RARE DISEASE
Neuroendocrine tumor of pancreas
Neuroendocrine tumor of pancreas
Neuroendocrine tumor of pancreas
Synonyms: PNET, Pancreatic NET, Pancreatic neuroendocrine tumor, Well-differentiated NEN of pancreas, Well-differentiated neuroendocrine neoplasm of pancreas, Well-differentiated pancreatic NEN, Well-differentiated pancreatic neuroendocrine neoplasm
Synonyms: PNET, Pancreatic NET, Pancreatic neuroendocrine tumor, Well-differentiated NEN of pancreas, Well-differentiated neuroendocrine neoplasm of pancreas, Well-differentiated pancreatic NEN, Well-differentiated pancreatic neuroendocrine neoplasm
Synonyms: PNET, Pancreatic NET, Pancreatic neuroendocrine tumor, Well-differentiated NEN of pancreas, Well-differentiated neuroendocrine neoplasm of pancreas, Well-differentiated pancreatic NEN, Well-differentiated pancreatic neuroendocrine neoplasm
Drug discovery
3
drugs
With orphan designations
Overview
Pancreatic neuroendocrine tumors (PNETs) are rare epithelial malignancies arising from pancreatic endocrine cells, accounting for ≤2% of pancreatic cancers [1][4]. They exhibit heterogeneous behavior, ranging from indolent to aggressive, with functional tumors (e.g., insulinomas, gastrinomas) causing hormonal syndromes and non-functional tumors presenting via mass effects [6][14]. Diagnosis combines biochemical testing, advanced imaging (somatostatin receptor PET/CT), and histopathological grading [1][3]. Management employs surgery for localized disease and multimodal strategies (locoregional therapies, somatostatin analogs, targeted agents, chemotherapy, and peptide receptor radionuclide therapy) for advanced cases [5][8][18].
Therapies
Surgical resection: Curative for localized tumors; parenchyma-sparing approaches preferred for insulinomas [1][8]
Systemic therapies:
- First-line: Somatostatin analogs (octreotide/lanreotide) for symptom/GFP control [3][13]
- Targeted agents (everolimus, sunitinib) and CAPTEM chemotherapy (capecitabine + temozolomide) for progressive disease [3][18]
- PRRT (177Lu-DOTATATE) for SSTR-positive tumors [18]
Categories: rare endocrine diseases, rare gastroenterological diseases, rare neoplastic diseases
Research Papers
2,205 drug discovery papers about Neuroendocrine tumor of pancreas, with 1 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,205 drug discovery papers about Neuroendocrine tumor of pancreas, with 1 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-09-16 | New and emerging somatostatin therapies for neuroendocrine tumors: "what is in the pipeline".
Somatostatin receptors (SSTRs) play a central role in all aspects of management of neuroendocrine/endocrine-neoplasms (NENs). This includes diagnosis, with radiolabeled SSTR ligands localizing the primary/tumor extent, and confirming their NEN nature. Non-radiolabeled-SSTR agonists are first line for controlling the hormone-excess-state for functional NENs (F-NENs) and for initial cytotoxic treatment of advanced tumor-growth. Radiolabeled-SSTR-ligands treat advanced disease. There is increasing need for improvement, because some patients do not respond to SSTA-therapies, others become resistant, in some current imaging with radiolabeled-SSTAs is negative and the ease of ligand use/availability is a problem. Additionally, newer groups of patients are being considered for possible SSTA-treatment with newer SSTA‑related-compounds. In this perspective, the authors briefly review recent advances that are resulting in, or may result in, new/emerging SSTAs that show promise for future use in NEN patients. This review involves both radiolabeled and non-radiolabeled agents for the future treatment of NENs, strongly supports the conclusion that in the future SSTR‑based-drugs will continue to play prominent roles in all aspects of NEN. Numerous recent studies firmly establish these conclusions, all of which are reviewed here; and they will likely be further supported by additional studies that are in progress and also cited here.
2026-08-30 | [Impact of liver metastatic burden on prognosis of patients with pancreatic neuroendocrine tumor and liver metastases after radical resection].
Objectives: To investigate the impact of liver metastatic burden on the prognosis of patients with pancreatic neuroendocrine tumor (pNET) complicated by synchronous liver metastases who undergo curative resection,and to evaluate the value of preoperative systemic therapy/postoperative adjuvant therapy in subgroups with different metastatic burdens. Methods: This is a retrospective case series study. A total of 54 patients with pNET and liver metastases who underwent synchronous curative resection at Peking University Third Hospital from January 2016 to December 2025 were enrolled. 26 males and 28 females; with an age (M(IQR)) of 52(38)years(range:17 to 78 years). A combined scoring system based on the number and maximum diameter of liver metastatic lesions was constructed, and patients were divided into a high-burden group (n=33) and a low-burden group (n=21) using X-tile software. Kaplan-Meier method,log-rank test, and Cox regression analysis were used to identify prognostic factors, and the value of different systemic therapy regimens was evaluated by stratification. Results: Liver metastatic burden was an independent adverse prognostic factor for recurrence-free survival (RFS) in patients with pNET and liver metastases after curative resection (HR=3.323,95%CI:1.455 to 7.594,P=0.001). Subgroup analysis showed that preoperative systemic therapy significantly affected RFS in the high-burden group (P=0.013). Among patients receiving preoperative systemic therapy,those treated with chemotherapy or targeted therapy achieved significantly superior RFS compared with patients receiving somatostatin analog (SSA) monotherapy (HR=10.27, 95%CI: 1.262 to 83.580, P=0.008) and patients without preoperative therapy (HR=6.537, 95%CI: 0.789 to 54.150, P=0.047). Preoperative systemic therapy exerted no significant influence on OS in either the high-or low-burden group (both P>0.05). Similarly, postoperative adjuvant therapy showed no significant effects on RFS or OS in both subgroups (all P>0.05). Preoperative chemotherapy or targeted therapy, preoperative SSA combined with chemotherapy or targeted therapy followed by postoperative SSA could significantly improve RFS in high-burden patients (P<0.01). Conclusions: Liver metastatic burden is an independent prognostic factor for RFS after synchronous curative resection. Preoperative chemotherapy or targeted therapy can improve RFS in high-burden patients,and the sequential systemic therapy strategy based on chemotherapy or targeted therapy and SSA can further enhance RFS in this subgroup.
2026-08-19 | [Current status and advances in adjuvant therapy after curative resection for pancreatic neuroendocrine tumors: from recurrence risk identification to therapeutic decision-making].
The incidence of pancreatic neuroendocrine tumor (pNET) is increasingly year by year. While curative resection is the primary treatment, with observation and follow-up generally adopted postoperatively, the risk of recurrence after surgery is high. The role of adjuvant therapy for patients with pNET after surgery remains controversial, with international guidelines favoring a risk-stratified approach and Chinese guidelines recommending adjuvant therapy for high-risk patients (with lymph node metastasis or high-grade tumors). Combining domestic and international guidelines as well as research evidence, this article systematically elaborates on the current status and advances of postoperative adjuvant therapy in patients with pNET, ranging from identification of risk factors for postoperative recurrence (clinical and pathological factors, biochemical markers, imaging factors, and predictive models) to therapeutic decision-making [somatostatin analogs (SSA), targeted therapy, chemotherapy, peptide receptor radionuclide therapy (PRRT)], so as to provide reference for clinical decision-making.
2026-08-13 | Multiple Incidental Pancreatic Neuroendocrine Tumors in a Patient With Suspected Duodenal Papillary Adenocarcinoma: A Case Report.
Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms that can mimic periampullary adenocarcinomas, presenting significant diagnostic challenges. Preoperative distinction is crucial due to the distinct prognostic and therapeutic implications of each entity. We report the case of a male patient with obstructive jaundice, whose initial investigation suggested duodenal papillary adenocarcinoma. Preoperative endoscopic biopsy was inconclusive for malignancy. Given the high clinical suspicion, the patient underwent duodenopancreatectomy. Anatomopathological examination of the surgical specimen unexpectedly revealed multiple implants of well-differentiated PNET (Grade G), without evidence of adenocarcinoma. This case illustrates the well-known limitation of endoscopic biopsy in periampullary tumors, which presents false-negative rates of up to a significant percentage. The final diagnosis of multiple Grade G PNETs, a rare condition frequently associated with genetic syndromes such as multiple endocrine neoplasia type 1, radically altered the patient's prognosis, which is significantly more favorable compared to papillary adenocarcinoma. Surgical resection remains an indispensable diagnostic and therapeutic tool in cases of biliary obstruction with high suspicion of malignancy, even with negative preoperative biopsies. The incidental finding of Grade G PNET reinforces the importance of complete histopathological analysis of the surgical specimen for adequate diagnosis, prognosis, and follow-up.
2026-08-03 | Insulin-secreting Large Cell Neuroendocrine Carcinoma of Pancreas Mimicking Primary Breast Carcinoma.
Functioning pancreatic neuroendocrine carcinoma (pNEC) is relatively less common. Here, we report a middle-aged lady, initially diagnosed as primary ductal carcinoma of the breast with multiple metastases, who was managed with excision biopsy of the breast tumor and palliative chemotherapy elsewhere. She later developed recurrent episodes of hypoglycemia following chemotherapy and was found to have hyperinsulinemic hypoglycemia, clearly suggestive of insulinoma. Ga-68 DOTANOC PET-CT scan showed DOTA-avid primary lesion in pancreas with intense uptake in several sites, including liver, bilateral adnexa, and intra-abdominal lymph nodes, favoring a probable functioning pancreatic neuroendocrine tumor (pNET) with distant metastases. Histopathology of her breast lesion was then re-examined, which showed features of neuroendocrine carcinoma (NEC) that was confirmed with immunohistochemistry (IHC), thus establishing the diagnosis of functioning pNEC. She was treated conservatively with octreotide and diazoxide for recurrent and refractory level 2 and 3 hypoglycemia. She was later discharged at her request on octreotide in a relatively stable condition, but died a week later. Despite being rare, diagnosing insulin-secreting pNEC is quite challenging. However, the diagnosis can be established based on radiological clues, somatostatin receptor expression based on functional imaging, and careful histopathological examination with appropriate IHC.
small molecules
2026-09-30 | Dual CHK1 and WNT inhibition as a synergistic therapy for gastrointestinal neuroendocrine carcinoma.
