bims-necame Biomed News
on Metabolism in small cell neuroendocrine cancers
Issue of 2026–03–22
thirteen papers selected by
Grigor Varuzhanyan, UCLA
  1. Synthetic lethality between RB-loss and E2F3 inhibition in small cell cancers targeted by pyrimidine synthesis blockade.
  2. The Wnt receptor Frizzled3 (FZD3) drives aggressive phenotypes in small cell lung cancer.
  3. TNIK overexpression is sufficient for chemoradiation resistance in limited-stage small cell lung cancer.
  4. SMARCA4-deficient thoracic malignancies with small cell lung cancer-like features: A clinicopathological and molecular study of a heterogeneous group.
  5. Targeting endoplasmic reticulum stress and nitroso-redox imbalance in cancer progression.
  6. Cervical neuroendocrine carcinoma with non-neuroendocrine components has a poorer prognosis than pure neuroendocrine carcinoma.
  7. Multi-omics reveals key molecular and cellular features of advanced small cell lung cancers associated with distinct therapeutic opportunities.
  8. Building a diagnostic scoring system for high-grade neuroendocrine neoplasms of the pancreas.
  9. Synthesis, Radiochemical Characterization, and Biodistribution of a 188Re Analogue of [131I]mIBG in a Neuroblastoma Xenograft Model.
  10. Distinct malignant cell states and myeloid glutamate signaling associated with aggressive pancreatic neuroendocrine tumors.
  11. Brief Report: Androgen Receptor Expression Is Associated With Male Predominance in Thymic Neuroendocrine Neoplasms.
  12. Exosomal ZFPL1 Identifies Neuroendocrine and Stem Cell-Like Prostate Cancer Subtypes?
  13. Rabdosin B suppresses proliferation of nonsmall cell lung cancer by regulating the SRC/PI3K/AKT signaling pathway.
  1. Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2532814123
    Synthetic lethality between RB-loss and E2F3 inhibition in small cell cancers targeted by pyrimidine synthesis blockade.
    Evan R Abt, Liang Wang, Grigor Varuzhanyan, Jack Freeland, Tian He, Guadalupe M Peña-Garcia, Lauryn Ruegg, Jami McLaughlin, Donghui Cheng, Nikolas G Balanis, Chia-Chun Chen, Yang Xu, Yi Xing, Sanaz Memarzadeh, Caius G Radu, Thomas G Graeber, Owen N Witte.
      Small cell carcinoma is a highly lethal cancer variant often found with neuroendocrine (NE) features, as exemplified by small cell lung cancer and small cell NE prostate cancer (SCPC). A genome-wide CRISPR dependency screen using SCPC models generated through human prostate cell transformation identifies a requirement for the transcription factor E2F3. E2F3 dependency is linked to RB inactivation, a near universal occurrence across small cell cancers. The requirement for E2F3 is shared by RB-deficient cells originating from the prostate, lung, and adnexa. In RB-deficient cancer cells, E2F3 inhibition restrains cell cycle progression, proliferation, and tumor growth in vivo. Inhibition of de novo pyrimidine synthesis limits E2F3 expression and suppresses small cell carcinoma proliferation in culture. Directly or indirectly targeting E2F3 to leverage a pan-cancer synthetic lethality resulting from RB inactivation represents a potential treatment strategy.
    Keywords:  RB tumor suppressor; nucleotide metabolism; small cell cancer; synthetic lethality
    DOI:  https://doi.org/10.1073/pnas.2532814123
  2. Respir Res. 2026 Mar 21.
    The Wnt receptor Frizzled3 (FZD3) drives aggressive phenotypes in small cell lung cancer.
    Mingjun Lu, Xiaoyue Zhu, Chenyang Wang, Jiabao Hou, Jingwei Guo, Jiaqi Zhao, Zhendong Qin, Jinghong Wu, Xiaoqing Cao, Tongmei Zhang, Dongchang Wang, Teng Ma.
