Pulmonary Carcinoid Surface Receptor Modulation Using Histone Deacetylase Inhibitors.

Rachael E Guenter,Eric Y Cheng,Danilea M Carmona Matos,X Margaret Liu,Jason Whitt,Tolulope Aweda,Herbert Chen,Suzanne E Lapi,Renata Jaskula-Sztul,Alexander W Chang

doi:10.3390/cancers11060767

Rachael E Guenter, Eric Y Cheng + Show 8 more

Open Access

https://doi.org/10.3390/cancers11060767

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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.

Highlights

The leading cause of cancer-related deaths worldwide is currently attributed to lung cancer, with pulmonary carcinoids accounting for 1–2% of all cases [1]
Somatostatin is an anti-cancer neuropeptide, which is associated with the prevention of hormone and growth factor secretions that contribute to tumor growth, inhibition of tumor cell proliferation, and the induction of apoptosis mediated by the five different SST receptor subtypes (SSTR1-5) [8,9]
We have found that histone deacetylase (HDAC) inhibitors can increase the expression of somatostatin receptor subtype 2 (SSTR2) in pulmonary carcinoid cell lines

Summary

Introduction

The leading cause of cancer-related deaths worldwide is currently attributed to lung cancer, with pulmonary carcinoids accounting for 1–2% of all cases [1]. NET imaging using PET/CT with radiolabeled somatostatin analogs that target somatostatin receptor subtype 2 (SSTR2) is becoming more standard as many NETs overexpress. Most prominently, [68 Ga]DOTATATE binds to SSTR2 with an order of magnitude higher in affinity than other [68 Ga]-DOTA-peptides [10,11,12]. This suggests that a higher incidence and density of SSTR2 would be beneficial for imaging and treating patients [8]. As the majority of pulmonary carcinoid patients have low or undetectable SSTR2 expression, the targeting might be inconsistent and peptide receptor radiotherapy (PRRT) can be limited only to patients with high level of SSTR2 [13].

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