Gastrointestinal neuroendocrine carcinoma (GIS-NEC) is a highly aggressive malignancy with limited therapeutic options. To identify a therapeutic target, we performed transcriptomic profiling of 34 GIS-NEC and 30 well-differentiated gastrointestinal neuroendocrine tumors (GIS-NET) and found that checkpoint kinase 1 (CHEK1) is significantly overexpressed in GIS-NEC. While CHEK1 expression was not prognostic across overall GIS-NEC, it was associated with poor outcome specifically in pancreatic NEC, where it correlated with replication stress-associated genes, including cell division cycle 6 (CDC6) and claspin (CLSPN), both at the inter-case level and across spatially distinct regions within individual tumors. Pharmacological inhibition of checkpoint kinase 1 (CHK1) using prexasertib (LY2606368) suppressed proliferation, induced cell-cycle arrest, and increased DNA damage in most GIS-NEC cell lines, recapitulating the effects of CHEK1 knockdown. Antitumor efficacy was further confirmed in vivo. However, pancreatic NEC cell lines exhibited relative resistance to CHK1 inhibition, and transcriptomic analysis revealed enrichment of WNT signaling-related genes in these cells. Low-density lipoprotein receptor-related protein 8 (LRP8) was highly expressed in pancreatic NEC cases with high CHEK1 expression. WNT inhibition suppressed MYC-dependent transcriptional programs and downregulated replication-associated genes, including CDC6, thereby impairing replication capacity. Combined WNT and CHK1 inhibition further exacerbated replication stress and DNA damage, even at low CHK1 inhibitor doses. Collectively, these findings identify CHK1 as a therapeutic vulnerability in GIS-NEC and indicate that WNT-MYC signaling contributes to resistance by sustaining replication programs. Dual targeting of CHK1 and WNT-MYC pathways may therefore represent a promising therapeutic strategy, particularly in pancreatic NEC.
2026-09-28 | VIPoma Presenting With Obstructive Jaundice: A Case Report.
VIPoma is a rare pancreatic neuroendocrine tumor characterized by the overproduction of vasoactive intestinal peptide (VIP), typically manifesting as watery diarrhea, hypokalaemia and metabolic acidosis. Its presentation can be atypical, complicating diagnosis. We report the case of a 30-year-old male who initially presented with obstructive jaundice and fatigue, with imaging revealing a pancreatic head mass and liver metastases. Histopathological analysis confirmed a lowgrade pancreatic neuroendocrine tumor. The clinical course was complicated by portal vein thrombosis and metastatic spread. Six months later, the patient developed persistent, refractory watery diarrhea with associated hypokalaemia. Elevated serum VIP levels and Gallium-68 DOTATATE positron-emission tomography and computed tomography (PET-CT) supported the diagnosis of VIPoma. Symptom resolution was achieved with subcutaneous octreotide, followed by transition to monthly long-acting release (LAR) octreotide. Approximately 60% of VIPoma cases are metastatic at the time of diagnosis, as demonstrated in this patient. The case highlighted the diagnostic challenges of VIPoma in the presence of atypical symptoms such as jaundice and absence of initial diarrhea. It also underscores the need for close multidisciplinary collaboration to determine the best course of action and to optimize patient outcomes.
2026-09-26 | The Use of Adjunct Therapies with Surgery for Gastroenteropancreatic Neuroendocrine Tumors: Indications, Timing, and Outcomes.
Background/Objectives: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare biologically heterogeneous neoplasms but with increasing incidence in recent years. Surgery remains the backbone of treatment; however, long-term recurrence is common even after curative resection. Despite expanding treatment options, the optimal perioperative integration of adjunct therapies in conjunction with surgery remains incompletely defined, as available evidence is largely retrospective and heterogeneous. This review critically synthesizes available evidence on the role of perioperative therapies in the surgical management of GEP-NENs, identifies key knowledge gaps, and highlights areas where multidisciplinary decision-making is required. Methods: A targeted narrative literature review was performed in PubMed/MEDLINE (2001-2026), supplemented by ClinicalTrials.gov and major society guidelines. Predefined search terms were used to include "gastroenteropancreatic neuroendocrine tumor", "GEP-NET", "pancreatic neuroendocrine tumor", "surgery", "palliative surgery", "neoadjuvant", "adjuvant", "PRRT", "somatostatin analogue", "chemotherapy", "targeted therapy", "immune checkpoint inhibitor", and "liver-directed therapy". Studies were selected based on relevance, with emphasis on comprehensive reviews, key clinical studies, and major guideline statements. This approach was chosen due to varied literature and scarce high-quality prospective evidence. Results: Neoadjuvant PRRT and CAPTEM-based chemotherapy demonstrate encouraging activity in selected patients with SSTR-positive or borderline resectable pNETs, though evidence is predominantly retrospective and R0 resection rates are inconsistent across modalities. Adjuvant systemic therapy lacks high-quality evidence of benefit in well-differentiated GEP-NETs whereas platinum-based chemotherapy following resection of NEC represents the only setting where adjuvant treatment is commonly recommended, albeit without randomized trial support. Liver-directed therapies, including thermal ablation, TACE, and TARE, play complementary roles in selected patients with hepatic metastases. The overall evidence base is largely retrospective and heterogenous. Management should be individualized through multidisciplinary discussion.
2026-09-19 | Immunogenic cell death as a mechanism of synergy between sunitinib and 177Lu-DOTATATE peptide receptor radionuclide therapy in pancreatic neuroendocrine tumors.
Peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-DOTATATE improves outcomes in neuroendocrine tumors (NETs), yet durable disease control remains limited in progressive pancreatic NET (pNET) and higher-grade disease. Combinations that enhance PRRT efficacy may be advantageous. As sunitinib has radiosensitizing and immunomodulatory effects, we explored the clinical activity and mechanistic basis of combining sunitinib with PRRT. Combination treatment with ¹⁷⁷Lu-DOTATATE (1-3 cycles; 7.4 GBq per cycle) and sunitinib at 37.5 mg/day was well tolerated and effective in a pilot group of heavily pretreated pNET patients with progressive disease. Treatment response was assessed by ⁶⁸Ga-DOTATOC PET/CT and serum tumor markers (CgA, NSE). Mechanistic studies were performed in QGP-1 pNET cells using proliferation and apoptosis assays, cell-cycle analysis, and immunogenic cell death (ICD) markers. Combination therapy was well tolerated and induced marked responses: three patients achieved near-complete responses and two partial responses on post-therapy ⁶⁸Ga-DOTATOC PET/CT. In vitro, ¹⁷⁷Lu-DOTATATE and sunitinib showed bidirectional sensitization: low-dose sunitinib reduced the LD50 of ¹⁷⁷Lu-DOTATATE, and low-activity ¹⁷⁷Lu-DOTATATE reduced the LD50 of sunitinib. ¹⁷⁷Lu-DOTATATE induced dose-dependent PARP cleavage and S/G2-M arrest; however, sunitinib shifted cell death toward late apoptosis/necrosis. The combination produced a more-than-additive increase in calreticulin exposure on the tumor cell surface and enhanced HMGB1 but not interleukin- 1ß- or interleukin-18-release compared with either monotherapy, indicating immunogenic late apoptosis/necrosis, without canonical inflammasome activation. Intermittent sunitinib combined with ¹⁷⁷Lu-DOTATATE PRRT demonstrated encouraging activity in progressive pNET. The mechanism of synergy in vitro was enhanced ICD, suggesting that immune responses contribute to the synergy in vivo.
2026-09-01 | Approach to the Patient: Theranostics as precision medicine for neuroendocrine tumors.
Theranostics has emerged as a precision medicine paradigm in neuroendocrine tumors (NETs), integrating receptor-based imaging with targeted radionuclide therapy to individualize treatment. This approach is particularly valuable in functional and biologically heterogeneous NETs, where hormonal control and variable clinical behavior dominate therapeutic priorities. We present a three-case series illustrating the application of theranostics across diverse NET contexts. Case 1 describes a patient with metastatic insulinoma with refractory hypoglycemia, in whom multimodal therapy, including locoregional intervention, was sequenced to prioritize hormonal control, with somatostatin receptor (SSTR) imaging ultimately enabling peptide receptor radionuclide therapy (PRRT) and durable glycemic response. Case 2 discusses a patient with metastatic pancreatic NET who, after prior benefit from PRRT, underwent successful retreatment guided by persistent SSTR expression and appropriate clinical selection, with individualized dosimetry used to optimize safety and efficacy. Case 3 describes metastatic small-intestinal NET grade 3 with carcinoid syndrome, where dual-tracer PET (SSTR and FDG) revealed biologic heterogeneity that informed sequencing of systemic and locoregional therapies alongside PRRT, in the setting of competing priorities including carcinoid heart disease. These cases highlight theranostics as a clinical framework that integrates tumor biology, functional imaging, and patient-specific priorities to guide management of NETs. Optimal care requires multidisciplinary coordination across endocrinology, oncology, nuclear medicine, and interventional and surgical specialties, particularly when hormonal morbidity and tumor progression compete in driving treatment decisions. Receptor-based imaging identifies candidates for targeted therapies and provides insight into tumor behavior, enabling sequencing of systemic and locoregional interventions to achieve biochemical and oncologic control.
cell therapies
2026-09-30 | Controversies in NEN: An ENETS position statement on the role of liver transplantation (LT) in patients with advanced small-intestinal and pancreatic NETs.