       BACKGROUND: Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy characterized by rapid progression and poor prognosis. This study integrates bioinformatics with experimental validation to characterize the role of Frizzled-3 (FZD3), a Wnt receptor, in SCLC progression.
    METHODS: We analyzed transcriptomic data from 102 SCLC and 55 normal lung tissues retrieved from the Gene Expression Omnibus (datasets GSE6044, GSE40275, and GSE60052). Differential expression analysis was performed using the limma package, followed by GO and KEGG pathway enrichment analyses. To screen for robust prognostic markers, we employed machine learning algorithms-specifically LASSO and Random Forest-to select hub genes. The prognostic significance of FZD3 was assessed using multivariate Cox regression and Kaplan-Meier survival analysis. Validation assays, including qRT-PCR, Western blotting, and functional assays (proliferation, migration, invasion, and apoptosis), were conducted in SCLC cell lines and clinical specimens.
    RESULTS: A total of 1,192 differentially expressed genes were identified. Enrichment analysis revealed significant involvement in immune-related pathways and Wnt signaling. FZD3 was selected as a key hub gene and found to be upregulated in SCLC tissues and cell lines. High FZD3 expression was correlated with advanced clinical stage(by Kruskal-Wallis test), and poor prognosis (by Survival analysis). In vitro function assays demonstrated that FZD3 knockdown significantly attenuated SCLC cell proliferation, migration, and invasion while inducing apoptosis.
    CONCLUSION: FZD3 is frequently overexpressed in SCLC and serves as an independent prognostic indicator for poor survival. Our findings elucidate the oncogenic role of FZD3 in SCLC, highlighting its potential as a therapeutic target and prognostic biomarker.
    Keywords:  FZD3; Machine learning; Small cell lung cancer (SCLC); Wnt signaling pathway
    DOI:  https://doi.org/10.1186/s12931-026-03634-1
  3. Mol Cancer Ther. 2026 Mar 16.
    TNIK overexpression is sufficient for chemoradiation resistance in limited-stage small cell lung cancer.
    Dipanwita Dutta Chowdhury, Eddie L Imada, Nick Connis, Jinhee Chang, Aaron Chan, Hwai Wei Tseng, Audrey Lafargue, Francesca A Carrieri, Triet Nguyen, Danielle N Waters, Elan R Simms, Amol C Shetty, Yang Song, Muhammad Ajmal Khan, Mohammad Rezaee, Phuoc T Tran, Luigi Marchionni, Christine L Hann.
      Small cell lung cancer (SCLC) is characterized by early metastasis, intrinsic chemoradiation resistance and tumor recurrence. Besides the lack of potentially targetable oncogenic drivers, therapeutic advancements are also hindered by the scarcity of surgically resected tissue specimens ideal for profiling studies. We used patient-derived xenografts (PDXs) to model SCLC chemoradiation resistance and identified chemoradiation resistance candidate genes using RNA sequencing. Additionally, we used human SCLC cell lines to confirm our in vivo results and delineate the underlying mechanism. Transcriptome profiling showed that the Traf2- and Nck-interacting kinase (TNIK) gene was consistently upregulated in an array of SCLC PDXs exposed to chemoradiation compared to monotherapy, which is consistent with previous observation of TNIK amplification in human samples. Genetic depletion (p<0.01) or pharmacological inhibition (p<0.0001) of TNIK reduced in vitro clonogenic survival of TNIKhigh SCLC cells and promoted sensitivity to chemoradiation. In vivo, pharmacological inhibition of TNIK enhanced chemoradiation sensitivity (p<0.0001) of H446 cell line-derived xenograft (CDX) in NOD-SCID mice. Furthermore, pharmacological inhibition of TNIK in vivo demonstrated sensitivity (p<0.0001) to chemoradiotherapy in LX33 PDX. These results indicate that TNIK plays a role in conferring resistance to chemoradiation in SCLC cell lines and in vivo in SCLC CDX and PDX models. Delineating the mechanism behind radiosensitization, suggested that TNIK inhibition may impair the DNA damage response in irradiated cells. Collectively, these findings suggest that TNIK may be a promising therapeutic target in limited-stage (LS) SCLC and support further investigation of TNIK inhibition in combination with standard chemoradiotherapy.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-25-0529
  4. Ann Diagn Pathol. 2026 Mar 13. pii: S1092-9134(26)00034-1. [Epub ahead of print]83 152638
    SMARCA4-deficient thoracic malignancies with small cell lung cancer-like features: A clinicopathological and molecular study of a heterogeneous group.
