Applying HDACis to increase SSTR2 expression and radiolabeled DOTA-TATE uptake: from cells to mice

Aims: This study aimed to evaluate the effect of histone deacetylase (HDAC) inhibitors (HDACis) on somatostatin receptor type-2 (SSTR2) expression and uptake of [¹¹¹In]In-/[¹⁷⁷Lu]Lu-DOTA-TATE in vitro and in vivo.

Materials and Methods: Human cell lines NCI-H69 (small-cell lung carcinoma) and BON-1 (pancreatic neuroendocrine tumor) were treated with various HDACis, including entinostat, mocetinostat (MOC), LMK-235, CI-994, and panobinostat (PAN). SSTR2 mRNA levels and [¹¹¹In]In-DOTA-TATE uptake were measured. Additionally, NCI-H69 and BON-1 tumor-bearing mice received HDACi or vehicle treatment, followed by radiolabeled DOTA-TATE injection and biodistribution studies. SSTR2 and HDAC mRNA expression levels in xenografts and the cell lines NCI-H69, BON-1, NCI-H727 (human pulmonary carcinoid), and GOT1 (human midgut neuroendocrine tumor) were also analyzed.

Key Findings: HDACi treatment produced expected effects in vitro, including increased SSTR2 expression. However, in vivo, HDACi treatment did not significantly enhance tumoral DOTA-TATE uptake in NCI-H69 tumor-bearing mice. Tumoral SSTR2 mRNA and/or protein levels increased significantly following treatment with MOC, CI-994, and PAN, with upregulation observed up to 2.1- and 1.3-fold, respectively. In PAN-treated BON-1 xenografts, only SSTR2 mRNA expression was elevated. Comparative analysis of HDAC and SSTR2 expression in BON-1 and NCI-H69 xenografts revealed higher expression of 6 out of 11 HDACs in BON-1 xenografts. Notably, HDAC3 expression showed a strong inverse correlation with SSTR2 expression (Pearson r = -0.92) across the studied cell lines.

Significance: While HDACi treatment increased SSTR2 expression in a context-dependent manner, it did not enhance tumoral uptake of radiolabeled DOTA-TATE in vivo. These findings suggest that HDACis can modulate SSTR2 expression but may not significantly impact radiolabeled DOTA-TATE uptake for therapeutic applications.