Well-differentiated Neuroendocrine Tumors Research Articles

Benign Islet Cells Within Peripancreatic Lymph Nodes

The presence of epithelial cells within lymph node parenchyma is typically indicative of a metastatic malignancy. However, there are rare instances in which non-neoplastic epithelial or epithelioid cells may be found within lymph nodes, either due to aberrant embryologic migration, mechanical displacement, or physiological trafficking. These can potentially lead to serious potential diagnostic pitfalls, as when such situations are encountered by surgical pathologists, there is substantial risk of overdiagnosing these as metastatic malignancy. Herein, we describe 2 cases of benign pancreatic islet cells within peripancreatic lymph nodes, and underscore the potential for misdiagnosis of this phenomenon as foci of metastatic well-differentiated neuroendocrine tumor. The benign nature of these intranodal islet cells was supported by: (1) the absence of a well-differentiated neuroendocrine tumor in the entirely submitted concomitant pancreatic resection specimen and (2) the presence of an admixture of insulin and glucagon expressing cells by immunohistochemistry in a distribution characteristic of non-neoplastic pancreatic islets. Both cases were incidental microscopic findings in pancreatic resections for intraductal papillary mucinous neoplasms that were previously biopsied and showed associated microscopic areas of fibrosis and chronic pancreatitis and thus this phenomenon may be related to mechanical displacement from prior injury and/or biopsy.

Personalized dosimetry as a key for optimizing radioligand therapy (RLT) with 177Lu- or 177Lu/90Y-DOTA-TATE in patients with well-differentiated neuroendocrine tumors - an update on the initial results of the DUONEN multicenter study

Personalized dosimetry as a key for optimizing radioligand therapy (RLT) with 177Lu- or 177Lu/90Y-DOTA-TATE in patients with well-differentiated neuroendocrine tumors - an update on the initial results of the DUONEN multicenter study

Sexual function, quality of life and gender-related differences in patients with well-differentiated neuroendocrine tumors

Sexual function, quality of life and gender-related differences in patients with well-differentiated neuroendocrine tumors

Volumetric parameters of 68[Ga]Ga-DOTA-TATE PET/CT in the prediction of response to treatment with long-acting somatostatin analogues in patients with well-differentiated NETs

Volumetric parameters of 68[Ga]Ga-DOTA-TATE PET/CT in the prediction of response to treatment with long-acting somatostatin analogues in patients with well-differentiated NETs

177Lu]Lu-DOTA-TATE in newly diagnosed patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors: Primary analysis of the phase 3 randomized NETTER-2 study

177Lu]Lu-DOTA-TATE in newly diagnosed patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors: Primary analysis of the phase 3 randomized NETTER-2 study

Preoperative assessment of lymph nodal metastases with [68Ga]Ga-DOTATOC PET radiomics for improved surgical planning in well-differentiated pancreatic neuroendocrine tumours.

Accurate identification of lymph node (LN) metastases is pivotal for surgical planning of pancreatic neuroendocrine tumours (PanNETs); however, current imaging techniques have sub-optimal diagnostic sensitivity. Aim of this study is to investigate whether [68Ga]Ga-DOTATOC PET radiomics might improve the identification of LN metastases in patients with non-functioning PanNET (NF-PanNET) referred to surgical intervention. Seventy-two patients who performed preoperative [68Ga]Ga-DOTATOC PET between December 2017 and March 2022 for NF-PanNET. [68Ga]Ga-DOTATOC PET qualitative assessment of LN metastases was measured using diagnostic balanced accuracy (bACC), sensitivity (SN), specificity (SP), positive and negative predictive values (PPV, NPV). SUVmax, SUVmean, Somatostatin receptor density (SRD), total lesion SRD (TLSRD) and IBSI-compliant radiomic features (RFs) were obtained from the primary tumours. To predict LN involvement, these parameters were engineered, selected and used to train different machine learning models. Models were validated using tenfold repeated cross-validation and control models were developed. Models' bACC, SN, SP, PPV and NPV were collected and compared (Kruskal-Wallis, Mann-Whitney). LN metastases were detected in 29/72 patients at histology. [68Ga]Ga-DOTATOC PET qualitative examination of LN involvement provided bACC = 60%, SN = 24%, SP = 95%, PPV = 78% and NPV = 65%. The best-performing radiomic model provided a bACC = 70%, SN = 77%, SP = 61%, PPV = 60% and NPV = 83% (outperforming the control model, p < 0.05*). In this study, [68Ga]Ga-DOTATOC PET radiomics allowed to increase diagnostic sensitivity in detecting LN metastases from 24 to 77% in NF-PanNET patients candidate to surgery. Especially in case of micrometastatic involvement, this approach might assist clinicians in a better patients' stratification.