    Jie-Rong Ding, Xue-Guang Li, Xuan Wang, Kai Cheng, Qiu-Yuan Xia, Man-Yu Xu, Ru-Song Zhang, Ru Fang, Xiao-Xia Wang, Nan Wu, Qiu Rao.
       OBJECTIVES: To characterize SMARCA4-deficient thoracic malignancies with small cell lung cancer (SCLC)-like features as a heterogeneous disease spectrum.
    MATERIALS AND METHODS: We retrospectively reviewed our pathological archives and identified three cases that exhibited both immunohistochemical loss of SMARCA4 and "SCLC-like features," defined as the presence of characteristic SCLC histomorphology (per WHO criteria) along with immunohistochemical positivity for at least one neuroendocrine marker (synaptophysin, chromogranin A, or CD56). All cases underwent comprehensive immunohistochemical profiling, including CKpan, neuroendocrine markers, SCLC subtype-defining transcription factors (ASCL1, NEUROD1, POU2F3), as well as RB1 and p53, coupled with targeted next-generation sequencing.
    RESULTS: All tumors showed invasive growth, extensive necrosis, and uniform round-to-spindle cells with oat-shaped nuclei. Each case harbored a pathogenic truncating SMARCA4 mutation with complete loss of SMARCA4 protein expression, yet fell into distinct diagnostic categories: Case 1, located in the right upper lobe, was a SMARCA4-deficient SCLC-ASCL1 subtype, positive for CKpan, TTF-1, and neuroendocrine markers (synaptophysin, chromogranin A, CD56), and carried co-mutations in TP53 and RB1. Case 2, originating in the middle mediastinum, was a SMARCA4-deficient SCLC triple-negative (SCLC-TN) subtype, positive for CKpan, TTF-1, and synaptophysin but negative for all SCLC lineage-defining transcription factors, and also harbored TP53 and RB1 co-mutations. Case 3, a right pulmonary hilar mass, was diagnosed as a SMARCA4-deficient undifferentiated tumor (SMARCA4-UT), lacking both CKpan and TTF-1 expression while showing synaptophysin positivity, with a TP53 mutation and retained wild-type RB1.
    CONCLUSION: Through multi-platform integrated analysis, this study confirms that thoracic malignancies with SCLC-like features and SMARCA4 deficiency constitute a heterogeneous group, forming a disease spectrum extending from classical SCLC-ASCL1 and SCLC-TN subtypes to SMARCA4-UT. These findings advocate for the adoption of a systematic, integrated diagnostic workflow in clinical practice and provides a theoretical foundation for developing subtype-specific treatment strategies across the different entities within this disease spectrum.
    Keywords:  SMARCA4; SMARCA4-Deficient Undifferentiated Tumor (SMARCA4-UT); Small Cell Lung cancer (SCLC); Thoracic Malignancies
    DOI:  https://doi.org/10.1016/j.anndiagpath.2026.152638
  5. Trends Mol Med. 2026 Mar 19. pii: S1471-4914(26)00037-7. [Epub ahead of print]
    Targeting endoplasmic reticulum stress and nitroso-redox imbalance in cancer progression.
    Himanshu Arora, Rehana Qureshi.
      Therapy-resistant cancers exploit cellular stress programs to survive. Evidence from neuroendocrine prostate cancer reveals that the loss of nitric oxide-dependent redox signaling amplifies endoplasmic reticulum stress and lineage plasticity. Restoring physiological nitroso-redox balance may reprogram stress adaptation and expose new vulnerabilities in aggressive cancers.
