bims-necame Biomed News
on Metabolism in small cell neuroendocrine cancers
Issue of 2025–11–09
seventeen papers selected by
Grigor Varuzhanyan, UCLA
  1. PLCG2 promotes cell survival and mitophagy of small cell lung cancer via regulating VCP.
  2. A calcium-sensing MCTP1/FYN/MEF2C circuit drives therapy-induced neuroendocrine prostate cancer.
  3. Immunotherapy for small cell lung cancer: current challenges and prospects.
  4. Marked under-diagnosis of Lambert-Eaton myasthenic syndrome in small cell lung cancer: an analysis of real-world claims data.
  5. Targeting endoplasmic reticulum stress and nitroso-redox imbalance in neuroendocrine prostate cancer: the therapeutic role of nitric oxide.
  6. Molecular imaging in the diagnostic process of neuroendocrine tumors: a systematic review on unknown primary origin and suspected NETs.
  7. Systematic review and network meta-analysis: evaluation of systemic therapies for platinum refractory or resistant small cell lung cancer.
  8. Management of Neuroendocrine Tumors: Making Strides or Inching Forward?
  9. Real-world survival patterns and multimodal therapy utilization in small cell lung cancer: a retrospective cohort study in a Chinese countryside hospital.
  10. Real World Efficacy and Safety of First Line Chemo Immunotherapy in Extensive Stage Small Cell Lung Cancer and its association with molecular subtype.
  11. Integrated circulating tumor DNA-based prognostic algorithm for limited stage small-cell lung cancer under definitive chemoradiotherapy and utility in consolidation immunotherapy benefit prediction.
  12. Efficacy and safety of anlotinib maintenance therapy in limited-stage small cell lung cancer.
  13. Prognostic and clinicopathological value of myeloid-derived suppressor cells in lung cancer: a comprehensive systematic review and meta-analysis.
  14. Cancer-testis antigens (CTAs) in lung cancer.
  15. TGFβ1 and SMAD3 Expression Are Associated With Survival After the Immune Checkpoint Inhibitor Therapy for Small Cell Lung Cancer.
  16. Plasma proteomics profiling identifies predictive biomarkers for immunotherapy response in small-cell lung cancer.
  17. Place in therapy of key treatments for platinum-sensitive, relapsed, extensive-stage small cell lung cancer with a focus on lurbinectedin: a narrative review with case studies.
  1. Anticancer Drugs. 2025 Oct 16.
    PLCG2 promotes cell survival and mitophagy of small cell lung cancer via regulating VCP.
    Juan Jiang, Ju Zhu, Yin Xiao, Lu Gan.
      Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer that is characterized by rapid growth. PLCG2 is an enzyme that plays a crucial role in intracellular signal transduction pathways. This study aims to discover the role of PLCG2 in SCLC and the underlying mechanism. Relative expression of PLCG2 was detected by reverse transcription-quantitative PCR and Western blot. Cell viability, proliferation, and apoptosis were assessed by cell counting kit-8, colony formation, and flow cytometry assays. Mitophagy-related protein levels were analyzed by Western blot. RNA immunoprecipitation and dual-luciferase reporter assays were used to analyze the interaction between PLCG2 and VCP. A xenograft mouse model was established to analyze the role of PLCG2 in vivo. Results showed that PLCG2 was upregulated in SCLC tissues and cells, with high diagnostic potential. Besides, PLCG2 deficiency inhibited cell survival and mitophagy and promoted apoptosis in SCLC cells. In addition, PLCG2 interacted with VCP, and VCP overexpression reversed the inhibitory effects of PLCG2 silencing. In vivo, PLCG2 silencing suppressed SCLC tumor growth. In conclusion, PLCG2 is a promising biomarker for SCLC diagnosis and might be a potential therapeutic target, with its interaction with VCP playing a role in SCLC cell survival and mitophagy.
    Keywords:  PLCG2; VCP; apoptosis; cell viability; mitophagy; small cell lung cancer
    DOI:  https://doi.org/10.1097/CAD.0000000000001770
  2. Neoplasia. 2025 Nov 01. pii: S1476-5586(25)00131-9. [Epub ahead of print]71 101251
    A calcium-sensing MCTP1/FYN/MEF2C circuit drives therapy-induced neuroendocrine prostate cancer.