False-Negative Neuroendocrine Tumor Identified With 68Ga-DOTATOC PET/CT: A Case of Well-Differentiated Somatostatinoma.

We report the case of a 25-year-old man who was undergoing follow-up for neurofibromatosis type 1. The man underwent 68Ga-DOTATOC PET/CT for a suspected well-differentiated duodenal neuroendocrine tumor. This examination did not reveal any significant uptake, whereas complementary 18F-FDG PET/CT showed moderate 18F-FDG uptake in the primary tumor as well as the adenopathy. Histology, a well-differentiated duodenal neuroendocrine tumor was confirmed, consistent with the diagnosis of somatostatinoma. Although rare, this well-differentiated neuroendocrine tumor should be kept in mind as a possible source of false-negative somatostatin receptor PET/CT findings.

NEC versus NET G3—is there a grey zone? Case report of pancreatic NET G3 with rapid disease progression

Summary Introduction Patients with well-differentiated neuroendocrine tumors of grade 3 (NET G3) exhibit a significantly better survival than patients with poorly differentiated neuroendocrine carcinomas (NEC). However, some cases of NET G3 with high Ki-67 index present with highly aggressive clinical behavior, prompting the question whether there are selected tumors representing a biological continuum between NET G3 and NEC. Case presentation Here we report the case of a 49-year-old man with pancreatic NET G3 metastasized to the liver. Surgery was not indicated, and the patient was initially treated with cisplatin/etoposide on account of the high proliferation rate (Ki-67 index of 50%). Restaging showed immediate disease progression with new liver metastases, so therapy with capecitabine/temozolomide was initiated and continued until progressive disease after 7 cycles. Comprehensive diagnostic evaluation, including functional imaging and genetic analyses, revealed no potential therapeutic targets, and further treatment options were limited. The patient died shortly after a therapeutic attempt with streptozotocin/5-fluorouracil. Conclusion This case exemplifies the unfortunate course of a rapidly progressive NET G3 and highlights the limited number of effective therapies for some tumors within the relatively new cohort of NET G3 with a yet unsatisfactory understanding of its underlying tumor biology and behavioral spectrum.

Hormonally Silent Multifocal Pheochromocytoma in the Setting of a Well-Differentiated Neuroendocrine Tumor of the Appendix: A Case Report

Hormonally Silent Multifocal Pheochromocytoma in the Setting of a Well-Differentiated Neuroendocrine Tumor of the Appendix: A Case Report

Consensus on the Clinical Diagnosis and Treatment of Grade 3 Pancreatic Neuroendocrine Tumors

The World Health Organization (WHO) 2017 classifications for neuroendocrine neoplasms (NENs) subdivided grade 3 pancreatic neoplasms (pNENs) into G3 well-differentiated pancreatic neuroendocrine tumors (G3 pNETs) and poorly-differentiated pancreatic neuroendocrine carcinomas (pNECs), according to the mitotic count, Ki-67 index and cell differentiation. As a new category, G3 pNETs remains a challenging group of tumors to manage by lacking large randomized trials and consensus to support its clinical practice. Therefore, the Chinese Pancreatic Surgery Association, Chinese Society of Surgery, Chinese Medical Association gathered experts in this field to formulate this consensus for the diagnosis and treatment of G3 pNETs.

[Current developments in the treatment of neuroendocrine tumors].

