Pancreatic neuroendocrine tumors (PNET) express high levels of somatostatin receptor type 2 (SSTR2), a unique target for both tumor imaging and therapy. This surface expression is lost in metastatic high-grade PNETs, making patients ineligible for SSTR2-targeted 177 Lutetium (Lu)-DOTATATE peptide receptor radionuclide therapy (PRRT), and represents an unmet clinical need. Here, we aimed to restore SSTR2 expression through the reversal of inhibitory epigenetic gene silencing to improve tumor responsiveness to PRRT. We first assessed human SSTR2 promoter methylation and expression levels in 96 patient samples. We then used three NET cell lines (QGP-1, BON-1, GOT-1) with variable SSTR2 expression profiles for functional in vitro studies using histone deacetylase inhibitors (HDACi). Finally, the QGP-1 xenograft mouse model, with low basal SSTR2 expression, was used to assess the therapeutic efficacy of combined HDACi and 177Lu-DOTATATE therapies. We confirm that SSTR expression is decreased and correlates with SSTR2 promoter methylation in patients with high-grade NETs. When exposed to HDACis, SSTR2 surface expression is increased in three NET cell lines in vitro. In an in vivo PNET xenograft model with low basal SSTR2 expression, our studies demonstrate significantly higher tumor uptake of SSTR2-targeted 177Lu-DOTATATE in animals pretreated with HDACis compared with controls. For the first time, we show that this higher tumor uptake results in significant antitumor response when compared with standard PRRT alone. These preclinical results provide a rationale for utilizing HDACi pretreatment to improve targeted radionuclide therapy in patients with SSTR2-negative, metastatic PNETs.

Pancreatic neuroendocrine neoplasms (pNENs) are a heterogeneous group of tumors derived from multiple neuroendocrine origin cell subtypes. Incidence rates for pNENs have steadily risen over the last decade, and outcomes continue to vary widely due to inability to properly screen. These tumors encompass a wide range of functional and non-functional subtypes, with their rarity and slow growth making therapeutic development difficult as most clinically used therapeutics are derived from retrospective analyses. Improved molecular understanding of these cancers has increased our knowledge of the tumor biology for pNENs. Despite these advances in our understanding of pNENs, there remains a dearth of models for further investigation. In this review, we will cover the current field of pNEN models, which include established cell lines, animal models such as mice and zebrafish, and three-dimensional (3D) cell models, and compare their uses in modeling various disease aspects. While no study model is a complete representation of pNEN biology, each has advantages which allow for new scientific understanding of these rare tumors. Future efforts and advancements in technology will continue to create new options in modeling these cancers.