    Phan Vu Thuy Dung, Wei-Yu Chen, Ming-Kun Liu, Shauh-Der Yeh, Gagan Kajla, Hsiu-Lien Yeh, Wei-Hao Chen, Kuo-Ching Jiang, Han-Ru Li, Cheng-Sheng Chen, Himisha Beltran, Yu-Ching Wen, Yen-Nien Liu.
      Neuroendocrine prostate cancer (NEPC) represents a highly aggressive, treatment‑refractory phenotype that frequently emerges after androgen‑deprivation therapy (ADT). Although perturbed calcium signaling has been implicated in prostate cancer bone metastasis, the specific molecular mechanisms governing NEPC progression remain incompletely characterized. Here, we delineate the MCTP1/FYN/MEF2C signaling axis as a pivotal modulator of intracellular calcium homeostasis that drives neuroendocrine differentiation (NED) and enhances tumor aggressiveness. We demonstrate that ADT upregulates MCTP1, a transmembrane protein with calcium-sensing capabilities, which subsequently activates the Src-family kinase FYN to initiate oncogenic signaling cascades. This activation induces transcriptional upregulation of bone morphogenesis-related genes, including MEF2C and ALPL. Mechanistically, calcium-responsive transcription factors ZEB1 and ZEB2 directly transactivate MEF2C, thereby integrating calcium flux with epithelial-to-mesenchymal transition (EMT) programs in prostate cancer. Elevated ZEB1/ZEB2-dependent MEF2C expression reinforces the MCTP1/FYN kinase pathway, potentiating neuroendocrine lineage commitment and ALPL enzymatic activity. Chromatin immunoprecipitation coupled with transcriptomic analyses reveals that MEF2C directly occupies regulatory elements of MCTP1, FYN, and ALPL, enabling their calcium-dependent transcriptional activation. Structure-based virtual screening identified a potent small-molecule antagonist targeting MCTP1, which markedly attenuates tumor burden, ALPL activity, and neuroendocrine marker expression in prostate cancer in vitro and in vivo models. Collectively, these findings establish MCTP1 as a novel therapeutically exploitable vulnerability in therapy-induced NEPC, providing critical insights into the calcium-dependent oncogenic signaling networks mediated by the MCTP1/FYN/MEF2C axis in advanced prostate cancer.
    Keywords:  ALPL; Androgen deprivation therapy; FYN; MCTP1; MEF2C; Neuroendocrine differentiation; Prostate cancer
    DOI:  https://doi.org/10.1016/j.neo.2025.101251
  3. Exp Hematol Oncol. 2025 Nov 05. 14(1): 130
    Immunotherapy for small cell lung cancer: current challenges and prospects.
    Jiaxin Zhong, Guangling Jie, Haorui Qin, Hongrui Li, Nuo Chen, Patiguli Aerxiding, Xia Zou, Xiaomin Niu.
      Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy with limited treatment options. While immunotherapy has revolutionized SCLC therapy and now serves as a front-line treatment, the disease continues to present significant clinical challenges. Despite therapeutic advances in lung cancer over the past decade, most SCLC tumors eventually reoccur. Growing insights into the tumor-immune microenvironment (TIME) highlights its critical role in SCLC progression and therapeutic resistance. In this review, we summarize distinctive features of the TIME in SCLC and evaluate current immunotherapeutic strategies, notably immune checkpoint inhibitors (ICIs), that have demonstrated survival benefits in a subset of patients. Furthermore, we explore emerging immunotherapeutic approaches and novel targets in SCLC, emphasizing the challenges limiting the successful application of immunotherapy in this disease.
    Keywords:  Antibody‒drug conjugates (ADCs); Immune checkpoint inhibitors (ICIs); Small cell lung cancer (SCLC); Tumor–immune microenvironment (TIME)
    DOI:  https://doi.org/10.1186/s40164-025-00720-w
  4. Front Oncol. 2025 ;15 1650373
    Marked under-diagnosis of Lambert-Eaton myasthenic syndrome in small cell lung cancer: an analysis of real-world claims data.
    Benjamin J Drapkin, David J Morrell, Regina Grebla, Guy Shechter, David E Gerber.