Liver transplantation (LT) may offer survival or symptomatic benefit for highly selected patients with advanced, well-differentiated small-intestinal or pancreatic neuroendocrine tumours and unresectable liver-dominant metastases. However, its role remains controversial, as LT is rarely curative, recurrence is common, and benefits must be weighed against perioperative risk, lifelong immunosuppression, alternative therapies, and organ allocation ethics. This ENETS position statement summarises current evidence and expert consensus, reframing LT within a transplant-benefit model rather than fixed eligibility criteria. It outlines biologically informed selection principles and multidisciplinary assessment, as well as addressing the need for standardised characterisation, prospective registries, and long-term outcome data to better define the net clinical benefit of LT in this rare patient population.
2026-05-14 | Surgical treatment of neuroendocrine tumors of the pancreas of distal localisation
Objective. To study the immediate and long-term results of surgical treatment of patients with distal neuroendocrine neoplasms of the pancreas. Material and methods. The results of examination and treatment of 39 patients with neuroendocrine tumors of pancreas body and tail who underwent distal resections are presented. The analysis on the nature of operations, morphological structure of masses, postoperative complications is carried out. The main attention was paid to the factors of unfavourable prognosis and their influence on the survival rate. Results. Complications of III A-B degree according to Clavien– Dindo occurred in 6 (15.4%) patients, there was no postoperative lethality. The 5-year cumulative overall and recurrence-free survival rates were 78.6% and 64.3%, respectively. Conclusion. Surgical treatment of patients with neuroendocrine distal pancreatic tumors is justified by low lethality and frequency of serious complications. Long-term results confirm oncological validity of active therapeutic tactics.
2023-11-09 | Supercharged NK Cell-Based Immuotherapy in Humanized Bone Marrow Liver and Thymus (Hu-BLT) Mice Model of Oral, Pancreatic, Glioblastoma, Hepatic, Melanoma and Ovarian Cancers.
In this paper, we review a number of in vitro and in vivo studies regarding the efficacy of supercharged NK (sNK) cell therapy in elimination or treatment of cancer. We have performed studies using six different types of cancer models of oral, pancreatic, glioblastoma, melanoma, hepatic and ovarian cancers using hu-BLT mice. Our in vitro studies demonstrated that primary NK cells preferentially target cancer stem-like cells (CSCs)/poorly differentiated tumors whereas sNK cells target both CSCs/poorly-differentiated and well-differentiated tumors significantly higher than primary activated NK cells. Our in vivo studies in humanized-BLT mice showed that sNK cells alone or in combination with other cancer therapeutics prevented tumor growth and metastasis. In addition, sNK cells were able to increase IFN-γ secretion and cytotoxic function by the immune cells in bone marrow, spleen, gingiva, pancreas and peripheral blood. Furthermore, sNK cells were able to increase the expansion and function of CD8+ T cells both in in vitro and in vivo studies. Overall, our studies demonstrated that sNK cells alone or in combination with other cancer therapeutics were not only effective against eliminating aggressive cancers, but were also able to increase the expansion and function of CD8+ T cells to further target cancer cells, providing a successful approach to eradicate and cure cancer.
2023-01-02 | Opsoclonus-myoclonus syndrome associated with pancreatic neuroendocrine tumor: a case report.
Opsoclonus-myoclonus syndrome (OMS) is a rare, immune-mediated neurological disorder. In adults, the pathogenesis can be idiopathic, post-infectious or paraneoplastic, the latter etiology belonging to the ever-expanding group of defined paraneoplastic neurological syndromes (PNS). In contrast to other phenotypes of PNS, OMS cannot be ascribed to a single pathogenic autoantibody. Here, we report the first detailed case of paraneoplastic, antibody-negative OMS occurring in association with a pancreatic neuroendocrine tumor (pNET). A 33-year-old female presented with a two-week history of severe ataxia of stance and gait, dysarthria, head tremor, myoclonus of the extremities and opsoclonus. Her past medical history was notable for a metastatic pancreatic neuroendocrine tumor, and she was subsequently diagnosed with paraneoplastic opsoclonus-myoclonus syndrome. Further workup did not reveal a paraneoplastic autoantibody. She responded well to plasmapheresis, as she was refractory to the first-line therapy with corticosteroids. This case expands current knowledge on tumors associated with paraneoplastic opsoclonus-myoclonus syndrome and the age group in which it can occur. It further adds evidence to the effectiveness of plasmapheresis in severe cases of opsoclonus-myoclonus syndrome with a lack of response to first-line therapy.
2018-05-10 | Preventive medicine of von Hippel–Lindau disease-associated pancreatic neuroendocrine tumors
Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8 cm vs ≥2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.
antibodies
2026-09-01 | MET expression by immunohistochemistry as a biomarker in pancreatic neuroendocrine tumours.
MET (c-MET) is a receptor tyrosine kinase implicated in numerous cancers, including pancreatic neuroendocrine tumours (pNETs), by promoting cell proliferation, survival, invasion and angiogenesis. Recognizing its oncogenic potential, there is significant interest in MET-targeted therapies for malignancies like pNETs, which often develop treatment resistance. Immunohistochemistry (IHC) has become a practical method for detecting MET overexpression in cancers. This study evaluates MET expression in pNETs by IHC and assesses its correlation with prognostic variables and survival outcomes. Tissue microarrays containing well-differentiated neuroendocrine tumours from the gastrointestinal tract were analysed. The study included 125 pNET cores from 112 patients after application of inclusion criteria. MET expression was determined using the H-score system. Different variables were assessed for H-score distribution and cross-tables. Survival analyses were conducted based on progression-free survival and overall survival. Positive MET expression was found in 83.5% of cases. Higher MET H-scores were seen in patients with lymphovascular invasion (LVI), distant metastases and higher tumour grade (P < 0.05). When assessing different variables for higher MET H-scores, a significant association emerged at the 150-cut-off-point for LVI, perineural invasion, radiological evidence of progression and overall survival. For survival analysis, at a MET H-score threshold of 200, high MET expression was significantly associated with shorter progression-free survival (mean 8.7 versus 13.4 years, P < 0.05) and overall survival (mean 3.6 versus 7.7 years, P < 0.05). Elevated MET expression is linked to adverse histopathological features and worse clinical outcomes in pNET. Standardizing MET IHC evaluation is critical as anti-MET therapies develop, and identifying patients likely to benefit from these treatments remains essential.
2026-07-01 | Prognostic relevance and molecular correlates of Claudin-1 expression in pancreatic neuroendocrine tumors.
Pancreatic neuroendocrine tumors (pNETs) are biologically heterogeneous neoplasms with variable clinical outcomes. Current prognostic assessment relies largely on mitotic count and Ki-67 index, which may be affected by intratumoral heterogeneity and sampling bias. Additional biomarkers are therefore needed to refine risk stratification and characterize aggressive disease biology. Here, we investigated the prognostic and biological significance of Claudin-1 (CLDN1), a tight junction protein implicated in epithelial tumor progression. CLDN1 expression was assessed by immunohistochemistry in 67 surgically resected pNETs using tissue microarrays. A data-driven cutoff (H-score >50) identified a CLDN1-high subset associated with significantly shorter disease-free survival (p = 0.009) and adverse clinicopathologic features. To define the molecular programs underlying CLDN1 overexpression, we performed RNA sequencing on 22 tumors matched for key clinical variables by propensity score matching. CLDN1-high tumors showed attenuation of endocrine lineage markers and enrichment of exocrine and fetal ductal transcriptional programs. Cell-of-origin deconvolution further revealed a shift from endocrine alpha/beta-cell identity toward ductal or acinar-like states. Transcriptomic clustering demonstrated partial convergence between CLDN1-high pNETs and pancreatic ductal adenocarcinoma profiles. In addition, CLDN1-high tumors exhibited activation of epithelial-mesenchymal transition, HIPPO signaling, and immune-related pathways, together with increased stromal and immune cell infiltration. Collectively, our findings identify CLDN1 as a marker of a biologically distinct and clinically aggressive pNET subset characterized by dedifferentiation, lineage plasticity, and tumor microenvironment remodeling, supporting further evaluation of CLDN1 as a candidate prognostic biomarker and potential therapeutic target in pNETs.
2026-06-27 | Evolving Therapeutic Strategies in Neuroendocrine Neoplasms: A New Era of Personalized Therapies.
Neuroendocrine neoplasms (NENs) represent a heterogeneous group of malignancies ranging from relatively indolent well-differentiated neuroendocrine tumors (NETs) to more aggressive poorly differentiated neuroendocrine carcinomas (NECs). The advent of somatostatin receptor (SSTR)-targeting therapies, particularly radioligand therapy (RLT), has transformed the therapeutic landscape of NETs. Ongoing efforts are aimed at maximizing the therapeutic benefit of RLT and include retreatment and combination strategies as well as novel α-emitter-based radiopharmaceuticals. The increasing use of molecular profiling has led to the identification of recurrent canonical alterations in pancreatic NETs, including in MEN1, ATRX/DAXX, PI3K/Akt/mTOR, and angiogenic signaling pathways, facilitating the development of effective targeted therapies. However, despite the addition of newer targeted therapies to the therapeutic armamentarium, resistance remains inevitable and highlights the need for improved predictive markers to inform therapy sequencing and novel biomarker-selected therapies. In addition, the development of novel therapeutic strategies including SSTR antagonists, nonpeptide drug conjugates, and novel radiopharmaceutical constructs highlights the potential of biomarker-informed therapies in this space. By contrast, treatment options for NECs remain limited, with modest therapeutic benefit of platinum-based chemotherapy. The identification of delta-like ligand 3 (DLL3) as a therapeutic target in high-grade NENs has led to the development of novel targeted therapies such as T-cell engagers, which have demonstrated promising activity in early phase clinical trials. In addition, other DLL3-targeting agents such as antibody-drug conjugates, trispecific engagers, and cellular therapies remain under investigation. Collectively, these advances underscore the potential of biomarker-informed treatment approaches to personalize treatment decisions and improve long-term outcomes across the NEN spectrum.
2026-06-15 | Robust response to pembrolizumab in temozolomide-associated hypermutated and microsatellite instability-high functional pancreatic neuroendocrine tumor.