The resistance of ovarian cancer towards front-line chemotherapy, usually cisplatin or carboplatin in combination with paclitaxel or docetaxel, remains a major clinical challenge. Resistance to these agents has been largely studied using cell lines selected for resistance to agents in vitro. We examined a series of paired cell lines derived from patients with ovarian cancer prior to chemotherapy (PEO1, PEO4, PEO14 and PEA1), and following the acquisition of resistance to a platinum-based chemotherapy regimen (PEO6, PEO23 and PEA2, respectively). All resistant patient lines showed resistance to cisplatin (2-5-fold), but this did not correspond with lowered accumulation. No general cross-resistance was observed for oxaliplatin, paclitaxel or docetaxel, and paclitaxel accumulation was not affected. PEO1 cells carrying BRCA2 mutations were hypersensitive to the PARP inhibitors olaparib and velaparib, but all other cell lines expressing functional forms of BRCA2 were less sensitive. While reduced drug accumulation was not observed, we believe these pairs of lines are of use to researchers studying Pt drug resistance and experimental therapeutics against drug-resistant ovarian cancer.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a family of tumors that arise throughout the gastrointestinal tract. These tumors are heterogeneous, with complex clinical symptoms and tumor behaviors, and demonstrate rising incidence rates worldwide. In addition to their nature, GEP-NETs possess limited diagnostic and therapeutic options, which results in poor survival rates for patients with metastatic tumors. Given these findings, a further analysis of these tumors’ biology is needed to determine new therapeutic strategies. The tumor microenvironment (TME) consists of several residual cell populations and non-cellular components whose altered behavior creates a tumor-supportive niche. Studies from other cancers demonstrate the TME’s significance in tumor initiation, progression, and spread. In this review, we discuss efforts to characterize the TME in GEP-NETs. Preliminary studies of the immune system in GEP-NETs have led to several major clinical trials, with limited success. Efforts to target signaling crosstalk between cancer-associated fibroblasts, vascular endothelial cells, and tumor cells has led to major discoveries and multiple approved therapies. Finally, alterations to the extracellular matrix may lead towards an improved understanding of GEP-NET development, behavior, and improved detection methods. While research has rapidly expanded our knowledge within the last decade, further work is needed to bring our understanding of the GEP-NET TME in line with other rare cancers.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a varied group of tumors that originate from neuroendocrine cells found throughout the gastrointestinal tract. These tumors encompass a broad spectrum of biological behaviors, ranging from slow-growing, well-differentiated neuroendocrine tumors (GEP-NETs) to aggressive and poorly differentiated neuroendocrine carcinomas (GEP-NECs), complicating their accurate classification and effective treatment. While advances in molecular research have refined our understanding of these tumors, their complexity, unpredictable progression, and differential response to therapies remain major clinical hurdles. A significant clinical challenge is the accurate grading and diagnosis of GEP-NENs, which is traditionally reliant on subjective methods. However, innovative technologies, such as artificial intelligence-based diagnostics, multi-omics approaches, and precision oncology, are now offering solutions for more precise and reliable classification. Meanwhile, emerging therapies aiming to activate the immune response or modify the tumor environment present promising avenues for improved outcomes. Realizing the full potential of these advances will require a thoughtful integration of molecular insights with standardized diagnostic practices and evolving therapeutic strategies, ensuring that progress in research meaningfully informs and enhances patient care across diverse clinical settings. This review discusses new advancements and explores future directions toward personalized and effective treatments for GEP-NENs.

Pancreatic neuroendocrine tumors (PNETs) are a rare and understudied set of cancers, with increasing incidence. Neuroendocrine tumors are unique in the fact that they express high levels of the somatostatin receptor type 2 (SSTR2), which represents a target for both tumor imaging and therapeutics. PNET grade inversely correlates with SSTR2 tumor staining and higher tumor grade is associated with poor patient prognosis. With no known mutations, SSTR2 expression is believed to be lost through aberrant epigenetic mechanisms. Enhanced knowledge of the epigenetic biology and players controlling SSTR2 expression may allow for identification of novel PNET imaging and treatment modalities. Through in-depth studies, we found that the specific de novo DNA methyltransferase (DNMT), DNMT3B, is responsible for SSTR2 gene CpG methylation and silencing. Using DNMT3B as a starting point, along with the concept of functional crosstalk between various epigenetic mechanisms, we further discovered that Polycomb Repressor Complexes 1 and 2 (PRC1 and PRC2) play important roles in silencing SSTR2. Moreover, we found several histone lysine demethylases, enzymes that remove activating histone H3K4 methylation marks, to be critical for silencing expression of SSTR2. We additionally identified several chromatin remodeling enzymes/complexes as cellular factors that negatively regulate SSTR2 expression. Finally, using the HiBiT luminescent reporter system, we exploited functional chemo-genomic screens to further expand our knowledge of SSTR2 epigenetic control. These screens both reinforced several of our initial findings and helped to identify additional silencing mechanism potentially regulating SSTR2 expression. A commonality in our findings point to the presence, or necessity, of Class I HDACs in nearly all the epigenetic silencing mechanisms characterized. Overall, our work demonstrates that SSTR2 gene expression is likely silenced through various dynamic and interconnected epigenetic events, resulting in a compacted, transcriptionally repressed chromatin environment. Our study offers novel potential therapeutic targets and combinations to best increase expression of SSTR2, which are currently being tested in pre-clinical studies from our group, with the goal of future clinical trials aimed at increasing SSTR2 expression in high-grade, SSTR2-low NET patients.