       Background: Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune neurologic condition causing progressive muscle weakness that can occur as a paraneoplastic disorder, most commonly in patients with small cell lung cancer (SCLC). In limited prospective and retrospective studies, LEMS incidence in SCLC populations ranges 3-6%. Because LEMS may present a diagnostic challenge, we determined the prevalence of LEMS in a large, real-world, U.S.-based SCLC cohort.
    Materials and methods: We conducted a retrospective analysis of administrative data from Symphony Health's PatientSource®, which represents over 300 million U.S. patients. In the primary analysis, we identified claims for LEMS (available starting in 2014) among patients with lung cancer claims between 2017 and 2022 who received etoposide and platinum-based chemotherapy (a validated approach to SCLC case identification).
    Results: Among 867,170 patients with lung cancer claims, 46,995 (5.4%) received platinum-etoposide-based therapy (putative SCLC cohort), of whom 77 (0.16%) had LEMS claims. In a subset of 8,513 patients with ≥12 months of claims preceding and following lung cancer diagnosis, 16 (0.19%) had LEMS claims. LEMS cases were more frequently diagnosed by neurologists (30%) than by oncologists (13%).
    Conclusions: In a large real-world cohort of patients with lung cancer, LEMS is diagnosed far less frequently than would be expected and rarely by oncologists. Because LEMS may convey substantial morbidity and specific LEMS treatments are available, further efforts to understand and address this discrepancy are warranted.
    Keywords:  Lambert-Eaton myasthenic syndrome (LEMS); autoimmune; claims data; neurology; oncology; paraneoplastic; real-world; small cell lung cancer (SCLC)
    DOI:  https://doi.org/10.3389/fonc.2025.1650373
  5. Cell Death Discov. 2025 Nov 06. 11(1): 502
    Targeting endoplasmic reticulum stress and nitroso-redox imbalance in neuroendocrine prostate cancer: the therapeutic role of nitric oxide.
    Fakiha Firdaus, Osmel Companioni Napoles, Raul Ariel Dulce, Anusha Edupuganti, Surinder Kumar, Khushi Shah, Salih Salihoglu, Derek J Van Booven, Richard Gasca, David B Lombard, Joshua M Hare, Fangliang Zhang, Rehana Qureshi, Himanshu Arora.
      Neuroendocrine prostate cancer (NEPC) is an aggressive and therapy-resistant subtype of prostate cancer characterized by high levels of endoplasmic reticulum (ER) stress and metabolic dysregulation. The subsequential metabolic adaptations in the cancer cells reinforce survival mechanisms that contribute to therapy resistance and metastasis. The oncogenic driver neuroblastoma-derived MYC (MYCN) exacerbates ER stress by increasing calcium ion efflux from the ER into mitochondria, promoting glycolytic and oxidative stress. Here, we demonstrate that nitric oxide (NO) signaling is dysregulated in NEPC, thus allowing impaired S-nitrosylation of MYCN and uncontrolled ER stress. We show that exogenous NO supplementation restores MYCN S-nitrosylation at Cys4, Cys186, and Cys464. This re-establishment significantly reduces ER stress markers, inhibits the unfolded protein response (UPR), and suppresses NEPC cell proliferation and colony formation in vitro. In an orthotopic NEPC murine model, NO treatment led to a substantial reduction in tumor burden and metastasis to the liver and brain, with corresponding decreases in chromogranin and synaptophysin expression. Additionally, NO supplementation attenuated glycolytic stress by limiting calcium-mediated mitochondrial dysfunction and modulating metabolic pathways. Our findings uncover a direct mechanistic link between MYCN-driven ER stress and NEPC progression and highlight NO supplementation as a potential therapeutic strategy to counteract lineage plasticity and metabolic adaptations in NEPC. These results provide a compelling rationale for further investigation into NO-based therapies as a novel intervention for NEPC, a cancer subtype with limited treatment options and poor prognosis.
    DOI:  https://doi.org/10.1038/s41420-025-02774-5
  6. EJNMMI Rep. 2025 Nov 06. 9(1): 38
    Molecular imaging in the diagnostic process of neuroendocrine tumors: a systematic review on unknown primary origin and suspected NETs.
    Laura Alonzo, Roberto Cannella, Riccardo Laudicella, Viviana Benfante, Pierpaolo Purpura, Giuseppe Micci, Massimo Galia, Giuseppe Brancatelli, Massimo Midiri, Pierpaolo Alongi.