Pancreatic neuroendocrine tumors (PanNETs) are typically characterized by low tumor mutational burden and limited responsiveness to immune checkpoint inhibitors. Emerging evidence suggests that prior exposure to alkylating chemotherapeutic agents may be associated with a hypermutated phenotype (along with DNA mismatch repair dysfunction or DNA damage response gene alterations), potentially sensitizing tumors to immunotherapy. We present a case of a 68-year-old woman with metastatic functional PanNET (VIPoma) who developed a treatment-associated hypermutated, microsatellite instability-high phenotype following capecitabine-temozolomide therapy. Treatment with pembrolizumab resulted in a robust clinical, biochemical, and radiographic response. This case highlights dynamic genomic evolution in PanNETs and underscores the importance of serial molecular profiling in guiding therapeutic decisions.
2026-06-11 | Pancreatic Neuroendocrine Tumor in Lynch Syndrome: Expanding the Tumor Spectrum of Mismatch Repair Deficiency.
Lynch syndrome is an autosomal dominant hereditary cancer syndrome caused by germline mutations in DNA mismatch repair genes. Currently, Lynch syndrome has well-established associations with colorectal and endometrial cancers. However, a definitive association between Lynch syndrome and pancreatic neuroendocrine tumors (P-NETs) remains unestablished. Herein, we report the case of a 38-year-old male with a maternal family history of Lynch syndrome who presented with hypoglycemia, abdominal pain, and diarrhea. Imaging revealed a 5.6 cm pancreatic tail mass with hepatic, lymph node, and osseous metastases. Synchronous sigmoid adenocarcinoma was identified during admission. Germline testing confirmed a pathogenic MLH1 mutation, and liver biopsy of the P-NET demonstrated loss of MLH1 and PMS2 expression. The patient was treated with capecitabine and temozolomide (CAPTEM) chemotherapy, pembrolizumab, long-acting repeatable octreotide (octreotide LAR), and diazoxide for hypoglycemia management. Disease progression with spinal epidural extension necessitated palliative radiation and intravenous immunoglobulin for severe thrombocytopenia. This case highlights the expanding phenotypic spectrum of Lynch syndrome and suggests that P-NETs may represent a rare but clinically significant manifestation. Early recognition of this association supports comprehensive genetic testing, enables the use of precision immunotherapy, and underscores the need for expanded surveillance strategies in patients with atypical tumor profiles.
other
2026-09-09 | Notch1 supports proliferation and bioenergetic activity in a pancreatic neuroendocrine neoplasm cell line.
Pancreatic neuroendocrine neoplasms (PNENs) arise from neuroendocrine cells of the pancreas. Therapeutic options are limited for patients with advanced disease and the molecular mechanisms that drive PNEN progression remain elusive. The Notch pathway regulates cell fate, proliferation, cell-cell communication, and survival in multicellular organisms. Dysregulation of one pathway member, Notch1, has been linked to the development and growth of several cancers; however, the role of Notch1 signaling in PNENs is not defined. Notch1 expression was evaluated in normal adult pancreas and PNENs using publicly available single-cell RNA sequencing data from the Human Protein Atlas and immunohistochemistry on PNEN tissue microarrays. A CRISPR/Cas9-mediated knockout of Notch1 was generated in a PNEN cell line ('BON'). The functional impact of Notch1 loss was assessed through proliferation assays, cell cycle analysis, bulk transcriptomics, and Seahorse metabolic flux assays. In vivo tumor growth was evaluated using subcutaneous xenografts, and global proteomic profiling was performed on resected tumors. Notch1 was found to be absent in normal adult pancreatic neuroendocrine cells but was re-expressed in 39-45% of primary and metastatic PNENs. Genetic deletion of Notch1 significantly reduced PNEN cell proliferation in both 2D and 3D conditions, induced G1 cell cycle arrest, and slowed xenograft tumor growth. We also found that Notch1 regulates proliferation and cellular bioenergetic pathways in PNEN cells. Our findings reveal a role for Notch1 in supporting proliferation and bioenergetics in a PNEN cell line, providing new insights into its potential oncogenic function and contribution to PNEN pathobiology.
2025-04-10 | Regorafenib plus avelumab in advanced gastroenteropancreatic neuroendocrine neoplasms: a phase 2 trial and correlative analysis.
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogeneous tumors with limited treatment options. This phase 2 Bayesian study evaluated the combination of regorafenib, a multikinase inhibitor, and avelumab, a programmed death 1 (PD1) ligand 1 inhibitor, in advanced grade 2-grade 3 well-differentiated GEP neuroendocrine tumors or grade 3 GEP neuroendocrine carcinomas after progression on prior therapies. A total of 47 participants were enrolled and 42 were evaluable for efficacy. Participants received regorafenib (160 mg per day) and avelumab (10 mg kg-1 biweekly) in 28-day cycles. The primary endpoint, 6-month objective response rate per the response evaluation criteria in solid tumors version 1.1, was 18% (95% confidence interval (CI): 8-31%), with a median progression-free survival of 5.5 months (95% CI: 3.6-8). Durable responses were noted (16.6 months; 95% CI: 3.7-no response). Treatment-related adverse events were manageable, with fatigue, diarrhea and palmar-plantar erythrodysesthesia being most common. Exploratory biomarker analysis identified PD1 and indoleamine 2,3-dioxygenase 1 expression and activity as potential resistance markers. These findings highlight the clinical potential of regorafenib and avelumab in GEP-NENs, emphasizing the need for predictive biomarkers and validation in future randomized trials. Clinical Trial registration: NCT03475953 .
2024-11-24 | Calcium sensing receptor expression is downregulated in gastroenteropancreatic neuroendocrine tumours via epigenetic mechanisms.
Gastroenteropancreatic neuroendocrine tumours (GEP-NETs), which may be hormone secreting (e.g., gastrinomas and insulinomas) or non-secreting (also known as non-functioning NETs) are associated with severe morbidity and have a median overall survival of 75-124 months. Studies have highlighted the importance of epigenetic mechanisms in GEP-NETs pathogenesis, with the most frequently mutated genes being the epigenetic regulators, MEN1, DAXX, and ATRX. However, the consequences of these aberrant epigenetic mechanisms are poorly understood. The calcium sensing receptor (CASR), a G protein coupled-receptor, is epigenetically silenced in cancers, and therefore we examined its role in GEP-NET subtypes. Using RNA-Scope and quantitative PCR analyses in two independent tumour cohorts from Europe (n = 18 patients) and the USA (n = 46 patients) we showed that CASR mRNA is almost completely absent in gastrinomas, insulinomas and non-functioning pancreatic NETs. Furthermore, immunohistochemical staining confirmed a significant reduction in CaSR protein expression in all GEP-NET subtypes, compared to normal islets. DNA methylationEPIC and ATAC-seq analyses in the pancreatic NET cell line QGP-1 showed the CaSR promoter was both hypermethylated and in a region of closed chromatin. Furthermore, transfection of wild type CaSR into QGP-1 cells decreased cell viability, in keeping with the CaSR having a role in cellular proliferation. In summary, our study reveals that CaSR expression is decreased in GEP-NETs and that this reduced expression is likely due to DNA methylation and chromatin changes. Moreover, we demonstrate that transfection of the CaSR into a PNET cell line reduces cell viability, thereby indicating that the CaSR acts as a tumour suppressor in this tumour type.
2022-07-11 | GFAP-directed Inactivation of Men1 Exploits Glial Cell Plasticity in Favor of Neuroendocrine Reprogramming
Efforts to characterize the signaling mechanisms that underlie gastroenteropancreatic neoplasms (GEP-NENs) are precluded by a lack of comprehensive models that recapitulate pathogenesis. Investigation into a potential cell-of-origin for gastrin-secreting NENs revealed a non-cell autonomous role for loss of menin in neuroendocrine cell specification, resulting in an induction of gastrin in enteric glia. Here, we investigated the hypothesis that cell autonomous Men1 inactivation in glial fibrillary acidic protein (GFAP)-expressing cells induced neuroendocrine differentiation and tumorigenesis.Transgenic GFAPΔMen1 mice were generated by conditional GFAP-directed Men1 deletion in GFAP-expressing cells. Cre specificity was confirmed using a tdTomato reporter. GFAPΔMen1 mice were evaluated for GEP-NEN development and neuroendocrine cell hyperplasia. Small interfering RNA-mediated Men1 silencing in a rat enteric glial cell line was performed in parallel.GFAPΔMen1 mice developed pancreatic NENs, in addition to pituitary prolactinomas that phenocopied the human MEN1 syndrome. GFAPΔMen1 mice exhibited gastric neuroendocrine hyperplasia that coincided with a significant loss of GFAP expression. Men1 deletion induced loss of glial-restricted progenitor lineage markers and an increase in neuroendocrine genes, suggesting a reprogramming of GFAP+ cells. Deleting Kif3a, a mediator of Hedgehog signaling, in GFAP-expressing cells attenuated neuroendocrine hyperplasia by restricting the neuroendocrine cell fate. Similar results in the pancreas were observed when Sox10 was used to delete Men1.GFAP-directed Men1 inactivation exploits glial cell plasticity in favor of neuroendocrine differentiation.