    Keywords:  MYCN; S-nitrosylation; endoplasmic reticulum stress; lineage plasticity; neuroendocrine prostate cancer; nitric oxide
    DOI:  https://doi.org/10.1016/j.molmed.2026.02.007
  6. J Gynecol Oncol. 2026 Feb 28.
    Cervical neuroendocrine carcinoma with non-neuroendocrine components has a poorer prognosis than pure neuroendocrine carcinoma.
    Sun Min Park, Chel Hun Choi, Kidong Kim, Hyojin Kim, Se Ik Kim, Chae Hyeong Lee.
       OBJECTIVE: To investigate whether neuroendocrine carcinoma of the cervix (NECC) with coexisting non-neuroendocrine tumor components (mixed subtype) is associated with a worse prognosis compared to the pure subtype.
    METHODS: A total of 121 patients diagnosed with NECC at 4 participating hospitals in the Republic of Korea between August 1997 and November 2023 were included. All diagnoses were confirmed through surgical specimens obtained via conization or hysterectomy. Clinical and pathological variables were collected through medical record review. The association between tumor heterogeneity (pure vs. mixed subtype) and progression-free survival (PFS) was analyzed using a Cox proportional hazards model.
    RESULTS: The majority of patients was diagnosed at stage I (62%), had small cell histology (63%), and presented with the pure subtype (66%). Most patients (n=106) underwent surgery with or without adjuvant therapy as initial treatment. In univariate analysis, there was no significant difference in PFS between the pure and mixed subtypes (p=0.952). However, after adjusting for covariates, the mixed subtype was significantly associated with worse PFS compared to the pure subtype (adjusted hazard ratio=3.16; 95% confidence interval=1.58-6.35; p=0.001).
    CONCLUSION: NECC with non-neuroendocrine components is associated with significantly worse prognosis than the pure subtype.
    Keywords:  Carcinoma, Neuroendocrine; Mixed Tumor, Malignant; Neuroendocrine Tumors; Progression-Free Survival; Uterine Cervical Neoplasms
    DOI:  https://doi.org/10.3802/jgo.2026.37.e80
  7. Genome Med. 2026 Mar 17.
    Multi-omics reveals key molecular and cellular features of advanced small cell lung cancers associated with distinct therapeutic opportunities.
    Katia Nones, Vanessa Lakis, Andrew J Dalley, Kimberley Ryan, Haarika Chittoory, Kaltin Ferguson, Kate Fitzgerald, Felicity Newell, Lambros T Koufariotis, Farzad Bashirzadeh, Jung Hwa Son, Mahendra Singh, Lakshmy Nandakumar, David Fairbairn, Margaret Cummings, Daniel Steinfort, Jemma J Christie, Matthew Gibney, Jonathan P Williamson, Andrew Pattison, Louise McIntosh, Carl Pahoff, Phan Tien Nguyen, Jelena Solujic, Michael Brown, Scott Twaddell, David Arnold, Christopher Grainge, Shailendra Gune, Oliver Holmes, Conrad Leonard, Scott Wood, John V Pearson, Sunil R Lakhani, Peter T Simpson, Nicola Waddell, David Fielding.
       BACKGROUND: Small cell lung cancer (SCLC) is an aggressive disease that is often diagnosed at an advanced stage when surgery is no longer feasible. The lack of tumor tissue and rapid clinical decline of patients have hindered the feasibility of large omics studies. However, with advances in omics technologies recent studies have started to unravel the molecular heterogeneity of SCLCs.
    METHODS: Here, 82 fresh EBUS-TBNA aspirates underwent methylation profiling (EPIC arrays), with subsets of those subjected to whole-genome sequencing (n = 76), RNA-seq (n = 48) and blood cfDNA sequencing (n = 69) to characterize the molecular features of SCLCs.
