Endocrine-related cancer最新文献

{"title":"Role of GDH and PARP inhibitors as novel treatments for SDHB-deficient PPGLs.","authors":"Mouna Tabebi, Sallam Abdallah, Ahmed El-Serafi, Peter Söderkvist, Oliver Gimm","doi":"10.1530/ERC-25-0173","DOIUrl":"10.1530/ERC-25-0173","url":null,"abstract":"<p><p>SDHB, one of the four genes encoding the subunits of the Krebs cycle enzyme succinate dehydrogenase (SDH), acts as a tumor suppressor in several human cancers, including pheochromocytomas/paragangliomas. Mutations in SDHB lead to a reduction or complete loss of enzymatic activity, linking SDHB to paraganglioma malignancy. Given the difficulty in curing metastatic paragangliomas and the limited value of surgery, new treatments are needed. Glutamine dehydrogenase 1 (GDH1), a key regulator of glutathione metabolism, and poly (ADP-ribose) polymerase (PARP), essential for repairing single- or double-stranded DNA breaks, are crucial in cancer initiation and progression. We treated the human pheochromocytoma cell line (hPheo1) with knocked-down SDHB using radiation, the GDH inhibitor 'R162', and the PARP inhibitor 'olaparib'. Combining R162 with radiation enhances anticancer effectiveness, reduces cell proliferation, and causes G2/M phase arrest in the wild-type and KD-SDHB hPheo1 cell line. KD-SDHB hPheo1 cells treated with olaparib alone were more resistant than wild-type cells but were more sensitive in combination with radiation, activated repair mechanisms, and halted cell cycle progression at the G2/M phase. These results suggest that enhancing radiation-induced DNA damage could be a potential treatment strategy for metastatic pheochromocytomas/paragangliomas. Inhibiting GDH1 and PARP activities, with radiation, may represent promising strategies for the treatment of SDHB-deficient pheochromocytoma/paraganglioma; however, their effects do not appear to be specific to SDHB-deficient cells and require further validation.</p>","PeriodicalId":93989,"journal":{"name":"Endocrine-related cancer","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GIPR in GH-PitNETs: molecular and functional insights.","authors":"Mattia Dalle Nogare, Serena Avallone, Eva Galletta, Giorgia Perbellini, Giorgia Pallafacchina, Luna Picello, Daniele Puggina, Mauro Vismara, Gabriele Sales, Giovanni Vazza, Daniela Regazzo, Gianluca Occhi","doi":"10.1530/ERC-25-0106","DOIUrl":"https://doi.org/10.1530/ERC-25-0106","url":null,"abstract":"<p><p>Acromegaly, primarily caused by GH-secreting pituitary neuroendocrine tumors (GH-PitNETs), in about half of cases exhibits resistance to somatostatin receptor ligands (SRLs), making surgery the primary treatment. Recent evidence suggests that glucose-dependent insulinotropic polypeptide receptor (GIPR) overexpression in a subset of GH-PitNETs contributes to disease heterogeneity, particularly in tumors showing a paradoxical GH rise after glucose load, which are associated with a less aggressive phenotype and better first-generation SRLs response. This study investigated the functional role of GIPR in somatotroph cells by generating stable human GIPR-expressing GH3 cells (GH3hGIPR) and comparing them with empty vector controls. Functional assays demonstrated that GIPR activation induces cAMP/PKA and MAPK/ERK signaling, enhances GH and prolactin secretion, and increases intracellular calcium oscillations, dependent on extracellular calcium influx. Transcriptomic analysis revealed differential gene expression patterns linked to cell motility, neuronal development, and extracellular matrix remodeling in GH3hGIPR cells, aligning with clinical observations in GIPR+ tumors. However, GIPR overexpression did not alter cell proliferation or viability, suggesting that its role in tumor behavior may depend on additional molecular or epigenetic factors. These findings highlight the importance of GIPR signaling in somatotroph cell function, and its potential influence on therapeutic responses, though further studies are needed to clarify its contribution to tumorigenesis and SRL sensitivity.