Well-differentiated neuroendocrine tumors (NET) are rare malignancies that are clinically very heterogeneous. Accordingly, their treatment is also complex and dependent on various factors. With currently available systemic therapies, the prognosis is often favorable. This article aims to provide an overview of current treatment strategies for NET, addressing the most important NET locations. The current European guidelines and further relevant literature on the treatment of NET were reviewed for this purpose. The therapeutic spectrum for NET is extremely broad: For NET of the stomach/duodenum, appendix, and rectum, endoscopic or surgical resection is often sufficient, and metastatic tumors are rare. NET of the pancreas, small intestine and lung should also undergo potentially curative resection in the early stages. In the metastatic stage, locoregional treatments such as surgery and liver tumor embolization play arole. Major advances have been made in drug therapy, with somatostatin analogs (octreotide and lanreotide), an mTOR inhibitor (everolimus), and atyrosine kinase inhibitor (sunitinib) being widely used. Peptide receptor radionuclide therapy (PRRT) is also an invaluable option. In some cases, classic chemotherapy is indicated. Many effective therapies are now available for NET. It is important to select the right therapy at the right time for each patient through interdisciplinary management.

[Current WHO classification (2022) of neuroendocrine neoplasms].

After the first description of the "carcinoid tumors" by the pathologist Siegfried Oberndorfer in Munich, the classification system of neuroendocrine neoplasms (NENs) is still achallenge and an evolving concept. The new WHO classification system proposed aframework for universal classification. The new WHO classification system recognizes two distinct families distinguished by genetic, morphology and clinical behaviour: Well differentiated NENs are defined as neuroendocrine tumor (NET G1, G2, G3), while poorly differentiated ones are defined as neuroendocrine carcinoma (NEC, G3) and further subdivided into small and large cell carcinoma. All NENs are characterized by the expression of synaptophysin and chromograninA, Ki-67 and morphology. The morphological NEN dichotomy is supported by genetic alterations. NECs show TP53 and RB1 alterations that are absent in NETs and are therefore useful for differentiating between NETs and NECs. All NENs are divided into well-differentiated neuroendocrine tumor (NET G1, G2, G3) or poorly differentiated neuroendocrine carcinoma (NEC, G3). They are categorized by morphology, mitotic count and immunohistochemistry with synaptophysin, chromogranin and Ki-67.

Sequencing Treatments in Patients with Advanced Well-Differentiated Pancreatic Neuroendocrine Tumor (pNET): Results from a Large Multicenter Italian Cohort.

Background: The optimal treatment sequencing for advanced, well-differentiated pancreatic neuroendocrine tumors (pNETs) is unknown. We performed a multicenter, retrospective study to evaluate the best treatment sequence in terms of progression-free survival to first-line (PFS1) and to second-line (PFS2), and overall survival among patients with advanced, well-differentiated pNETs. Methods: This multicenter study retrospectively analyzed the prospectively collected data of patients with sporadic well-differentiated pNETs who received at least two consecutive therapeutic lines, with evidence of radiological disease progression before change of treatment lines. Results: Among 201 patients, 40 (19.9%) had a grade 1 and 149 (74.1%) a grade 2 pNET. Primary tumor resection was performed in 98 patients (48.8%). First-line therapy was performed in 128 patients with somatostatin analogs (SSA), 35 received SSA + radioligand therapy (RLT), 21 temozolomide-based chemotherapy, and 17 SSA + targeted therapy. PFS was significantly longer in patients with grade 1 pNETs compared to those with grade 2, in patients who received primary tumor surgery, and in patients treated with RLT compared to other treatments. At multivariate analysis, the use of upfront RLT was independently associated with improved PFS compared to SSA. Second-line therapy was performed in 94 patients with SSA + targeted therapy, 35 received chemotherapy, 45 SSA + RLT, and 27 nonconventional-dose SSA or SSA switch. PFS was significantly longer in patients treated with RLT compared to other treatments. At multivariate analysis, the type of second-line therapy was independently associated with the risk for progression. OS was significantly longer in patients who received primary tumor surgery, with Ki67 < 10%, without extrahepatic disease, and in patients who received SSA-RLT sequence compared to other sequences. Conclusions: In this large, multicenter study, RLT was associated with better PFS compared to other treatments, and the SSA-RLT sequence was associated with the best survival outcomes in patients with pNETs with Ki67 < 10%. Primary tumor surgery was also associated with improved survival.

