6000kb long and encodes for two proteins which catalyse retro-transposition i.e.…”

Section: Dna Methylation In Pnetsmentioning

confidence: 99%

“…(Hu et al, 2021) These drugs have been assessed using the human PNET cell lines (BON-1 (derived from a lymph node with metastatic insulinoma) (Townsend et al, 1993), QGP-1 (derived from a pancreatic somatostatinoma) (Kaku et al, 1980) and/or CM (derived from ascitic fluid from a metastatic insulinoma)) (Baroni et al, 1999) and were found to increase expression of RASSF1A (Malpeli et al, 2011) and SSTR2 in vitro and in an in vivo (mouse xenograft) model. (Evans et al, 2022a, Taelman et al, 2016 Despite being used clinically for other malignancies e.g. haematological malignancies, this class of drug has only been used in one small clinical trial of nine patients with NETs, including two patients with PNETs, who exhibited low baseline SSTR2 expression on 68Ga-DOTATE imaging.…”

Section: Therapeutic Targeting Of Aberrant Dna Methylationmentioning

confidence: 99%

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The role of DNA methylation in human pancreatic neuroendocrine tumours

2023

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Pancreatic neuroendocrine tumours (PNETs) are the second most common pancreatic tumour. However, relatively little is known about their tumourigenic drivers, other than mutations involving the Multiple Endocrine Neoplasia 1 (MEN1), ATRX Chromatin Remodeler (ATRX), and Death Domain Associated Protein (DAXX) genes, which are found in ~ 40% of sporadic PNETs. PNETs have a low mutational burden, thereby suggesting that other factors likely contribute to their development, including epigenetic regulators. One such epigenetic process, DNA methylation, silences gene transcription via 5’methylcytosine (5mC), and this is usually facilitated by DNA methyltransferase enzymes at CpG rich areas around gene promoters. However, 5’hydroxymethylcytosine (5hmC), which is the first epigenetic mark during cytosine demethylation, and opposes the function of 5mC, is associated with gene transcription, although the significance of this remains unknown, as it is indistinguishable from 5mC when conventional bisulfite conversion techniques are solely used. Advances in array-based technologies have facilitated investigation of PNET methylomes and enabled PNETs to be clustered by methylome signatures, which has assisted in prognosis and discovery of new aberrantly regulated genes contributing to tumourigenesis. This review will discuss the biology of DNA methylation, its role in PNET development, and impact on prognostication and discovery of epigenome-targeted therapies.

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Epigenetic potentiation of somatostatin-2 by guadecitabine in neuroendocrine neoplasias as a novel method to allow delivery of peptide receptor radiotherapy

Cited by 11 publications

References 36 publications

Epigenetic regulation of SST2 expression in small intestinal neuroendocrine tumors

Epigenetic regulation of SST2 expression in small intestinal neuroendocrine tumors

Study protocol of LANTana: a phase Ib study to investigate epigenetic modification of somatostatin receptor-2 with ASTX727 to improve therapeutic outcome with [177Lu]Lu-DOTA-TATE in patients with metastatic neuroendocrine tumours, UK

The role of DNA methylation in human pancreatic neuroendocrine tumours

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