Gastero-entero-pancreatic NETs (GEP-NETs) are slow growing tumors that are often diagnosed at late stage, making them difficult to treat. A current primary therapy for GEP-NETs is use of activators of Somatostatin receptor 2 (Sstr2), which suppress hormonal secretion and tumor cell proliferation in inoperable tumors. Sstr2 is a peptide receptor that is often highly expressed in GEP-NETs. A promising, recently approved therapy for GEP-NETs makes use of radioactive forms of Sstr2 activators (called PRRT), which deliver radiation specifically to the tumors. However, this therapy often is not curative because of residual, untargeted tumor, and is limited to patients with high-level expression of...

Read More

Gastero-entero-pancreatic NETs (GEP-NETs) are slow growing tumors that are often diagnosed at late stage, making them difficult to treat. A current primary therapy for GEP-NETs is use of activators of Somatostatin receptor 2 (Sstr2), which suppress hormonal secretion and tumor cell proliferation in inoperable tumors. Sstr2 is a peptide receptor that is often highly expressed in GEP-NETs. A promising, recently approved therapy for GEP-NETs makes use of radioactive forms of Sstr2 activators (called PRRT), which deliver radiation specifically to the tumors. However, this therapy often is not curative because of residual, untargeted tumor, and is limited to patients with high-level expression of Sstr2 in their tumors prior to therapy. In this project, we will explore ways to increase Sstr2 expression in GEP-NET tumors, thereby widening the patient population suited for PRRT and increasing the efficacy of treatment. Specifically, we will leverage recent published data indicating that Sstr2 expression may be suppressed by epigenetic enzymes, and our new findings indicating that Sstr2 is subjected to degradation by proteins within the Wnt signaling pathway. We will demonstrate that combining inhibitors of these two pathways provides a maximal increase in Sstr2 expression in vitro and in pre-clinical tumor models, and also significantly enhances PRRT efficacy. Importantly, our inhibitory strategies will make use of drugs either already approved or in current clinical trials for use in other cancers, thus offering a quick path to clinical translation.

Read Less