Phase II study of pembrolizumab and lenvatinib in advanced well-differentiated neuroendocrine tumors

Immune checkpoint inhibitors (CPIs) have not been shown to be active in well-differentiated neuroendocrine tumors (NETs), with response rates <5%. Lenvatinib is a multitargeted tyrosine kinase inhibitor which binds to vascular endothelial growth factor and fibroblast growth factor receptors and has demonstrated efficacy in pancreatic and gastrointestinal NETs [44% and 16% objective radiographic response rate (ORR), respectively]. The combination of antiangiogenic and CPI therapies can be synergistic. We therefore evaluated the combination of lenvatinib and pembrolizumab in well-differentiated gastrointestinal (GI) and thoracic NETs. A prospective, phase II trial evaluated patients with advanced GI/thoracic NETs (pancreatic NETs were excluded due to high response rate of lenvatinib monotherapy in this patient population), with evidence of progression within 8 months of study entry and at least two prior lines of systemic therapy. Patients received lenvatinib 20 mg daily and pembrolizumab 200 mg intravenously every 3 weeks until unacceptable toxicity or progression of disease. Primary endpoint was objective response rate, and an interim analysis was planned once 20 patients were enrolled. Four ORRs were required to continue enrollment. Twenty patients were enrolled on protocol from April 2021 to January 2022 (nine small intestine, five lung, two thymic, two unknown primary, one cecal, one presacral primaries). Two patients (10%) achieved a partial response (atypical lung and small intestinal primaries). Median progression-free survival (PFS) was 8 months (95% confidence interval 5.8-10.2 months). Twelve (60%) patients experienced probably or definitely associated grade 3 adverse events (10 hypertension). Fourteen patients (70%) required dose reductions or discontinued one of the medications. Two patients discontinued treatment before radiographic assessment. The combination of pembrolizumab and lenvatinib did not show sufficient response in patients with NETs to warrant continued enrollment on trial.

INSM1 is a useful neuroendocrine marker to differentiate pancreatic serous cystadenoma from pancreatic well-differentiated neuroendocrine tumors in cytology and surgical specimens

IntroductionDifferentiating pancreatic serous cystadenoma (SCA) from well-differentiated neuroendocrine tumors (WDNETs) based on histomorphology is critical yet challenging, particularly in small biopsy samples. Our study aimed to examine the expression profile of INSM1 in cytologic and surgical resection specimens from pancreatic SCA to evaluate its potential as a discriminative marker against pancreatic WDNET. MethodsWe characterized INSM1 immunohistochemistry in 34 patients with pancreatic SCA, comprising 23 surgical resections and 11 cytology specimens. As a control, we used 28 cytology specimens from pancreatic WDNET. Clinical information was retrieved through a review of electronic medical records. ResultsAll 11 pancreatic SCA cytology specimens and 15 of 23 pancreatic SCA surgical resections exhibited absent INSM1 immunostaining. Each of the remaining eight surgical resection specimens demonstrated 1 % immunoreactivity. In contrast, 27 out of 28 (96 %) pancreatic WDNET cytology specimens were positive for INSM1 immunostaining, with a median immunoreactivity of 90 % and a range of 30–90 %. Overall, INSM1 immunostains perform similarly to chromogranin and synaptophysin in pancreatic SCA. ConclusionsThe results indicate that INSM1 immunohistochemistry staining may serve as a useful neuroendocrine marker to differentiate pancreatic SCA from pancreatic WDNET in clinical practice. To our knowledge, this represents the first large-scale study to evaluate INSM1 immunostaining in surgical and cytology specimens from pancreatic SCA.