2020-12-29 | Delta-24-RGD, an Oncolytic Adenovirus, Increases Survival and Promotes Proinflammatory Immune Landscape Remodeling in Models of AT/RT and CNS-PNET
Abstract Purpose: Atypical teratoid/rhabdoid tumors (AT/RT) and central nervous system primitive neuroectodermal tumors (CNS-PNET) are pediatric brain tumors with poor survival and life-long negative side effects. Here, the aim was to characterize the efficacy and safety of the oncolytic adenovirus, Delta-24-RGD, which selectively replicates in and kills tumor cells. Experimental Design: Delta-24-RGD determinants for infection and replication were evaluated in patient expression datasets. Viral replication and cytotoxicity were assessed in vitro in a battery of CNS-PNET and AT/RT cell lines. In vivo, efficacy was determined in different orthotopic mouse models, including early and established tumor models, a disseminated AT/RT lesion model, and immunocompetent humanized mouse models (hCD34+-NSG-SGM3). Results: Delta-24-RGD infected and replicated efficiently in all the cell lines tested. In addition, the virus induced dose-dependent cytotoxicity [IC50 value below 1 plaque-forming unit (PFU)/cell] and the release of immunogenic markers. In vivo, a single intratumoral Delta-24-RGD injection (107 or 108 PFU) significantly increased survival and led to long-term survival in AT/RT and PNET models. Delta-24-RGD hindered the dissemination of AT/RTs and increased survival, leading to 70% of long-term survivors. Of relevance, viral administration to established tumor masses (30 days after engraftment) showed therapeutic benefit. In humanized immunocompetent models, Delta-24-RGD significantly extended the survival of mice bearing AT/RTs or PNETs (ranging from 11 to 27 days) and did not display any toxicity associated with inflammation. Immunophenotyping of Delta-24-RGD–treated tumors revealed increased CD8+ T-cell infiltration. Conclusions: Delta-24-RGD is a feasible therapeutic option for AT/RTs and CNS-PNETs. This work constitutes the basis for potential translation to the clinical setting.
proteins
2026-09-16 | New and emerging somatostatin therapies for neuroendocrine tumors: "what is in the pipeline".
Somatostatin receptors (SSTRs) play a central role in all aspects of management of neuroendocrine/endocrine-neoplasms (NENs). This includes diagnosis, with radiolabeled SSTR ligands localizing the primary/tumor extent, and confirming their NEN nature. Non-radiolabeled-SSTR agonists are first line for controlling the hormone-excess-state for functional NENs (F-NENs) and for initial cytotoxic treatment of advanced tumor-growth. Radiolabeled-SSTR-ligands treat advanced disease. There is increasing need for improvement, because some patients do not respond to SSTA-therapies, others become resistant, in some current imaging with radiolabeled-SSTAs is negative and the ease of ligand use/availability is a problem. Additionally, newer groups of patients are being considered for possible SSTA-treatment with newer SSTA‑related-compounds. In this perspective, the authors briefly review recent advances that are resulting in, or may result in, new/emerging SSTAs that show promise for future use in NEN patients. This review involves both radiolabeled and non-radiolabeled agents for the future treatment of NENs, strongly supports the conclusion that in the future SSTR‑based-drugs will continue to play prominent roles in all aspects of NEN. Numerous recent studies firmly establish these conclusions, all of which are reviewed here; and they will likely be further supported by additional studies that are in progress and also cited here.
2026-08-30 | [Impact of liver metastatic burden on prognosis of patients with pancreatic neuroendocrine tumor and liver metastases after radical resection].
Objectives: To investigate the impact of liver metastatic burden on the prognosis of patients with pancreatic neuroendocrine tumor (pNET) complicated by synchronous liver metastases who undergo curative resection,and to evaluate the value of preoperative systemic therapy/postoperative adjuvant therapy in subgroups with different metastatic burdens. Methods: This is a retrospective case series study. A total of 54 patients with pNET and liver metastases who underwent synchronous curative resection at Peking University Third Hospital from January 2016 to December 2025 were enrolled. 26 males and 28 females; with an age (M(IQR)) of 52(38)years(range:17 to 78 years). A combined scoring system based on the number and maximum diameter of liver metastatic lesions was constructed, and patients were divided into a high-burden group (n=33) and a low-burden group (n=21) using X-tile software. Kaplan-Meier method,log-rank test, and Cox regression analysis were used to identify prognostic factors, and the value of different systemic therapy regimens was evaluated by stratification. Results: Liver metastatic burden was an independent adverse prognostic factor for recurrence-free survival (RFS) in patients with pNET and liver metastases after curative resection (HR=3.323,95%CI:1.455 to 7.594,P=0.001). Subgroup analysis showed that preoperative systemic therapy significantly affected RFS in the high-burden group (P=0.013). Among patients receiving preoperative systemic therapy,those treated with chemotherapy or targeted therapy achieved significantly superior RFS compared with patients receiving somatostatin analog (SSA) monotherapy (HR=10.27, 95%CI: 1.262 to 83.580, P=0.008) and patients without preoperative therapy (HR=6.537, 95%CI: 0.789 to 54.150, P=0.047). Preoperative systemic therapy exerted no significant influence on OS in either the high-or low-burden group (both P>0.05). Similarly, postoperative adjuvant therapy showed no significant effects on RFS or OS in both subgroups (all P>0.05). Preoperative chemotherapy or targeted therapy, preoperative SSA combined with chemotherapy or targeted therapy followed by postoperative SSA could significantly improve RFS in high-burden patients (P<0.01). Conclusions: Liver metastatic burden is an independent prognostic factor for RFS after synchronous curative resection. Preoperative chemotherapy or targeted therapy can improve RFS in high-burden patients,and the sequential systemic therapy strategy based on chemotherapy or targeted therapy and SSA can further enhance RFS in this subgroup.
2026-08-19 | [Current status and advances in adjuvant therapy after curative resection for pancreatic neuroendocrine tumors: from recurrence risk identification to therapeutic decision-making].
The incidence of pancreatic neuroendocrine tumor (pNET) is increasingly year by year. While curative resection is the primary treatment, with observation and follow-up generally adopted postoperatively, the risk of recurrence after surgery is high. The role of adjuvant therapy for patients with pNET after surgery remains controversial, with international guidelines favoring a risk-stratified approach and Chinese guidelines recommending adjuvant therapy for high-risk patients (with lymph node metastasis or high-grade tumors). Combining domestic and international guidelines as well as research evidence, this article systematically elaborates on the current status and advances of postoperative adjuvant therapy in patients with pNET, ranging from identification of risk factors for postoperative recurrence (clinical and pathological factors, biochemical markers, imaging factors, and predictive models) to therapeutic decision-making [somatostatin analogs (SSA), targeted therapy, chemotherapy, peptide receptor radionuclide therapy (PRRT)], so as to provide reference for clinical decision-making.
2026-08-13 | Multiple Incidental Pancreatic Neuroendocrine Tumors in a Patient With Suspected Duodenal Papillary Adenocarcinoma: A Case Report.
Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms that can mimic periampullary adenocarcinomas, presenting significant diagnostic challenges. Preoperative distinction is crucial due to the distinct prognostic and therapeutic implications of each entity. We report the case of a male patient with obstructive jaundice, whose initial investigation suggested duodenal papillary adenocarcinoma. Preoperative endoscopic biopsy was inconclusive for malignancy. Given the high clinical suspicion, the patient underwent duodenopancreatectomy. Anatomopathological examination of the surgical specimen unexpectedly revealed multiple implants of well-differentiated PNET (Grade G), without evidence of adenocarcinoma. This case illustrates the well-known limitation of endoscopic biopsy in periampullary tumors, which presents false-negative rates of up to a significant percentage. The final diagnosis of multiple Grade G PNETs, a rare condition frequently associated with genetic syndromes such as multiple endocrine neoplasia type 1, radically altered the patient's prognosis, which is significantly more favorable compared to papillary adenocarcinoma. Surgical resection remains an indispensable diagnostic and therapeutic tool in cases of biliary obstruction with high suspicion of malignancy, even with negative preoperative biopsies. The incidental finding of Grade G PNET reinforces the importance of complete histopathological analysis of the surgical specimen for adequate diagnosis, prognosis, and follow-up.
2026-08-03 | Insulin-secreting Large Cell Neuroendocrine Carcinoma of Pancreas Mimicking Primary Breast Carcinoma.
Functioning pancreatic neuroendocrine carcinoma (pNEC) is relatively less common. Here, we report a middle-aged lady, initially diagnosed as primary ductal carcinoma of the breast with multiple metastases, who was managed with excision biopsy of the breast tumor and palliative chemotherapy elsewhere. She later developed recurrent episodes of hypoglycemia following chemotherapy and was found to have hyperinsulinemic hypoglycemia, clearly suggestive of insulinoma. Ga-68 DOTANOC PET-CT scan showed DOTA-avid primary lesion in pancreas with intense uptake in several sites, including liver, bilateral adnexa, and intra-abdominal lymph nodes, favoring a probable functioning pancreatic neuroendocrine tumor (pNET) with distant metastases. Histopathology of her breast lesion was then re-examined, which showed features of neuroendocrine carcinoma (NEC) that was confirmed with immunohistochemistry (IHC), thus establishing the diagnosis of functioning pNEC. She was treated conservatively with octreotide and diazoxide for recurrent and refractory level 2 and 3 hypoglycemia. She was later discharged at her request on octreotide in a relatively stable condition, but died a week later. Despite being rare, diagnosing insulin-secreting pNEC is quite challenging. However, the diagnosis can be established based on radiological clues, somatostatin receptor expression based on functional imaging, and careful histopathological examination with appropriate IHC.
small molecules
2026-09-30 | Dual CHK1 and WNT inhibition as a synergistic therapy for gastrointestinal neuroendocrine carcinoma.
Gastrointestinal neuroendocrine carcinoma (GIS-NEC) is a highly aggressive malignancy with limited therapeutic options. To identify a therapeutic target, we performed transcriptomic profiling of 34 GIS-NEC and 30 well-differentiated gastrointestinal neuroendocrine tumors (GIS-NET) and found that checkpoint kinase 1 (CHEK1) is significantly overexpressed in GIS-NEC. While CHEK1 expression was not prognostic across overall GIS-NEC, it was associated with poor outcome specifically in pancreatic NEC, where it correlated with replication stress-associated genes, including cell division cycle 6 (CDC6) and claspin (CLSPN), both at the inter-case level and across spatially distinct regions within individual tumors. Pharmacological inhibition of checkpoint kinase 1 (CHK1) using prexasertib (LY2606368) suppressed proliferation, induced cell-cycle arrest, and increased DNA damage in most GIS-NEC cell lines, recapitulating the effects of CHEK1 knockdown. Antitumor efficacy was further confirmed in vivo. However, pancreatic NEC cell lines exhibited relative resistance to CHK1 inhibition, and transcriptomic analysis revealed enrichment of WNT signaling-related genes in these cells. Low-density lipoprotein receptor-related protein 8 (LRP8) was highly expressed in pancreatic NEC cases with high CHEK1 expression. WNT inhibition suppressed MYC-dependent transcriptional programs and downregulated replication-associated genes, including CDC6, thereby impairing replication capacity. Combined WNT and CHK1 inhibition further exacerbated replication stress and DNA damage, even at low CHK1 inhibitor doses. Collectively, these findings identify CHK1 as a therapeutic vulnerability in GIS-NEC and indicate that WNT-MYC signaling contributes to resistance by sustaining replication programs. Dual targeting of CHK1 and WNT-MYC pathways may therefore represent a promising therapeutic strategy, particularly in pancreatic NEC.