    RESULTS: Methylation profiling revealed four sub-groups associated with distinct survival and extrinsic/intrinsic tumor features. Groups 1 and 2 presented increased expression of ASCL1. Group 1 tumors had a greater proportion of CD8 + T cells (immune enriched-NE) and patients with better survival. Group 2 (SCLC-A) harbored the largest number of cases, and high expression of SLFN11 and DLL3, as potential therapeutic options. Group 3 tumors presented increased expression and hypomethylation of NEUROD1 (SCLC-N), with a greater proportion of fibroblasts. Group 4 tumors expressed POU2F3 and/or YAP1, had increased expression of non-neuroendocrine genes (non-NE) and had the worst survival. TACSTD2 expression was higher in Group 4, suggesting a potential therapeutic option for this group. SEZ6, another potential therapeutic option, was highly expressed in most SCLCs. These results highlight that novel therapeutic options may need to be considered in the context of SCLC heterogeneity.
    CONCLUSIONS: We showed that methylation of the most common source of tumor tissue in the clinical setting can stratify SCLCs with distinct clinical outcomes and potentially tailored therapeutic options. Methylation can characterize the intrinsic and extrinsic heterogeneity of SCLCs and fuel the discovery of novel therapeutic vulnerabilities to help bridge the gap between research and clinical application to improve care for SCLC patients.
    Keywords:  CfDNA; DNA methylation; Multi-omics; Precision oncology; Small cell lung cancer; Transcriptomics; Tumor heterogeneity; Whole-genome sequencing
    DOI:  https://doi.org/10.1186/s13073-026-01624-y
  8. Am J Clin Pathol. 2026 Mar 03. pii: aqaf154. [Epub ahead of print]165(3):
    Building a diagnostic scoring system for high-grade neuroendocrine neoplasms of the pancreas.
    Yuko Kinowaki, Charlotte Wang, Yuki Fukumura, Maria Ganci, M Lisa Zhang, Masanori Kobayashi, Keiichi Akahoshi, Atsushi Kudo, Keiichi Kinowaki, Keita Kai, Yumi Mihara, Ayumi Murakami, Hung Ngoc Nguyen, Ryoichi Hanazawa, Akihiro Hirakawa, Liang Minggao, Morito Kurata, Fumihiko Ishikawa, Carlos Fernandez-Del Castillo, Mari Mino-Kenudson.
       OBJECTIVE: High-grade neuroendocrine neoplasms of the pancreas (PanNENs), which comprise well-differentiated pancreatic neuroendocrine tumors, grade 3 (PanNET G3s) and pancreatic neuroendocrine carcinomas (PanNECs), are rare but aggressive tumors. Accurate differentiation between PanNET G3s and PanNECs remains a diagnostic challenge, despite their distinct biological behavior and treatment strategies. This study aimed to develop a scoring system to improve diagnostic accuracy using readily available clinicopathologic and immunohistochemical data.
    METHODS: Sixty-six high-grade PanNEN cases underwent clinicopathologic review, immunohistochemistry, and next-generation sequencing. After exclusion of 4 mixed acinar-neuroendocrine carcinomas, 1 diagnostically ambiguous case, and 3 cases with insufficient tissue for next-generation sequencing, 58 cases (29 PanNET G3, 29 PanNEC) were analyzed.
    RESULTS: Lasso logistic regression identified predictive features of PanNEC, and multivariable logistic regression was used to assign weights to each factor. Positive predictors of PanNEC included p53 alterations (+4), Rb1 loss (+3), interstitial reaction (+3), co-existing non-neuroendocrine carcinoma (+3), abundant mitoses (+2), and a Ki67 proliferation index greater than 40% (+1). Negative predictors included co-existing PanNET G1/2 (-2), plasmacytoid cells (-1), DAXX/ATRX loss (-1), and somatostatin receptor subtype 2A 3+ (-1). In validation, the average score for PanNEC was 9.52 (median, 10.0); the average score of PanNET G3s was -1.31 (median, -1.0). Using a cutoff of 5.0, the model achieved an area under the curve of 0.989 for distinguishing PanNEC from PanNET G3.