Treatment strategies for borderline resectable pancreatic neuroendocrine tumors: a narrative review.

Well-differentiated pancreatic neuroendocrine tumors (pNETs) are a group of rare, heterogeneous tumors that originate in the endocrine tissue of the pancreas and account for 1-2% of all pancreatic neoplasms. The majority of pNETs are non-functional and typically follow a more indolent course. Especially at early stages, the primary management of pNETs is surgical resection which is associated with relatively low rates of recurrence and excellent long-term prognosis. On the other hand, some patients will present with locally advanced primary tumors or low volume metastatic disease in which complete surgical resection may be more difficult to achieve and recurrence rates are significant. Unlike treatment of borderline resectable (BR) pancreatic adenocarcinoma, in which neoadjuvant treatment strategies are becoming standardized, borderline resectability is not a currently established terminology for pNETs and the optimal multidisciplinary treatment approach is poorly understood. We performed a literature search on PubMed, Google Scholar, and ClinicalTrials.gov using keywords, including 'pancreatic neuroendocrine tumor' and 'borderline resectable'. All studies and review articles in English with full text were considered. Each publication was independently reviewed. We introduce the concept of BR-pNETs, focusing on important criteria that should be included in their definition by balancing the feasibility of resection and the clinical utility of surgery. We suggest that extended resection, involving vascular reconstruction, adjacent organ resection, and/or liver metastasis, should be considered at experienced, high volume centers. Furthermore, we outline multidisciplinary treatment strategies, including systemic and locoregional treatment options, for optimizing outcomes for this growing patient population. Formalizing the definition of resectability in pNETs through multidisciplinary collaborative research will be important for standardizing the indications for multimodality treatment and aggressive surgical approaches for patients.

Updates on Urinary Bladder Tumors With Neuroendocrine Features.

The most common neuroendocrine tumor in the urinary bladder is small cell carcinoma, which can be pure or mixed with components of urothelial or other histologic subtypes. Large cell neuroendocrine carcinoma of the bladder is rare and remains ill-defined but is increasingly recognized. Well-differentiated neuroendocrine tumor and paraganglioma can arise in the bladder but are very rare in this location. Recent advances in molecular characterization allowed for better classification and may offer improved stratification of these tumors.

Abstract 6825: Epigenetic dysregulation in well-differentiated pancreatic neuroendocrine tumor (PNET): An immunohistochemistry (IHC) analysis

Abstract Epigenetic dysregulation through DNA Methyltransferase 1 (DNMT1) is integral to pancreatic neuroendocrine tumorigenesis. We aim to investigate the interplay between epigenetic modifiers and pathogenetic markers in the PNET microenvironment. 12 paraffin-embedded PNET specimens and 12 benign adjacent tissue specimens, used as controls, were obtained from Cooper University Hospital Pathology Department (IRB 23-130). IHC was performed using epigenetic markers, including DNMT1, DNMT3A, DNMT3B, and 5-Hydroxymethylcytosine (5-HMC), and pathogenic markers, including Multiple Endocrine Neoplasia 1 (MEN1), Protein-Tyrosine Phosphatase (PTEN), and Ras Association Domain Family 1 (RASSF1). Image J software was utilized for IHC scoring under the guidance of a board-certified pathologist. DNMT1 was upregulated in PNET tumor specimens with a mean density score of 72.02 +/- 31 versus 16.02 +/- 17 in adjacent benign tissue (p&amp;lt;.001). Grade 2 tumors displayed increased DNMT1 expression compared to Grade 1 tumors with a mean score of 37 +/-21 versus 71 +/- 23 (p&amp;lt;.05). Decreased expression of 5-HMC was noted in tumor specimens in comparison to benign tissue with a mean score of 3.92 +/- 5.05 versus 19.37 +/- 5.05 (p&amp;lt;.05). Loss of 5-HMC was observed in higher tumor grades with a mean score of .79 +/- 2 versus 8.2+/-2 (p&amp;lt;.01). DNMT3B was upregulated in PNET tumor specimens with a mean score of 13.16 +/- 3.94 versus 7.02+/- 2.553 (p&amp;lt;.01) in adjacent benign tissue and was positively correlated to DNMT1 expression. DNMT3A was not found to have a difference in expression between tumor and benign tissue. MEN1 was downregulated in PNET, with 45% of tumor specimens displaying loss of MEN1 expression. Mean MEN1 density in tumor tissue was 4.47 +/- 5.95 versus 11.41 +/- 3.53 in adjacent benign (p&amp;lt;.01). Increased expression of DNMT1 found to negatively correlate with MEN1 expression (R2=.23). Loss of RASSF1 expression was present in 70% of tumor specimens with a mean score of 1.32 +/- 1.99 versus 9.50+/- 6.89 (p&amp;lt;.001) in adjacent benign tissue. RASSF1 expression correlated negatively with DNMT1 (R2=.21). PTEN expression showed intratumoral homogeneity to benign tissue, and its expression was not correlated with any epigenetic markers. Our work provides a framework of epigenetic regulators involved in the pathobiology of PNET, and can refine prognostic evaluation while providing therapeutic benefits for patients with PNET. Citation Format: Zena Saleh, Yazid Ghanem, Hansa Joshi, Mathew C. Moccia, Helen Toma, Yahui Li, Upsana Joneja, Tao Gao, Young Hong. Epigenetic dysregulation in well-differentiated pancreatic neuroendocrine tumor (PNET): An immunohistochemistry (IHC) analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6825.