</p>","PeriodicalId":93989,"journal":{"name":"Endocrine-related cancer","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145260290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-line lenvatinib and sorafenib in RR-DTC from a shared real-life context.","authors":"Vincenzo Marotta, Anna Tortora, Mariafelicia Valeriani, Alessia Caleo, Sara Gaeta, Teresa Infante, Francesco Stanzione, Luca Scafuri, Claudio Gambardella, Francesca Di Gennaro, Francesco Perri, Antongiulio Faggiano, Mario Vitale, Luciano Pezzullo","doi":"10.1530/ERC-24-0215","DOIUrl":"10.1530/ERC-24-0215","url":null,"abstract":"<p><p>The kinase-inhibitors lenvatinib and sorafenib represent the first-line options for radioiodine-refractory differentiated thyroid cancer (RR-DTC). Comparative studies in the same study population or between similar cohorts are scarce. Our objective was to compare lenvatinib and sorafenib in naïve RR-DTC in a homogeneous real-life context. We performed a retrospective study involving two Institutions from the Italian region Campania. Primary endpoints were progression-free survival (PFS) and overall-survival (OS). Secondary endpoints were objective response rate (ORR), disease-control rate, adverse events graded ≥ 3, toxicity-related treatment withdrawal and dose reductions/interruptions. Forty-eight RR-DTC were included (median follow-up 45.5 months): 24 received lenvatinib from 2015 to 2021 and 24 sorafenib from 2012 to 2016. The sorafenib group showed higher disease-related symptoms rate (p=0.022), tumor burden (p=0.002) and cumulative radioiodine dose compared to lenvatinib. At univariate analysis, median PFS and OS were significantly longer for lenvatinib (30 and 53 months, respectively) compared to sorafenib (10 and 38 months, respectively) (p <0.001 and =0.037, respectively). At multivariate analysis, the significance was retained for PFS and lost for OS. ORR was higher for lenvatinib compared to sorafenib (p<0.001). Dose reductions and interruptions were more frequent for lenvatinib compared to sorafenib (p = 0.003 and 0.01, respectively). In our real-life context, RR-DTC treated with first-line sorafenib had more advanced disease compared to lenvatinib. Lenvatinib exerted stronger antitumor activity (improved PFS and ORR) compared to sorafenib, but did not improve OS. Sorafenib was more manageable.</p>","PeriodicalId":93989,"journal":{"name":"Endocrine-related cancer","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145234799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reciprocal cancer risks between thyroid and breast cancer: a systematic review and meta-analysis.","authors":"Patrícia Pacheco Viola, Matheus Wohlfahrt Baumgarten, Dimitris Rucks Varvaki Rados, Letycia Ribeiro, Ana Luiza Maia, Iuri Martin Goemann","doi":"10.1530/ERC-24-0338","DOIUrl":"10.1530/ERC-24-0338","url":null,"abstract":"<p><p>Thyroid cancer (TC) and breast cancer (BC) are common in females, with growing evidence of their higher-than-expected co-occurrence. The purpose of this systematic review and meta-analysis was to evaluate the relationship between TC and BC and to examine the likelihood of developing BC after TC (TC1-BC2) and TC after BC (BC1-TC2). A systematic search was conducted in PubMed and Embase for articles with epidemiological evidence of TC and BC, published until 2024. For BC1-TC2 studies, subgroup analysis was performed on age at diagnosis and treatment type. The standardized incidence ratio (SIR) was used to calculate the risk of second primary malignancy. The MOOSE guidelines were followed, and the Newcastle-Ottawa scale was used to assess the quality of studies. Sixteen studies comprising 511,787 patients were included in the meta-analysis of TC1-BC2 and showed an increased risk of BC after TC (SIR = 1.4, 95% CI: 1.2-1.6, P < 0.01). Moreover, 28 studies with 2,486,870 patients were included for the BC1-TC2 meta-analysis and also demonstrated an increased risk of TC after BC (SIR = 1.5, 95% CI: 1.3-1.7, P < 0.01). The risk of TC was higher in BC patients under 50 (SIR = 1.8, 95% CI: 1.2-2.3) and in those treated with chemotherapy (SIR = 1.6, 95% CI: 1.5-1.7). Radiotherapy for BC was not linked to an increased risk of TC. Here, we demonstrated an increased risk of TC or BC as secondary malignancies. Furthermore, studies are needed to better understand this association and its implications for patient follow-up and management strategies.