    CONCLUSIONS: This novel scoring system demonstrated excellent diagnostic performance in differentiating PanNEC from PanNET by integrating morphologic and immunohistochemical features. Prospective studies with larger cohorts are warranted to validate its clinical utility.
    Keywords:  Lasso logistical regression; PanNEC; PanNET G3; diagnostic scoring system; immunohistochemistry; molecular pathology; pancreas
    DOI:  https://doi.org/10.1093/ajcp/aqaf154
  9. J Labelled Comp Radiopharm. 2026 Mar;69(3): e70025
    Synthesis, Radiochemical Characterization, and Biodistribution of a 188Re Analogue of [131I]mIBG in a Neuroblastoma Xenograft Model.
    Navin Sakhare, Dheeraj Kumar, Soumen Das, Arpit Mitra, Shubhangi Mirapurkar, G Rani, M Sheela, Viju Chirayil, Bhabani Mohanty, Anupam Mathur, Madhava B Mallia, Pradip Chaudhari.
      [131I]meta-iodobenzylguanidine (mIBG) in variable dosage forms is widely used for the therapy of neuroendocrine tumors. Our group previously reported a 99mTc analogue of [131I]mIBG that demonstrated high specificity in vitro towards norepinephrine transporter (NET)-positive neuroblastoma cells. Considering that the 99mTc/188Re pair serves as a useful theranostic combination, we herein describe the synthesis of its 188Re analogue and evaluate its potential for therapeutic applications. A benzylguanidine derivative functionalized at the meta position via an isonitrile moiety ("1") was employed for 188Re complexation following Re-"4 + 1" chemistry. Synthesized 188Re complex 6 was evaluated in NET-positive SK-N-SH neuroblastoma cells and corresponding xenograft models. Cellular uptake studies revealed that the 188Re complex 6 exhibited ~50% of the uptake observed for [125I]mIBG. Nonetheless, it retained significant NET specificity (~60%), as confirmed by inhibition experiments using desmethylimipramine (DMI). Biodistribution studies in SK-N-SH xenograft-bearing mice demonstrated tumor uptake of 4.07 ± 0.08%ID/g at 30 min (p > 0.05), with significant retention up to 3 h (4.99 ± 0.08%ID/g). Tumor uptake was shown to be NET-specific, as pre-treatment with excess DMI significantly inhibited tracer accumulation in vivo. Bioevaluation of the synthesized 188Re complex 6 confirmed its affinity for NETs; however, limited in vivo stability restricted its suitability for therapeutic application.
    Keywords:  131I‐mIBG; 188Re; NET; neuroendocrine tumor; theranostic
    DOI:  https://doi.org/10.1002/jlcr.70025
  10. Clin Cancer Res. 2026 Mar 18.
    Distinct malignant cell states and myeloid glutamate signaling associated with aggressive pancreatic neuroendocrine tumors.
    Jeanna M Arbesfeld-Qiu, Jae-Won Cho, Phuong T T Nguyen, Nicole A Lester, Jennifer Su, Carina Shiau, Jimmy A Guo, Hannah Hoffman, Nicholas Caldwell, Shugo Muratani, Miranda Galvan, Jessica E Proctor, Zackery Ely, Steven Wang, Maria Ganci, Ruben Dries, Theodore Hong, Jennifer Wo, Genevieve Boland, Carlos Fernandez-Del Castillo, Cristina R Ferrone, Christopher M Heaphy, M Lisa Zhang, Mari Mino-Kenudson, Martin Hemberg, William L Hwang.
       PURPOSE: Pancreatic neuroendocrine tumors (PNET) are rare malignancies of the endocrine pancreas with diverse clinical outcomes. While some PNETs are indolent, others are aggressive and metastasize quickly. However, clinically-relevant molecular stratification for PNET to predict outcomes and guide therapeutic decision-making is limited. Thus, there is an urgent need to understand the molecular heterogeneity of PNETs to refine prognostication and discover novel therapeutic vulnerabilities.