Abstract 3814: Molecular background conditioning by temozolomide in neuroendocrine tumors

Abstract Temozolomide (TMZ)-based regimens represent a valid therapeutic option in well-differentiated neuroendocrine tumors (NETs G2 and G3). As an alkylating agent, it increases DNA alteration by altering guanine residues, which either triggers cell death or results in novel missense mutations especially in MGMT deficient cells. Here, we describe an exploratory case series of TMZ-treated NETs cases that underwent NGS analysis at the University Hospital of Verona. Methods. We included 32 patients (16 G2 and 16 G3). NGS was performed before TMZ treatment for 22 cases (54%), after for 19 (46%) and in both for 4 cases (13%). We performed NGS on tissue samples for 73% of assays and via liquid biopsy for the remaining 27%. For tissue NGS, in 77% of samples we used an in-house panel encompassing 174 genes and in 23% commercial test interrogating at least 500 genes. Only ACMG/AMP class IV-V molecular alterations were considered for further analysis. Main Results From 2021 we performed NGS analysis on 32 NETs (G2 and G3) treated with TMZ-based regimes. Most cases (28 pf 32, 84.4%) were pancreatic NETs. Mean Ki-67 at baseline was 24.5% (range 3-60). The mean number treatments prior to TMZ were 1.4 and 0.5 between CAPTEM and subsequent NGS. The top five altered genes at baseline were MEN1 (32%), TP53 (14%), DAXX (14%), PTEN (9%) and SMAD4 (9%). None of the patients showed a high TMB (&amp;gt;15Mut/Mb) at baseline, while 26% of post-TMZ samples displayed that feature. Mean TMB at baseline and after treatment was 6,51 (range 1-10.6) and 22,9 mut/Mb (range 1-216) respectively. Alterations in DDR systems genes, including ATM, ATR, CHEK2, BRCA1, BRCA2, MLH1, MLH2, PMS2 MLH6 and MUTYH, were found in 8 patients (47%) after TMZ exposure; only one DDR-specific alteration (MUTYH) was found at baseline. DDR defects were enriched in patients exposed to higher numbers of treatments. The increase in mean TMB and enrichment in mutations in the DDR system is also confirmed when analysing the 6 cases having both pre- and post-TMZ treatment samples. Among other pathways, cell cycle deregulating genes (CDKN1A, CDKN2B, CDKN1B, CDK12, CDK6, RB1) were altered in 2 (11%) and 5 (29%) pre- and post-TMZ NGS samples respectively, the mTOR pathway (MTOR, NF1, PIK3CA, AKT, TSC1, TSC2, PTEN) in 2 (11%) and 8 (47%), and the MAPK pathway (KRAS and BRAF) in 1 (5%) and 2 (12%). Conclusions. The wide and effective use of temozolomide in neuroendocrine tumors, together with the potential therapeutic implications of DDR defects make this topic of great interest. The DDR pathway was one of the most affected by alterations in post-TMZ samples, although the genotoxic agent caused a general increase in the rate of somatic mutation. The status of DDR systems, either germinal or somatic, may represent an important selection and/or stratification parameter for future immunotherapy clinical studies also in neuroendocrine tumours provided that the analysis is carried out in a systematic, comprehensive and longitudinal way. Citation Format: Elena Trevisani, Anna Reni, Irene Torresan, Alice Rossi, Michele Borghesani, Silvia Nicolini, Claudio Luchini, Luca Landoni, Davide Melisi, Aldo Scarpa, Michele Milella, Andrea Mafficini, Sara Cingarlini. Molecular background conditioning by temozolomide in neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3814.