</p>","PeriodicalId":93989,"journal":{"name":"Endocrine-related cancer","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145126850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictive value of metabolic state on PanNET response to mTOR inhibitors.","authors":"Jérôme Cros, Margot Bucau, Matthieu Tihy, Maxime Palazzo, Pierre Bourgoin, Anais Chassac, Miguel Albuquerque, Alain Sauvanet, Safi Dokmak, Marco Dioguardi Burgio, Valérie Paradis, Olivia Hentic, Philippe Ruszniewski, Louis de Mestier, Vinciane Rebours, Anne Couvelard","doi":"10.1530/ERC-24-0331","DOIUrl":"10.1530/ERC-24-0331","url":null,"abstract":"<p><p>mTOR inhibitors such as everolimus and BEZ235 have demonstrated efficacy in pancreatic neuroendocrine tumors (PanNET) at the cost of severe side effects, and no biomarker currently predicts response. To identify molecular pathways of resistance, precision-cut slices of 17 fresh well-differentiated PanNET were cultured with everolimus or BEZ235 for 2 days and immunostained with cleaved caspase-3 and mTOR pathway markers. Transcriptomes of sensitive and resistant tumors were compared, and candidate pathways validated by immunohistochemistry. The predictive value of key proteins was then assessed in 26 PanNET patients treated with everolimus. mTOR inhibitors induced significant apoptosis and loss of pS6 and p4EBP1 in tumor slices, with 6/17 tumors considered sensitive. Transcriptomic analysis revealed that sensitive tumors displayed a mitochondrial-based metabolism, whereas resistant tumors exhibited a hypoxic and glycolytic profile, confirmed by high expression of CAIX, GLUT1, ATP5O, and mtTFA. Necrosis was absent and microvessel density similar in both groups, suggesting a pseudohypoxic metabolism in resistant tumors. High expression of CAIX and LDHA, two markers of pseudohypoxia/glycolysis, was associated with shorter progression-free survival in patients treated with everolimus. This study demonstrates that tissue culture can effectively assess drug response in PanNET and identifies a pseudohypoxic/glycolytic profile as a determinant of resistance to mTOR inhibition, detectable by immunohistochemistry and potentially noninvasively by 18F-FDG PET-CT.</p>","PeriodicalId":93989,"journal":{"name":"Endocrine-related cancer","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145077050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of sex hormones on development and progression in NEN: a new therapeutic target?","authors":"Roberta Modica, Alessia Liccardi, Elena Zago, Nevena Mikovic, Franz Sesti, Sofia Ballarini, Renata Simona Auriemma, Annamaria Colao","doi":"10.1530/ERC-25-0164","DOIUrl":"10.1530/ERC-25-0164","url":null,"abstract":"<p><p>Neuroendocrine neoplasms (NEN) are a rare and heterogeneous group of malignancies with rising incidence, requiring multidisciplinary and personalized management. Sex is emerging as a crucial factor in NEN development and progression. Genetic, epigenetic, and hormonal mechanisms have been proposed as potential contributors influencing treatment response and prognosis, but an in-depth analysis of the role of sex hormones and their receptors in NEN is still lacking. This review aims to analyze the impact of sex hormones and their receptors in sporadic NEN to provide potential therapeutic targets in the context of precision medicine. An overview of current preclinical and clinical evidence focused on different primary NEN, including gastroenteropancreatic, lung, prostate, and medullary thyroid cancers, focusing on estrogen, progesterone, and androgen receptors, has been made to clarify their role in NEN. Variable and conflicting results emerged across different primaries. Progesterone receptors appear to play a pivotal role in pancreatic and lung NEN, while estrogen receptors are more frequently involved in small intestine NEN and medullary thyroid carcinoma, suggesting a possible role in metastatic spread. Further studies are required to increase knowledge of the underlying mechanism of sex differences in NEN to define potential therapeutic targets for personalized care.