    EXPERIMENTAL DESIGN: We performed single-nucleus RNA sequencing on untreated, resected primary and metastatic PNETs (n = 18). We inferred gene expression programs (GEPs) of malignant and non-malignant cells and investigated associations with clinical outcomes. Next, we inferred interactions in the tumor microenvironment (TME) and performed transwell migration assays for functional validation. Finally, we explored genomic and transcriptomic evolution in a unique case study of an untreated primary PNET with two asynchronous hepatic metastases.
    RESULTS: A malignant GEP enriched for neural/synaptic signaling genes was associated with worse overall survival, broad chromosomal loss of heterozygosity, and alternative lengthening of telomeres. Another malignant GEP enriched for VEGF signaling increased throughout metastatic progression in our case study. We found that macrophage-derived glutamate drives polarization towards an immunosuppressive phenotype and activates the MAPK/ERK pathway in malignant cells to increase migratory capacity.
    CONCLUSIONS: This study provides a detailed single-nucleus transcriptomic classification of malignant, stromal, and immune cell types and states in PNETs, their interactions in the TME, and associations with clinical outcomes. The refined molecular taxonomy of PNET may guide the development of more efficacious biomarkers and therapeutic strategies.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-2565
  11. JTO Clin Res Rep. 2026 Apr;7(4): 100973
    Brief Report: Androgen Receptor Expression Is Associated With Male Predominance in Thymic Neuroendocrine Neoplasms.
    Christopher S Nabel, Chad B Sussman, Charles A Whittaker, Vincent L Butty, Jennifer L Peterson, Haley K Martin, Abner Louissaint, Eva Bru-Tari, Simona Chera, Azra H Ligon, Beow Y Yeap, Pedro L Herrera, Yin P Hung.
       Introduction: Neuroendocrine neoplasms represent a rare and poorly understood collection of malignancies. A better understanding of their biology is needed to improve treatment options. Male predominance to the incidence of neuroendocrine neoplasms of the thymus suggests a biological basis for this observation.
    Methods: This single-institution, retrospective cohort study evaluated androgen receptor (AR) expression and other clinicopathologic features in thymic neuroendocrine neoplasms compared with thymic epithelial tumors and neuroendocrine neoplasms of other sites. Expression of neuroendocrine and prostate markers was also assessed. For further molecular characterization, copy number analysis of AR and other relevant genes was assessed by single nucleotide polymorphism array. Last, analysis of single genes and thymic epithelial gene sets was performed using published thymic tumor transcriptomes.
    Results: A cohort was assembled from 17 patients with neuroendocrine malignancies of primary thymic origin with assessable tissue for immunohistochemical analysis. The cohort was predominantly male (12 males, five females). Immunohistochemical analysis of the AR demonstrated positive staining in nine cases, all of which were male. Compared with thymic neuroendocrine neoplasms, AR expression is considerably less frequent in thymomas, thymic carcinoma, and neuroendocrine neoplasms of other sites of origin. No relevant copy number changes in the AR were identified. Further molecular characterization revealed expression of ASCL1 and limited expression of common prostate lineage and differentiation markers within our cohort, including thymic neuroendocrine epithelial gene set enrichment in published transcriptomes of thymic neuroendocrine neoplasms.
    Conclusion: The AR is expressed in a considerable fraction of thymic neuroendocrine neoplasms and is associated with male predominance. This observation has implications for investigation of androgen deprivation and receptor blockade.
    Keywords:  Androgen receptor; Molecular characterization; Neuroendocrine neoplasms; Thymic epithelial tumors; Thymic neuroendocrine tumor
    DOI:  https://doi.org/10.1016/j.jtocrr.2026.100973
  12. Prostate. 2026 Mar 15.
    Exosomal ZFPL1 Identifies Neuroendocrine and Stem Cell-Like Prostate Cancer Subtypes?
    Neshat Masud, Johnmesha Sanders, Kenneth A Iczkowski, Girish V Shah.
