Abstract
Background: To improve peptide receptor radionuclide therapy (PRRT), we aimed to enhance the expression of somatostatin type-2 receptors (SSTR2) in vitro and in vivo, using valproic acid (VPA). Methods: Human NCI-H69 small-cell lung carcinoma cells were treated with VPA, followed by [111In]In-DOTATATE uptake studies, RT-qPCR and immunohistochemistry analysis. Furthermore, NCI-H69 xenografted mice were treated with VPA or vehicle, followed by [177Lu]Lu-DOTATATE injection. Biodistribution studies were performed, and tissues were collected for further analysis. Results: VPA significantly increased SSTR2 expression in vitro. In animals, a statistically significant increased [177Lu]Lu-DOTATATE tumoral uptake was observed when VPA was administered eight hours before [177Lu]Lu-DOTATATE administration, but increased tumor SSTR2 expression levels were lacking. The animals also presented significantly higher [177Lu]Lu-DOTATATE blood levels, as well as an elevated renal tubular damage score. This suggests that the enhanced tumor uptake was presumably a consequence of the increased radiotracer circulation and the induced kidney damage. Conclusions: VPA increases SSTR2 expression in vitro. In vivo, the observed increase in tumoral [177Lu]Lu-DOTATATE uptake is not caused by SSTR2 upregulation, but rather by other mechanisms, e.g., an increased [177Lu]Lu-DOTATATE circulation time and renal toxicity. However, since both drugs are safely used in humans, the potential of VPA to improve PRRT remains open for investigation.
Highlights
SSTR2-mediated peptide receptor radionuclide therapy (PRRT) improved the progression-free survival of neuroendocrine tumors (NETs) patients, complete responses are rare [1,2]
We examined the effect of valproic acid (VPA) treatment on SSTR2 expression level and
We studied the effect of VPA and several other histone deacetylase inhibitors (HDACis) in BON-1, NCI-H727 and GOT1 cells [6], showing the superior effects of VPA
Summary
Peptide receptor radionuclide therapy (PRRT) is an approved and efficient therapy for patients with somatostatin type-2 receptor (SSTR2) positive neuroendocrine tumors (NETs). Lu-DOTATATE) is used, which binds with high affinity to the SSTR2 frequently overexpressed on NETs. SSTR2-mediated PRRT improved the progression-free survival of NET patients, complete responses are rare [1,2]. Research is performed to improve PRRT outcomes via the upregulation of the target receptor SSTR2, using inhibitors which target the epigenetic machinery. To improve peptide receptor radionuclide therapy (PRRT), we aimed to enhance the expression of somatostatin type-2 receptors (SSTR2) in vitro and in vivo, using valproic acid (VPA). Methods: Human NCI-H69 small-cell lung carcinoma cells were treated with VPA, followed by [111 In]In-DOTATATE uptake studies, RT-qPCR and immunohistochemistry analysis. NCI-H69 xenografted mice were treated with VPA or vehicle, followed by [177 Lu]Lu-DOTATATE injection. Biodistribution studies were performed, and tissues were collected for further analysis
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