</p>","PeriodicalId":93989,"journal":{"name":"Endocrine-related cancer","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145076990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Defining aging-associated factors that increase susceptibility to prostate cancer.","authors":"Shile Zhang, Ernie Lee, Sachi Bopardikar, Andrew S Goldstein","doi":"10.1530/ERC-25-0026","DOIUrl":"10.1530/ERC-25-0026","url":null,"abstract":"<p><p>Age is a major risk factor for a range of diseases, including prostate cancer. Understanding how age influences the susceptibility of normal prostate epithelial cells to cancer initiation is complicated by the fact that aging affects all tissues in the body. Assessing how various aging mechanisms influence the prostate epithelium is a necessary step to determine the critical factors associated with aging that increase prostate cancer risk. Here, we take a broad view of both prostate epithelial cell-intrinsic and cell-extrinsic factors that change with age and are likely to contribute to age-related risk of prostate tumorigenesis. For each factor, we discuss the impact of these age-related changes on cancer risk. We highlight important areas where additional research is required to help decipher the specific age-associated changes that contribute to prostate cancer initiation. Finally, we address the potential impact of various therapeutic interventions on aging phenotypes and cancer risk.</p>","PeriodicalId":93989,"journal":{"name":"Endocrine-related cancer","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12476893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical presentation of bone metastases in neuroendocrine tumors: a retrospective cohort study.","authors":"Elisabetta Lavezzi, Simona Jaafar, Isabella Chiardi, Alessandro Brunetti, Emanuela Morenghi, Roberta Elisa Rossi, Miriam Cellini, Maria Francesca Birtolo, Silvia Uccella, Alessandro Zerbi, Alice Laffi, Alexia Bertuzzi, Fabio Vescini, Gherardo Mazziotti, Andrea Gerardo Antonio Lania","doi":"10.1530/ERC-25-0147","DOIUrl":"10.1530/ERC-25-0147","url":null,"abstract":"<p><p>Bone metastases (BMs) are a rare and late event in patients with neuroendocrine tumors (NETs). The aim of our study was to investigate the clinical presentation and outcome of BMs in a large cohort of patients with NETs. A retrospective study was performed at two referral centers of Northern Italy (IRCCS Humanitas Research Hospital in Milan and Santa Maria della Misericordia University Hospital in Udine). Three hundred fifty-two consecutive patients with either gastroenteropancreatic or non-gastroenteropancreatic NETs were included: 52 patients with synchronous or metachronous BMs (BM-positive) and 300 patients with metastatic disease without BMs (BM-negative). Patients with BMs showed a higher prevalence of smoking habit (41.2 vs 21.8%, P = 0.004) and carcinoid syndrome (28.8 vs 5.7%, P <0.001) compared to patients without BMs. In addition, higher levels of chromogranin A (P = 0.001), urinary 5-hydroxyindoleacetic acid (P <0.001), parathyroid hormone (P = 0.022), and alkaline phosphatase (P = 0.018) were found compared to the BM-negative group. Patients with BMs had more frequently a primary lung NET compared to the BM-negative group (19.2 vs 0.7%, P = 0.001) and grade G2 or G3 gastroenteropancreatic tumors (P <0.001) compared to the BM-negative group. During a median follow-up of 4.2 years, a higher mortality rate was registered in the BM-positive group as compared to BM-negative group (42.3 vs 4.0%, P = 0.001). BMs were more common in patients with lung NETs, G2-G3 grade tumors, and in those with carcinoid syndrome. BMs affected patients' prognosis, highlighting the importance of investigating and managing this condition in patients with NETs.</p>","PeriodicalId":93989,"journal":{"name":"Endocrine-related cancer","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neoadjuvant palbociclib in women with operable, hormone receptor-positive breast cancer.","authors":"Takayuki Ueno, Louis W C Chow, Wonshik Han, Chiun Sheng Huang, G Bruce Mann, Satoshi Morita, Hironori Haga, Elham Fakhrejahani, Takayuki Kobayashi, Hiroko Bando, Kenichi Inoue, Mariko Tokiwa, Hirofumi Suwa, Tomoyuki Aruga, Sachiko Minamiguchi, Yosuke Yamada, Yuko Tanabe, Masahiro Takada, Toshinari Yamashita, Hiroji Iwata, Chi-Feng Chung, Sachiko Takahara, Eriko Tokunaga, Shigeru Imoto, Eun Sook Lee, Yasuaki Sagara, Jee Hyun Kim, Richard H DeBoer, Hyun-Ah Kim, Hung Wen Lai, Ming Feng Hou, Michelle White, Yoshiko Umeyama, Masakazu