2026-09-28 | VIPoma Presenting With Obstructive Jaundice: A Case Report.
VIPoma is a rare pancreatic neuroendocrine tumor characterized by the overproduction of vasoactive intestinal peptide (VIP), typically manifesting as watery diarrhea, hypokalaemia and metabolic acidosis. Its presentation can be atypical, complicating diagnosis. We report the case of a 30-year-old male who initially presented with obstructive jaundice and fatigue, with imaging revealing a pancreatic head mass and liver metastases. Histopathological analysis confirmed a lowgrade pancreatic neuroendocrine tumor. The clinical course was complicated by portal vein thrombosis and metastatic spread. Six months later, the patient developed persistent, refractory watery diarrhea with associated hypokalaemia. Elevated serum VIP levels and Gallium-68 DOTATATE positron-emission tomography and computed tomography (PET-CT) supported the diagnosis of VIPoma. Symptom resolution was achieved with subcutaneous octreotide, followed by transition to monthly long-acting release (LAR) octreotide. Approximately 60% of VIPoma cases are metastatic at the time of diagnosis, as demonstrated in this patient. The case highlighted the diagnostic challenges of VIPoma in the presence of atypical symptoms such as jaundice and absence of initial diarrhea. It also underscores the need for close multidisciplinary collaboration to determine the best course of action and to optimize patient outcomes.
2026-09-26 | The Use of Adjunct Therapies with Surgery for Gastroenteropancreatic Neuroendocrine Tumors: Indications, Timing, and Outcomes.
Background/Objectives: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare biologically heterogeneous neoplasms but with increasing incidence in recent years. Surgery remains the backbone of treatment; however, long-term recurrence is common even after curative resection. Despite expanding treatment options, the optimal perioperative integration of adjunct therapies in conjunction with surgery remains incompletely defined, as available evidence is largely retrospective and heterogeneous. This review critically synthesizes available evidence on the role of perioperative therapies in the surgical management of GEP-NENs, identifies key knowledge gaps, and highlights areas where multidisciplinary decision-making is required. Methods: A targeted narrative literature review was performed in PubMed/MEDLINE (2001-2026), supplemented by ClinicalTrials.gov and major society guidelines. Predefined search terms were used to include "gastroenteropancreatic neuroendocrine tumor", "GEP-NET", "pancreatic neuroendocrine tumor", "surgery", "palliative surgery", "neoadjuvant", "adjuvant", "PRRT", "somatostatin analogue", "chemotherapy", "targeted therapy", "immune checkpoint inhibitor", and "liver-directed therapy". Studies were selected based on relevance, with emphasis on comprehensive reviews, key clinical studies, and major guideline statements. This approach was chosen due to varied literature and scarce high-quality prospective evidence. Results: Neoadjuvant PRRT and CAPTEM-based chemotherapy demonstrate encouraging activity in selected patients with SSTR-positive or borderline resectable pNETs, though evidence is predominantly retrospective and R0 resection rates are inconsistent across modalities. Adjuvant systemic therapy lacks high-quality evidence of benefit in well-differentiated GEP-NETs whereas platinum-based chemotherapy following resection of NEC represents the only setting where adjuvant treatment is commonly recommended, albeit without randomized trial support. Liver-directed therapies, including thermal ablation, TACE, and TARE, play complementary roles in selected patients with hepatic metastases. The overall evidence base is largely retrospective and heterogenous. Management should be individualized through multidisciplinary discussion.
2026-09-19 | Immunogenic cell death as a mechanism of synergy between sunitinib and 177Lu-DOTATATE peptide receptor radionuclide therapy in pancreatic neuroendocrine tumors.
Peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-DOTATATE improves outcomes in neuroendocrine tumors (NETs), yet durable disease control remains limited in progressive pancreatic NET (pNET) and higher-grade disease. Combinations that enhance PRRT efficacy may be advantageous. As sunitinib has radiosensitizing and immunomodulatory effects, we explored the clinical activity and mechanistic basis of combining sunitinib with PRRT. Combination treatment with ¹⁷⁷Lu-DOTATATE (1-3 cycles; 7.4 GBq per cycle) and sunitinib at 37.5 mg/day was well tolerated and effective in a pilot group of heavily pretreated pNET patients with progressive disease. Treatment response was assessed by ⁶⁸Ga-DOTATOC PET/CT and serum tumor markers (CgA, NSE). Mechanistic studies were performed in QGP-1 pNET cells using proliferation and apoptosis assays, cell-cycle analysis, and immunogenic cell death (ICD) markers. Combination therapy was well tolerated and induced marked responses: three patients achieved near-complete responses and two partial responses on post-therapy ⁶⁸Ga-DOTATOC PET/CT. In vitro, ¹⁷⁷Lu-DOTATATE and sunitinib showed bidirectional sensitization: low-dose sunitinib reduced the LD50 of ¹⁷⁷Lu-DOTATATE, and low-activity ¹⁷⁷Lu-DOTATATE reduced the LD50 of sunitinib. ¹⁷⁷Lu-DOTATATE induced dose-dependent PARP cleavage and S/G2-M arrest; however, sunitinib shifted cell death toward late apoptosis/necrosis. The combination produced a more-than-additive increase in calreticulin exposure on the tumor cell surface and enhanced HMGB1 but not interleukin- 1ß- or interleukin-18-release compared with either monotherapy, indicating immunogenic late apoptosis/necrosis, without canonical inflammasome activation. Intermittent sunitinib combined with ¹⁷⁷Lu-DOTATATE PRRT demonstrated encouraging activity in progressive pNET. The mechanism of synergy in vitro was enhanced ICD, suggesting that immune responses contribute to the synergy in vivo.
2026-09-01 | Approach to the Patient: Theranostics as precision medicine for neuroendocrine tumors.
Theranostics has emerged as a precision medicine paradigm in neuroendocrine tumors (NETs), integrating receptor-based imaging with targeted radionuclide therapy to individualize treatment. This approach is particularly valuable in functional and biologically heterogeneous NETs, where hormonal control and variable clinical behavior dominate therapeutic priorities. We present a three-case series illustrating the application of theranostics across diverse NET contexts. Case 1 describes a patient with metastatic insulinoma with refractory hypoglycemia, in whom multimodal therapy, including locoregional intervention, was sequenced to prioritize hormonal control, with somatostatin receptor (SSTR) imaging ultimately enabling peptide receptor radionuclide therapy (PRRT) and durable glycemic response. Case 2 discusses a patient with metastatic pancreatic NET who, after prior benefit from PRRT, underwent successful retreatment guided by persistent SSTR expression and appropriate clinical selection, with individualized dosimetry used to optimize safety and efficacy. Case 3 describes metastatic small-intestinal NET grade 3 with carcinoid syndrome, where dual-tracer PET (SSTR and FDG) revealed biologic heterogeneity that informed sequencing of systemic and locoregional therapies alongside PRRT, in the setting of competing priorities including carcinoid heart disease. These cases highlight theranostics as a clinical framework that integrates tumor biology, functional imaging, and patient-specific priorities to guide management of NETs. Optimal care requires multidisciplinary coordination across endocrinology, oncology, nuclear medicine, and interventional and surgical specialties, particularly when hormonal morbidity and tumor progression compete in driving treatment decisions. Receptor-based imaging identifies candidates for targeted therapies and provides insight into tumor behavior, enabling sequencing of systemic and locoregional interventions to achieve biochemical and oncologic control.
cell therapies
2026-09-30 | Controversies in NEN: An ENETS position statement on the role of liver transplantation (LT) in patients with advanced small-intestinal and pancreatic NETs.
Liver transplantation (LT) may offer survival or symptomatic benefit for highly selected patients with advanced, well-differentiated small-intestinal or pancreatic neuroendocrine tumours and unresectable liver-dominant metastases. However, its role remains controversial, as LT is rarely curative, recurrence is common, and benefits must be weighed against perioperative risk, lifelong immunosuppression, alternative therapies, and organ allocation ethics. This ENETS position statement summarises current evidence and expert consensus, reframing LT within a transplant-benefit model rather than fixed eligibility criteria. It outlines biologically informed selection principles and multidisciplinary assessment, as well as addressing the need for standardised characterisation, prospective registries, and long-term outcome data to better define the net clinical benefit of LT in this rare patient population.
2026-05-14 | Surgical treatment of neuroendocrine tumors of the pancreas of distal localisation
Objective. To study the immediate and long-term results of surgical treatment of patients with distal neuroendocrine neoplasms of the pancreas. Material and methods. The results of examination and treatment of 39 patients with neuroendocrine tumors of pancreas body and tail who underwent distal resections are presented. The analysis on the nature of operations, morphological structure of masses, postoperative complications is carried out. The main attention was paid to the factors of unfavourable prognosis and their influence on the survival rate. Results. Complications of III A-B degree according to Clavien– Dindo occurred in 6 (15.4%) patients, there was no postoperative lethality. The 5-year cumulative overall and recurrence-free survival rates were 78.6% and 64.3%, respectively. Conclusion. Surgical treatment of patients with neuroendocrine distal pancreatic tumors is justified by low lethality and frequency of serious complications. Long-term results confirm oncological validity of active therapeutic tactics.
2023-11-09 | Supercharged NK Cell-Based Immuotherapy in Humanized Bone Marrow Liver and Thymus (Hu-BLT) Mice Model of Oral, Pancreatic, Glioblastoma, Hepatic, Melanoma and Ovarian Cancers.