Abstract 3578: A systematic NEN spheroid drug screen reveals a novel drug resistance mechanism in small bowel NETs

Abstract Neuroendocrine neoplasms (NENs) are rare cancers that arise from neuroendocrine cells. NENs are classified as well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Small bowel NETs (SBNETs) and pancreatic NETs (PNETs) are generally slow growing but they commonly metastasize to the liver and can become aggressive cancers. NECs are rapidly growing, and patients have poor prognosis. Little is known about the drug sensitivity profile of SBNETs, PNETs and NECs due to a paucity of cellular and animal models of these malignancies. We have successfully cultured NEN cells from clinical samples as patient-derived spheroids (PDS) and showed that they express appropriate tumor markers. We systematically screened 20 NEN (12 SBNET, 5 PNET, and 3 NEC) spheroid cultures against a library of 175 compounds (147 FDA-approved anti-cancer drugs, 8 lab selected compounds, and 20 structurally diverse molecules) and compared their drug sensitivity profiles to identify the most effective drug classes and to better understand the biology of each NEN subtype. Top drug hits were validated for their anti-tumor properties in NEN PDS and patient-derived xenograft (PDX) mouse models. Our NEN PDS cultures identified common and unique drug sensitivity profiles for each type of NEN. SBNET spheroids were more resistant to many classes of anti-cancer drugs, which was due to overexpression of cytochrome P450 genes. Consistent with clinical findings, PNET spheroids showed increased sensitivity to tyrosine kinase and mTOR/PI3K inhibitors compared to SBNET &amp; NEC spheroids. NEC spheroids showed the broadest sensitivity to many anti-neoplastic compounds. The top candidate drug identified from our screen was romidepsin, a histone deacetylase inhibitor. Romidepsin displayed anti-tumor properties in vitro and in vivo for all 3 NEN models and was highly synergistic with rapamycin, an mTOR inhibitor similar to the SBNET approved drug everolimus. Excitingly, low-dose romidepsin effectively inhibited tumor growth when combined with low-dose rapamycin in an SBNET PDX mouse model. These NEN PDS drug screens enabled direct drug testing in primary tumor cultures to identify promising drugs that could be used alone or in combination with currently approved-NEN therapies. Histone deacetylase inhibitors, such as romidepsin, may be effective against SBNETs. NEN PDS models also serve as a valuable resource for understanding the unique biology and mechanisms of drug resistance for specific NEN subtypes. Citation Format: Catherine G. Tran, Luis C. Borbon, Dane H. Tow, Jonathan Shilyansky, Guiying Li, James Egan, Scott K. Sherman, Ellen Abusada, Jing Tang, Ramaswamy govindan, Ryan C. Fields, Terry A. Braun, Carlos HF Chan, Chandrikha Chandrasekharan, Douglas Spitz, Dawn E. Quelle, Andrew M. Bellizzi, James R. Howe, Po Hien Ear. A systematic NEN spheroid drug screen reveals a novel drug resistance mechanism in small bowel NETs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3578.