Toi","doi":"10.1530/ERC-24-0353","DOIUrl":"10.1530/ERC-24-0353","url":null,"abstract":"<p><p>The addition of a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor to endocrine therapy augments biological response in breast cancer. This phase III randomized, double-blind study evaluated the efficacy of adding palbociclib to neoadjuvant endocrine therapy (NET) for operable, hormone receptor-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Patients randomly received 16 weeks of endocrine therapy (letrozole for postmenopausal and tamoxifen plus ovarian function suppression for pre-/perimenopausal patients) plus palbociclib or placebo. The co-primary endpoints included preoperative endocrine prognostic index (PEPI) score and EndoPredict (EPclin) risk score according to the gatekeeping procedure. Of 141 randomized patients, 130 completed the treatment with surgical samples evaluable for endpoints in 126 patients. The proportion of patients with a low, moderate, and high PEPI score was 15.2, 50.0, and 34.8% in the palbociclib arm and 13.3, 55.0, and 31.7% in the placebo arm, respectively, with no statistical difference (one-sided P = 0.563). Statistical analysis was not performed on EPclin risk score. No new safety signals were reported. Permanent treatment discontinuation by adverse events was reported for seven (9.7%) and zero patients in the palbociclib and placebo arms, respectively. In conclusion, the addition of palbociclib to NET did not improve the efficacy. ClinicalTrials.gov NCT03969121.</p>","PeriodicalId":93989,"journal":{"name":"Endocrine-related cancer","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12433830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144983795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-tumor potential of combinatory GSK3 inhibition in human 3D models of pancreatic neuroendocrine tumors and patient-derived GEP-NET primary cultures.","authors":"Svenja Nölting, Edlira Luca, Igor Shapiro, Katharina Wang, Christoph J Auernhammer, Felix Beuschlein, Kathrin Zitzmann, Huguette Debaix, Constanze Hantel","doi":"10.1530/ERC-25-0073","DOIUrl":"10.1530/ERC-25-0073","url":null,"abstract":"<p><p>Activation of signaling pathways that regulate survival, proliferation, motility, inflammation, metabolism, and stemness fuel tumor growth, metastasis, and recurrence. Therapies targeting signaling pathway components, including candidates such as GSK3 and TNFα, drastically affect cellular viability in preclinical cancer models but have limited success in the clinic. However, in recent years, spheroids and organoids have been demonstrated to more accurately reflect tumor characteristics and to be better predictors of therapeutic response than monolayer cultures. Here, we used 3D models from the pancreatic neuroendocrine tumor (pNET) model BON1 to evaluate the effect of GSK3 inhibition along with TNFα or insulin and extended our results in primary gastroenteropancreatic (GEP-)NET culture. The multidimensional configuration of BON1 spheroids imparted aggressive characteristics and a lack of anti-proliferative effects upon single treatments. However, GSK3 inhibition alone resulted in dispersion of spheroids, indicating that GSK3 is necessary for cell-cell adhesions and participates in spheroid architecture. Interestingly, GSK3 inhibition in combination with TNFα or insulin led to drastically reduced cell proliferation. In fresh patient-derived 2D primary cultures from (GEP-)NETs, we demonstrate that insulin has tumor-promoting effects, while GSK3 inhibition and metformin display significant anti-tumor activity mediated through common effects on GSK3/insulin signaling. Both agents show strong efficacy in a patient-derived insulinoma without affecting the corresponding normal pancreatic tissue. We conclude that treatment efficacy depends on three-dimensional architecture and that combinatorial treatments which target cellular dispersion in addition to cellular viability might have beneficial clinical applications, but metastatic potential of remaining single cells needs further characterization before clinical implementation.</p>","PeriodicalId":93989,"journal":{"name":"Endocrine-related cancer","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144983757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}