In this paper, we review a number of in vitro and in vivo studies regarding the efficacy of supercharged NK (sNK) cell therapy in elimination or treatment of cancer. We have performed studies using six different types of cancer models of oral, pancreatic, glioblastoma, melanoma, hepatic and ovarian cancers using hu-BLT mice. Our in vitro studies demonstrated that primary NK cells preferentially target cancer stem-like cells (CSCs)/poorly differentiated tumors whereas sNK cells target both CSCs/poorly-differentiated and well-differentiated tumors significantly higher than primary activated NK cells. Our in vivo studies in humanized-BLT mice showed that sNK cells alone or in combination with other cancer therapeutics prevented tumor growth and metastasis. In addition, sNK cells were able to increase IFN-γ secretion and cytotoxic function by the immune cells in bone marrow, spleen, gingiva, pancreas and peripheral blood. Furthermore, sNK cells were able to increase the expansion and function of CD8+ T cells both in in vitro and in vivo studies. Overall, our studies demonstrated that sNK cells alone or in combination with other cancer therapeutics were not only effective against eliminating aggressive cancers, but were also able to increase the expansion and function of CD8+ T cells to further target cancer cells, providing a successful approach to eradicate and cure cancer.
2023-01-02 | Opsoclonus-myoclonus syndrome associated with pancreatic neuroendocrine tumor: a case report.
Opsoclonus-myoclonus syndrome (OMS) is a rare, immune-mediated neurological disorder. In adults, the pathogenesis can be idiopathic, post-infectious or paraneoplastic, the latter etiology belonging to the ever-expanding group of defined paraneoplastic neurological syndromes (PNS). In contrast to other phenotypes of PNS, OMS cannot be ascribed to a single pathogenic autoantibody. Here, we report the first detailed case of paraneoplastic, antibody-negative OMS occurring in association with a pancreatic neuroendocrine tumor (pNET). A 33-year-old female presented with a two-week history of severe ataxia of stance and gait, dysarthria, head tremor, myoclonus of the extremities and opsoclonus. Her past medical history was notable for a metastatic pancreatic neuroendocrine tumor, and she was subsequently diagnosed with paraneoplastic opsoclonus-myoclonus syndrome. Further workup did not reveal a paraneoplastic autoantibody. She responded well to plasmapheresis, as she was refractory to the first-line therapy with corticosteroids. This case expands current knowledge on tumors associated with paraneoplastic opsoclonus-myoclonus syndrome and the age group in which it can occur. It further adds evidence to the effectiveness of plasmapheresis in severe cases of opsoclonus-myoclonus syndrome with a lack of response to first-line therapy.
2018-05-10 | Preventive medicine of von Hippel–Lindau disease-associated pancreatic neuroendocrine tumors
Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8 cm vs ≥2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.
antibodies
2026-09-01 | MET expression by immunohistochemistry as a biomarker in pancreatic neuroendocrine tumours.
MET (c-MET) is a receptor tyrosine kinase implicated in numerous cancers, including pancreatic neuroendocrine tumours (pNETs), by promoting cell proliferation, survival, invasion and angiogenesis. Recognizing its oncogenic potential, there is significant interest in MET-targeted therapies for malignancies like pNETs, which often develop treatment resistance. Immunohistochemistry (IHC) has become a practical method for detecting MET overexpression in cancers. This study evaluates MET expression in pNETs by IHC and assesses its correlation with prognostic variables and survival outcomes. Tissue microarrays containing well-differentiated neuroendocrine tumours from the gastrointestinal tract were analysed. The study included 125 pNET cores from 112 patients after application of inclusion criteria. MET expression was determined using the H-score system. Different variables were assessed for H-score distribution and cross-tables. Survival analyses were conducted based on progression-free survival and overall survival. Positive MET expression was found in 83.5% of cases. Higher MET H-scores were seen in patients with lymphovascular invasion (LVI), distant metastases and higher tumour grade (P < 0.05). When assessing different variables for higher MET H-scores, a significant association emerged at the 150-cut-off-point for LVI, perineural invasion, radiological evidence of progression and overall survival. For survival analysis, at a MET H-score threshold of 200, high MET expression was significantly associated with shorter progression-free survival (mean 8.7 versus 13.4 years, P < 0.05) and overall survival (mean 3.6 versus 7.7 years, P < 0.05). Elevated MET expression is linked to adverse histopathological features and worse clinical outcomes in pNET. Standardizing MET IHC evaluation is critical as anti-MET therapies develop, and identifying patients likely to benefit from these treatments remains essential.
2026-07-01 | Prognostic relevance and molecular correlates of Claudin-1 expression in pancreatic neuroendocrine tumors.
Pancreatic neuroendocrine tumors (pNETs) are biologically heterogeneous neoplasms with variable clinical outcomes. Current prognostic assessment relies largely on mitotic count and Ki-67 index, which may be affected by intratumoral heterogeneity and sampling bias. Additional biomarkers are therefore needed to refine risk stratification and characterize aggressive disease biology. Here, we investigated the prognostic and biological significance of Claudin-1 (CLDN1), a tight junction protein implicated in epithelial tumor progression. CLDN1 expression was assessed by immunohistochemistry in 67 surgically resected pNETs using tissue microarrays. A data-driven cutoff (H-score >50) identified a CLDN1-high subset associated with significantly shorter disease-free survival (p = 0.009) and adverse clinicopathologic features. To define the molecular programs underlying CLDN1 overexpression, we performed RNA sequencing on 22 tumors matched for key clinical variables by propensity score matching. CLDN1-high tumors showed attenuation of endocrine lineage markers and enrichment of exocrine and fetal ductal transcriptional programs. Cell-of-origin deconvolution further revealed a shift from endocrine alpha/beta-cell identity toward ductal or acinar-like states. Transcriptomic clustering demonstrated partial convergence between CLDN1-high pNETs and pancreatic ductal adenocarcinoma profiles. In addition, CLDN1-high tumors exhibited activation of epithelial-mesenchymal transition, HIPPO signaling, and immune-related pathways, together with increased stromal and immune cell infiltration. Collectively, our findings identify CLDN1 as a marker of a biologically distinct and clinically aggressive pNET subset characterized by dedifferentiation, lineage plasticity, and tumor microenvironment remodeling, supporting further evaluation of CLDN1 as a candidate prognostic biomarker and potential therapeutic target in pNETs.
2026-06-27 | Evolving Therapeutic Strategies in Neuroendocrine Neoplasms: A New Era of Personalized Therapies.
Neuroendocrine neoplasms (NENs) represent a heterogeneous group of malignancies ranging from relatively indolent well-differentiated neuroendocrine tumors (NETs) to more aggressive poorly differentiated neuroendocrine carcinomas (NECs). The advent of somatostatin receptor (SSTR)-targeting therapies, particularly radioligand therapy (RLT), has transformed the therapeutic landscape of NETs. Ongoing efforts are aimed at maximizing the therapeutic benefit of RLT and include retreatment and combination strategies as well as novel α-emitter-based radiopharmaceuticals. The increasing use of molecular profiling has led to the identification of recurrent canonical alterations in pancreatic NETs, including in MEN1, ATRX/DAXX, PI3K/Akt/mTOR, and angiogenic signaling pathways, facilitating the development of effective targeted therapies. However, despite the addition of newer targeted therapies to the therapeutic armamentarium, resistance remains inevitable and highlights the need for improved predictive markers to inform therapy sequencing and novel biomarker-selected therapies. In addition, the development of novel therapeutic strategies including SSTR antagonists, nonpeptide drug conjugates, and novel radiopharmaceutical constructs highlights the potential of biomarker-informed therapies in this space. By contrast, treatment options for NECs remain limited, with modest therapeutic benefit of platinum-based chemotherapy. The identification of delta-like ligand 3 (DLL3) as a therapeutic target in high-grade NENs has led to the development of novel targeted therapies such as T-cell engagers, which have demonstrated promising activity in early phase clinical trials. In addition, other DLL3-targeting agents such as antibody-drug conjugates, trispecific engagers, and cellular therapies remain under investigation. Collectively, these advances underscore the potential of biomarker-informed treatment approaches to personalize treatment decisions and improve long-term outcomes across the NEN spectrum.
2026-06-15 | Robust response to pembrolizumab in temozolomide-associated hypermutated and microsatellite instability-high functional pancreatic neuroendocrine tumor.
Pancreatic neuroendocrine tumors (PanNETs) are typically characterized by low tumor mutational burden and limited responsiveness to immune checkpoint inhibitors. Emerging evidence suggests that prior exposure to alkylating chemotherapeutic agents may be associated with a hypermutated phenotype (along with DNA mismatch repair dysfunction or DNA damage response gene alterations), potentially sensitizing tumors to immunotherapy. We present a case of a 68-year-old woman with metastatic functional PanNET (VIPoma) who developed a treatment-associated hypermutated, microsatellite instability-high phenotype following capecitabine-temozolomide therapy. Treatment with pembrolizumab resulted in a robust clinical, biochemical, and radiographic response. This case highlights dynamic genomic evolution in PanNETs and underscores the importance of serial molecular profiling in guiding therapeutic decisions.
2026-06-11 | Pancreatic Neuroendocrine Tumor in Lynch Syndrome: Expanding the Tumor Spectrum of Mismatch Repair Deficiency.
