Comparing the Effect of Multiple Histone Deacetylase Inhibitors on SSTR2 Expression and [(111)In]In-DOTATATE Uptake in NET Cells

SIMPLE SUMMARY: Patients diagnosed with neuroendocrine tumors (NETs) are often treated with peptide receptor radionuclide therapy (PRRT). This therapy targets the somatostatin type-2 receptors (SSTR2) frequently overexpressed on these types of tumors. Although this therapy has proven to be effective, complete responses are rare and therapy improvement is desirable. We aimed to increase SSTR2 expression on NET cells, potentially increasing the number of patients eligible for SSTR2-targeted PRRT and improving clinical outcomes. We used histone deacetylase inhibitors (HDACis) to manipulate the epigenetic machinery and hereby aimed to increase SSTR2 gene transcription. Our results showed that the HDACis increased SSTR2 expression in several NET cell lines. Moreover, the uptake of radiolabeled DOTATATE, the tracer used for PRRT, was enhanced. The observed reversibility profile after HDACi withdrawal of the induced effects suggests that proper timing of HDACi treatment is likely essential. ABSTRACT: The aim of this study was to increase somatostatin type-2 receptor (SSTR2) expression on neuroendocrine tumor (NET) cells using histone deacetylase inhibitors (HDACis), potentially increasing the uptake of SSTR2-targeted radiopharmaceuticals and subsequently improving treatment efficacy of peptide receptor radionuclide therapy (PRRT). Human NET cell lines BON-1, NCI-H727, and GOT1 were treated with HDACis (i.e., CI-994, entinostat, LMK-235, mocetinostat, panobinostat, or valproic acid (VPA); entinostat and VPA were the HDACis tested in GOT1 cells) to examine SSTR2 mRNA expression levels and uptake of SSTR2-targeting radiotracer [(111)In]In-DOTATATE. Reversibility of the induced effects was examined after drug-withdrawal. Finally, the effect of VPA on radiosensitivity was investigated. A strong stimulatory effect in BON-1, NCI-H727, and GOT1 cells was observed after HDACi treatment, both on SSTR2 mRNA expression levels and [(111)In]In-DOTATATE uptake. The effects of the HDACis were largely reversible over a period of seven days, demonstrating largest reductions within the first day. The reversibility profile of the induced effects suggests that proper timing of HDACi treatment is most likely essential for a beneficial outcome. In addition to increasing SSTR2 expression levels, VPA enhanced the radiosensitivity of all cell lines. In conclusion, HDACi treatment increased SSTR2 expression, and radiosensitivity was also enhanced upon VPA treatment.