       BACKGROUND: Calcitonin (CT) and its receptor promote prostate cancer (PC) progression and metastasis. Identifying downstream CT-regulated genes may provide clinically useful biomarkers.
    METHODS: Subtraction hybridization was used to identify CT-inducible genes. Expression of zinc finger protein-like 1 (ZFPL1) was examined in malignant versus benign prostate tissues and evaluated for regulation by CT and androgens. Exosomal secretion of ZFPL1 protein was assessed, and plasma levels were measured in PC patients compared with cancer-free individuals. Immunohistochemistry was performed to assess ZFPL1 localization with neuroendocrine (NE) and stem cell markers.
    RESULTS: ZFPL1 was strongly expressed in malignant prostates but nearly absent in benign tissues. Its expression was upregulated by both CT and androgens. ZFPL1 protein was secreted through exosomes, and plasma concentrations in PC patients were at least fourfold higher than in cancer-free controls. Immunohistochemistry confirmed ZFPL1 co-localization with NE and stem cell markers, suggesting an association with aggressive, androgen-resistant PC.
    CONCLUSIONS: ZFPL1 is a CT- and androgen-regulated protein selectively expressed in malignant prostate cells and secreted via exosomes. Its elevated plasma levels and association with aggressive disease highlight its promise as a non-invasive biomarker for PC detection and monitoring.
    Keywords:  calcitonin; cancer marker; neuroendocrine; prostate cancer; zinc finger protein like 1
    DOI:  https://doi.org/10.1002/pros.70148
  13. Pharm Biol. 2026 Dec;64(1): 451-470
    Rabdosin B suppresses proliferation of nonsmall cell lung cancer by regulating the SRC/PI3K/AKT signaling pathway.
    Xinfei Chen, Jiacong Hao, Chenfeng Guo, Jinyu Zhang, Lu Lv, Youmei Peng, Na Li, Qinyuan Xie, Xiudan Wang, Huiping Chen, Yan Zhang.
       CONTEXT: Rabdosin B (RB), an active compound derived from the Chinese herb Isodon japonicus (Burm. f.) H. Hara, has demonstrated inhibitory effects on non-small cell lung cancer (NSCLC) cell proliferation in prior studies. However, its precise mechanism of action remains unclear.
    OBJECTIVE: To investigate the mechanism of RB against NSCLC and its synergistic effect with cisplatin (CDDP) via the SRC/PI3K/AKT signaling pathway.
    MATERIALS AND METHODS: In vitro assays, CCK-8, colony formation, flow cytometry, scratch, Transwell, and Western blot assessed proliferation, apoptosis and migration. Network pharmacology, molecular docking, molecular dynamics simulation (MDS) and cellular thermal shift assay (CETSA) were employed to validate molecular targets. King's formula was used to evaluate the combined effect of RB and CDDP, with xenograft models confirming in vivo efficacy.
    RESULTS: In vitro, RB significantly suppressed NSCLC proliferation, migration, and invasion while inducing apoptosis. Mechanistically, network pharmacology predicted SRC as a core target. MDS and CETSA subsequently confirmed the direct and stable binding of RB to SRC. Western blot analysis revealed that RB exerted its effect by inhibiting SRC/PI3K/AKT signaling. Notably, RB synergistically enhanced CDDP sensitivity by blocking SRC/PI3K/AKT pathway activation, thereby potentiating apoptosis. Finally, in vivo experiments validated that RB effectively suppressed tumor growth with favorable safety.
    DISCUSSION AND CONCLUSIONS: RB inhibits NSCLC progression and sensitizes cells to CDDP by directly targeting SRC to inactivate the PI3K/AKT pathway. These findings identify a novel mechanism of RB against NSCLC and suggest its potential as a therapeutic strategy.
    Keywords:  Rabdosin B; SRC/PI3K/AKT signaling pathway; cisplatin; network pharmacology; nonsmall cell lung cancer
    DOI:  https://doi.org/10.1080/13880209.2026.2641262
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