Effect of epigenetic treatment on SST 2 expression in neuroendocrine tumour patients

Abstract

Dear Editor, Several preclinical studies have uncovered that epige-netic drugs can upregulate somatostatin receptor subtype 2 (SST 2) expression in neuroendocrine tumour (NET) models, 1,2 which could be of eminent importance for NET patients with low tumoural SST expression. In a prospective clinical proof-of-concept trial involving nine advanced NET patients with low SST expression, we were able to show that epigenetic treatment with the histone deacetylase (HDAC) inhibitor valproic acid and the DNA methyltransferase (DNMT) inhibitor hydralazine did not lead to an increase in tumour-uptake of 68 Ga-DOTATATE, contradicting the in vitro data. A prerequisite for the treatment of advanced NETs with (radiolabelled) somatostatin analogues (SSA) is the expression of SST 2 on the tumour cell surface, providing rationale for the inferior outcome in patients with low uptake on functional SST imaging. 3 Several previous in vitro studies and one in vivo study achieved stimulation of SST 2 expression levels and binding of SSAs by increasing his-tone acetylation levels and reducing DNA methylation of the SST 2 gene promoter region in NET cells by epigenetic drugs. 1,2,4 Despite these promising results, there are only data from one study showing limited increase of 68 Ga-DOTATOC uptake by HDAC inhibitor vorinostat in five NET patients already expressing SST at baseline. 5 In the present study, which was approved by the Ethics Committee of the Erasmus Medical Center Rotterdam and registered at the Netherlands Trial Register (NL7726), nine patients with advanced NETs (Table 1) and low SST expression at baseline on 68 Ga-DOTATATE/PET (Table 2), defined as tumour uptake below or equal to the physiological uptake in the liver, were included and provided written informed consent. Patients were treated for 14 days simultaneously with the HDAC inhibitor valproic acid (30-mg/kg body weight/day, max. 3000 mg/day) and the DNMT inhibitor hydralazine (150 mg/day). One week after start of treatment, valproic acid dosage was This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. TA B L E 1 Baseline characteristics of the neuroendocrine tumour patients included in the clinical trial. Values are shown as median (interquartile range [IQR]) or number (%) Patient characteristics Total (n = 9) Age, years (IQR) 67 (54, 75) Sex (male), n (%) 5 (56) Origin Pancreas NET, n (%) 2 (22) Small intestinal NET, n (%) 1 (11) Lung NET, n (%) 4 (44) Rectum NET, n (%) 1 (11) Thymus NET, n (%) 1 (11) Metastases Lymph nodes, n (%) 9 (100) Liver, n (%) 5 (56) Mesenterial, n (%) 1 (11) Bone, n (%) 3 (33) Lung, n (%) 1 (11) Other, n (%) 4 (44) Ki67 index 0%-2%, n (%) 3 (33) 5%-10%, n (%) 4 (44) 30% 1 (11) Unknown 1 (11) Grading G1, n (%) 4 (44) G2, n (%) 4 (44) G3, n (%) 1 (11) Previous treatments Surgery, n (%) 3 (33) Somatostatin analogue, n (%) 2 (22) Chemotherapy, n (%) 1 (11) Other, n (%) 3 (33) Abbreviations: Bpm, beats per minute; n, number; NET, neuroendocrine tumour; IQR, interquartile range; SUV, standard uptake values. Clin. Transl. Med. 2022;12:e957. wileyonlinelibrary.com/journal/ctm2 1 of 5 https://doi.