Lynch syndrome is an autosomal dominant hereditary cancer syndrome caused by germline mutations in DNA mismatch repair genes. Currently, Lynch syndrome has well-established associations with colorectal and endometrial cancers. However, a definitive association between Lynch syndrome and pancreatic neuroendocrine tumors (P-NETs) remains unestablished. Herein, we report the case of a 38-year-old male with a maternal family history of Lynch syndrome who presented with hypoglycemia, abdominal pain, and diarrhea. Imaging revealed a 5.6 cm pancreatic tail mass with hepatic, lymph node, and osseous metastases. Synchronous sigmoid adenocarcinoma was identified during admission. Germline testing confirmed a pathogenic MLH1 mutation, and liver biopsy of the P-NET demonstrated loss of MLH1 and PMS2 expression. The patient was treated with capecitabine and temozolomide (CAPTEM) chemotherapy, pembrolizumab, long-acting repeatable octreotide (octreotide LAR), and diazoxide for hypoglycemia management. Disease progression with spinal epidural extension necessitated palliative radiation and intravenous immunoglobulin for severe thrombocytopenia. This case highlights the expanding phenotypic spectrum of Lynch syndrome and suggests that P-NETs may represent a rare but clinically significant manifestation. Early recognition of this association supports comprehensive genetic testing, enables the use of precision immunotherapy, and underscores the need for expanded surveillance strategies in patients with atypical tumor profiles.
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2026-09-09 | Notch1 supports proliferation and bioenergetic activity in a pancreatic neuroendocrine neoplasm cell line.
Pancreatic neuroendocrine neoplasms (PNENs) arise from neuroendocrine cells of the pancreas. Therapeutic options are limited for patients with advanced disease and the molecular mechanisms that drive PNEN progression remain elusive. The Notch pathway regulates cell fate, proliferation, cell-cell communication, and survival in multicellular organisms. Dysregulation of one pathway member, Notch1, has been linked to the development and growth of several cancers; however, the role of Notch1 signaling in PNENs is not defined. Notch1 expression was evaluated in normal adult pancreas and PNENs using publicly available single-cell RNA sequencing data from the Human Protein Atlas and immunohistochemistry on PNEN tissue microarrays. A CRISPR/Cas9-mediated knockout of Notch1 was generated in a PNEN cell line ('BON'). The functional impact of Notch1 loss was assessed through proliferation assays, cell cycle analysis, bulk transcriptomics, and Seahorse metabolic flux assays. In vivo tumor growth was evaluated using subcutaneous xenografts, and global proteomic profiling was performed on resected tumors. Notch1 was found to be absent in normal adult pancreatic neuroendocrine cells but was re-expressed in 39-45% of primary and metastatic PNENs. Genetic deletion of Notch1 significantly reduced PNEN cell proliferation in both 2D and 3D conditions, induced G1 cell cycle arrest, and slowed xenograft tumor growth. We also found that Notch1 regulates proliferation and cellular bioenergetic pathways in PNEN cells. Our findings reveal a role for Notch1 in supporting proliferation and bioenergetics in a PNEN cell line, providing new insights into its potential oncogenic function and contribution to PNEN pathobiology.
2025-04-10 | Regorafenib plus avelumab in advanced gastroenteropancreatic neuroendocrine neoplasms: a phase 2 trial and correlative analysis.
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogeneous tumors with limited treatment options. This phase 2 Bayesian study evaluated the combination of regorafenib, a multikinase inhibitor, and avelumab, a programmed death 1 (PD1) ligand 1 inhibitor, in advanced grade 2-grade 3 well-differentiated GEP neuroendocrine tumors or grade 3 GEP neuroendocrine carcinomas after progression on prior therapies. A total of 47 participants were enrolled and 42 were evaluable for efficacy. Participants received regorafenib (160 mg per day) and avelumab (10 mg kg-1 biweekly) in 28-day cycles. The primary endpoint, 6-month objective response rate per the response evaluation criteria in solid tumors version 1.1, was 18% (95% confidence interval (CI): 8-31%), with a median progression-free survival of 5.5 months (95% CI: 3.6-8). Durable responses were noted (16.6 months; 95% CI: 3.7-no response). Treatment-related adverse events were manageable, with fatigue, diarrhea and palmar-plantar erythrodysesthesia being most common. Exploratory biomarker analysis identified PD1 and indoleamine 2,3-dioxygenase 1 expression and activity as potential resistance markers. These findings highlight the clinical potential of regorafenib and avelumab in GEP-NENs, emphasizing the need for predictive biomarkers and validation in future randomized trials. Clinical Trial registration: NCT03475953 .
2024-11-24 | Calcium sensing receptor expression is downregulated in gastroenteropancreatic neuroendocrine tumours via epigenetic mechanisms.
Gastroenteropancreatic neuroendocrine tumours (GEP-NETs), which may be hormone secreting (e.g., gastrinomas and insulinomas) or non-secreting (also known as non-functioning NETs) are associated with severe morbidity and have a median overall survival of 75-124 months. Studies have highlighted the importance of epigenetic mechanisms in GEP-NETs pathogenesis, with the most frequently mutated genes being the epigenetic regulators, MEN1, DAXX, and ATRX. However, the consequences of these aberrant epigenetic mechanisms are poorly understood. The calcium sensing receptor (CASR), a G protein coupled-receptor, is epigenetically silenced in cancers, and therefore we examined its role in GEP-NET subtypes. Using RNA-Scope and quantitative PCR analyses in two independent tumour cohorts from Europe (n = 18 patients) and the USA (n = 46 patients) we showed that CASR mRNA is almost completely absent in gastrinomas, insulinomas and non-functioning pancreatic NETs. Furthermore, immunohistochemical staining confirmed a significant reduction in CaSR protein expression in all GEP-NET subtypes, compared to normal islets. DNA methylationEPIC and ATAC-seq analyses in the pancreatic NET cell line QGP-1 showed the CaSR promoter was both hypermethylated and in a region of closed chromatin. Furthermore, transfection of wild type CaSR into QGP-1 cells decreased cell viability, in keeping with the CaSR having a role in cellular proliferation. In summary, our study reveals that CaSR expression is decreased in GEP-NETs and that this reduced expression is likely due to DNA methylation and chromatin changes. Moreover, we demonstrate that transfection of the CaSR into a PNET cell line reduces cell viability, thereby indicating that the CaSR acts as a tumour suppressor in this tumour type.
2022-07-11 | GFAP-directed Inactivation of Men1 Exploits Glial Cell Plasticity in Favor of Neuroendocrine Reprogramming
Efforts to characterize the signaling mechanisms that underlie gastroenteropancreatic neoplasms (GEP-NENs) are precluded by a lack of comprehensive models that recapitulate pathogenesis. Investigation into a potential cell-of-origin for gastrin-secreting NENs revealed a non-cell autonomous role for loss of menin in neuroendocrine cell specification, resulting in an induction of gastrin in enteric glia. Here, we investigated the hypothesis that cell autonomous Men1 inactivation in glial fibrillary acidic protein (GFAP)-expressing cells induced neuroendocrine differentiation and tumorigenesis.Transgenic GFAPΔMen1 mice were generated by conditional GFAP-directed Men1 deletion in GFAP-expressing cells. Cre specificity was confirmed using a tdTomato reporter. GFAPΔMen1 mice were evaluated for GEP-NEN development and neuroendocrine cell hyperplasia. Small interfering RNA-mediated Men1 silencing in a rat enteric glial cell line was performed in parallel.GFAPΔMen1 mice developed pancreatic NENs, in addition to pituitary prolactinomas that phenocopied the human MEN1 syndrome. GFAPΔMen1 mice exhibited gastric neuroendocrine hyperplasia that coincided with a significant loss of GFAP expression. Men1 deletion induced loss of glial-restricted progenitor lineage markers and an increase in neuroendocrine genes, suggesting a reprogramming of GFAP+ cells. Deleting Kif3a, a mediator of Hedgehog signaling, in GFAP-expressing cells attenuated neuroendocrine hyperplasia by restricting the neuroendocrine cell fate. Similar results in the pancreas were observed when Sox10 was used to delete Men1.GFAP-directed Men1 inactivation exploits glial cell plasticity in favor of neuroendocrine differentiation.
2020-12-29 | Delta-24-RGD, an Oncolytic Adenovirus, Increases Survival and Promotes Proinflammatory Immune Landscape Remodeling in Models of AT/RT and CNS-PNET
Abstract Purpose: Atypical teratoid/rhabdoid tumors (AT/RT) and central nervous system primitive neuroectodermal tumors (CNS-PNET) are pediatric brain tumors with poor survival and life-long negative side effects. Here, the aim was to characterize the efficacy and safety of the oncolytic adenovirus, Delta-24-RGD, which selectively replicates in and kills tumor cells. Experimental Design: Delta-24-RGD determinants for infection and replication were evaluated in patient expression datasets. Viral replication and cytotoxicity were assessed in vitro in a battery of CNS-PNET and AT/RT cell lines. In vivo, efficacy was determined in different orthotopic mouse models, including early and established tumor models, a disseminated AT/RT lesion model, and immunocompetent humanized mouse models (hCD34+-NSG-SGM3). Results: Delta-24-RGD infected and replicated efficiently in all the cell lines tested. In addition, the virus induced dose-dependent cytotoxicity [IC50 value below 1 plaque-forming unit (PFU)/cell] and the release of immunogenic markers. In vivo, a single intratumoral Delta-24-RGD injection (107 or 108 PFU) significantly increased survival and led to long-term survival in AT/RT and PNET models. Delta-24-RGD hindered the dissemination of AT/RTs and increased survival, leading to 70% of long-term survivors. Of relevance, viral administration to established tumor masses (30 days after engraftment) showed therapeutic benefit. In humanized immunocompetent models, Delta-24-RGD significantly extended the survival of mice bearing AT/RTs or PNETs (ranging from 11 to 27 days) and did not display any toxicity associated with inflammation. Immunophenotyping of Delta-24-RGD–treated tumors revealed increased CD8+ T-cell infiltration. Conclusions: Delta-24-RGD is a feasible therapeutic option for AT/RTs and CNS-PNETs. This work constitutes the basis for potential translation to the clinical setting.
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Drug Discovery Landscape
3 orphan drug designations for Neuroendocrine tumor of pancreas, including 1 approved therapy.
3 orphan drug designations for Neuroendocrine tumor of pancreas, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Foslinanib | small molecules | FDA | TaiRx, Inc. | |
cabozantinib [Cabometyx] | small molecules | FDA | Approved | Exelixis, Inc. |
surufatinib | small molecules | FDA | Hutchison MediPharma Ltd. |
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