ABSTRACT Neuroendocrine tumors (NETs) are hormone secreting neoplasms, including carcinoids, islet cell tumors, and medullary thyroid cancers. Management of NETs has been problematic since the disease is often diagnosed at metastatic stage when therapeutic options are limited. While, Positron Emission Tomography (PET)/CT based on the radiolabeled sugar analogue [18F]FDG is used to diagnose and stage NETs, it is often suboptimal due to low metabolic activity in these tumors. More recently, a newly approved technique for NET imaging, [68Ga]DOTATATE PET/CT, that specifically targets somatostatin receptor subtype 2 (SSTR2) is becoming more standard, as many NETs overexpress SSTR2. This imaging technique plays an important role in patient care as the outcomes are used to stratify patients for SSTR2 targeted treatment. However, NET patients with diminished SSTR2 expression as determined by imaging are not eligible for any type of SSTR2-specific treatment. Herein, we propose a method to enhance and enable targeted therapies for these patients. We have found that the epigenetic modifiers such as histone deacetylase (HDAC) inhibitors: thailandepsin A (TDP-A) and valproic acid (VPA) can upregulate the expression of SSTR2 in NETs. Our approach will likely result in a new targeted treatment strategy for NET patients who have very limited therapeutic options. The specific objective of this application is to rigorously characterize the HDAC inhibitors enhanced SSTR2 expression in NET cell lines and xenografts. We propose to assess these changes using gold standard biological methods and will then develop strategies to validate this upregulation in vivo in a longitudinal, non-invasive manner using existing state-of-the-art clinically translatable imaging techniques. Our central hypothesis is that these HDAC inhibitors can upregulate SSTR2 which can be assessed by advanced imaging techniques thus making patients eligible for subsequent SSTR2 targeted therapy with the radiotherapeutic [177Lu]DOTATATE. To test this hypothesis, we propose to fully evaluate this targeted therapy in two Specific Aims. First, we will use a non- cytotoxic dose of TDP-A and VPA to induce SSTR2 expression in NET cell lines and elucidate the receptor density and functional activity. In this aim, we will also assess the SSTR2 basal expression in NET patients’ tissue microarray (TMA) blocks (Aim1). Next, we will test the in vivo [68Ga]DOTATATE uptake and biodistribution as a result of target upregulation using NET xenografts. We will conduct a highly translational method of imaging of SSTR2 expression alterations in NET xenografts before and after treatment using [68Ga]DOTATATE small animal PET/CT (Aim2). Our long-term goal is to translate this novel strategy to achieve improved imaging and potential curative therapy through the specific targeting of enhanced SSTR2 expression.