Pulmonary Carcinoid Surface Receptor Modulation Using Histone Deacetylase Inhibitors

Abstract

Pulmonary carcinoids are a type of neuroendocrine tumor (NET) accounting for 1–2% of lung cancer cases. Currently, Positron Emission Tomography (PET)/CT based on the radiolabeled sugar analogue [18F]-FDG is used to diagnose and stage pulmonary carcinoids, but is suboptimal due to low metabolic activity in these tumors. A new technique for pulmonary carcinoid imaging, using PET/CT with radiolabeled somatostatin analogs that specifically target somatostatin receptor subtype 2 (SSTR2), is becoming more standard, as many tumors overexpress SSTR2. However, pulmonary carcinoid patients with diminished SSTR2 expression are not eligible for this imaging or any type of SSTR2-specific treatment. We have found that histone deacetylase (HDAC) inhibitors can upregulate the expression of SSTR2 in pulmonary carcinoid cell lines. In this study, we used a non-cytotoxic dose of HDAC inhibitors to induce pulmonary carcinoid SSTR2 expression in which we confirmed in vitro and in vivo. A non-cytotoxic dose of the HDAC inhibitors: thailandepsin A (TDP-A), romidepsin (FK228), suberoylanilide hydroxamic acid (SAHA), AB3, and valproic acid (VPA) were administered to promote SSTR2 expression in pulmonary carcinoid cell lines and xenografts. This SSTR2 upregulation technique using HDAC inhibitors could enhance radiolabeled somatostatin analog-based imaging and the development of potential targeted treatments for pulmonary carcinoid patients with marginal or diminished SSTR2 expression.

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

“…In line with our results, previous studies also reported on the effects of HDACi treatment, showing SSTR2 upregulation and/or increased uptake of radiolabeled SSAs in different NET models [ 16 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. However, the strength of our study was the use of HDACi-specific and cell line-based IC 50 values allowing for a comparison of effects induced by HDACis targeting different classes of HDAC enzymes.…”

Neuroendocrine syndrome in bronchial carcinoid tumors

“…Bronchial carcinoid tumors have a rate of occurrence of 10-20% out of all carcinoids, being rarer when compared with intestinal carcinoids (9). Atypical carcinoid tumor appears in 2% of all cases (10,11), the mean age at diagnostic being 45-55 years.…”

177Lu-DOTA-EB-TATE, a Radiolabeled Analogue of Somatostatin Receptor Type 2, for the Imaging and Treatment of Thyroid Cancer

“…Therefore, we investigated potential ways to upregulate SSTR2 in preclinical models and tested SST analogs characterized by different binding capacities and pharmacokinetics. SSTR2 expression has been shown to be regulated by epigenetic modulators (21,(35)(36)(37)(38). We screened three epigenetic regulators of SSTR2 expression and utilized the most potent among them-HDAC inhibitor VAC, which is commonly used for the treatment of epilepsy and shown to have an excellent safety profile (39).…”