Epigenetic regulation of somatostatin receptors in neuroendocrine tumors: A Novel Therapeutic Approach?

The overexpression of somatostatin type-2 receptors (SSTR2) on neuroendocrine tumor (NET) cells forms a pivotal biomarker for theranostic approaches. Radiolabeled somatostatin analogues (SSAs), most frequently [68Ga]Ga-DOTATATE and [177Lu]Lu-DOTATATE for nuclear imaging and therapy, respectively, have shown to be of great importance for NET disease management. [177Lu]Lu-DOTATATE treatment, known as peptide receptor radionuclide therapy (PRRT), is EMA and FDA approved for unresectable or metastatic, progressive, well-differentiated SSTR2-positive gastroenteropancreatic NET patients. However, complete responses after therapy are rare and progressive disease is often observed. Approaches to further improve PRRT efficacy are thus of great need. The aim of the studies described in this thesis is to upregulate SSTR2 on NET cells by modulating the epigenetic machinery, in order to increase radiolabeled SSA uptake and ultimately improve treatment response. Furthermore, we aimed to gain more insights into the interaction between epigenetic marks and the regulation of SSTR2 expression. Our studies were performed preclinically using different NET cell lines. In addition to in vitro studies with these cell lines, mice with tumors derived from these cell lines and NET patient tissue samples were used. Furthermore, the effect of epigenetic drugs on the uptake of [68Ga]Ga-DOTATATE was investigated in NET patients.