       BACKGROUND: Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms often arising in the gastrointestinal tract, pancreas, and lungs. Diagnosing NETs can be challenging due to their small size, slow growth, and low metabolic activity, especially in cases of unknown primary origin (CUP-NETs). Timely identification of the primary lesion is critical for tailored treatment planning, including peptide receptor radionuclide therapy (PRRT), surgery, or somatostatin analogue administration.
    OBJECTIVE: This systematic review evaluates the diagnostic performance and clinical impact of molecular imaging-especially PET/CT with radiolabeled somatostatin analogs-in patients with suspected NETs or CUP-NETs.
    METHODS: Following PRISMA guidelines, a comprehensive literature search was conducted in PubMed and Scopus. Data on study design, tracers used, detection rates, and impact on patient management were extracted. Quality assessment was performed using CASP tools.
    RESULTS: PET/CT using [68 Ga]Ga-DOTA-peptides (DOTATATE, DOTATOC, DOTANOC) consistently outperformed conventional SPECT imaging with [111In]Pentetreotide (Octreoscan), achieving primary tumor detection rates of 38%-83% versus < 10% with SPECT. In suspected NETs, PET/CT demonstrated high sensitivity (up to 95%) and specificity ( > 85%), with changes in clinical management reported in up to 33% of cases. Dual-tracer imaging ([68 Ga]Ga-DOTATATE and [18F]FDG) and newer tracers such as [18F]DOPA and [18F]AlF-NOTA-octreotide ([18F]-OC) provided added diagnostic value, particularly in aggressive or rare subtypes (e.g. paragangliomas, insulinomas). Detection of unknown primaries commonly led to curative surgical options or more targeted therapies.
    CONCLUSIONS: Molecular imaging-particularly [68Ga]Ga-DOTA-peptide PET/CT-represents an essential component in the diagnostic evaluation of undefined/suspected NETs. It not only improves diagnostic accuracy but also has a profound impact on clinical decision-making. Its integration into diagnostic algorithms should be strongly considered for both known and suspected cases of neuroendocrine neoplasia.
    Keywords:  CUP; Dota-peptides; Neuroendocrine tumor; Positron-emission-tomography; Single photon emission tomography; Somatostatine receptor; UPO
    DOI:  https://doi.org/10.1186/s41824-025-00274-4
  7. Lung Cancer. 2025 Nov 03. pii: S0169-5002(25)00704-4. [Epub ahead of print]210 108812
    Systematic review and network meta-analysis: evaluation of systemic therapies for platinum refractory or resistant small cell lung cancer.
    Rahul K Desai, Elena J Zhou, Kelvin K W Chan.
       BACKGROUND: Platinum-refractory/resistant (r/r) small cell lung cancer (SCLC) is associated with poor prognosis and limited treatment options. While chemotherapy has been the standard, recent randomized controlled trials (RCTs) have investigated immunotherapy and targeted therapies. In 2025, the DeLLphi-304 trial showed tarlatamab significantly improved overall survival (OS) and progression-free survival (PFS) versus standard chemotherapy (SC). However, no network meta-analysis (NMA) has compared systemic therapies in this setting.
    METHODS: We systematically searched major databases through June 2025 for phase III RCTs evaluating systemic therapies in platinum r/r SCLC. Extracted outcomes included OS, PFS, quality-of-life (QoL), overall response rate (ORR), and treatment-related adverse events (AEs). Indirect comparisons were performed using Markov Chain Monte Carlo methods, with treatment rankings assessed via SUCRA probabilities.
    RESULTS: Six phase III RCTs were identified. Tarlatamab and nivolumab improved OS over other treatments, with tarlatamab ranking highest (SUCRA 0.96) and demonstrating superior safety.
    CONCLUSIONS: Tarlatamab provides the most favorable outcomes, supporting its consideration as a preferred therapy for platinum r/r SCLC.
    Keywords:  Advanced disease; Chemotherapy; Immunotherapy; Meta-analysis; Oat cell lung cancer; Small cell cancer of the lung; Small cell lung cancer (SCLC); Small cell lung carcinoma; Taralatamab; Targeted therapy
    DOI:  https://doi.org/10.1016/j.lungcan.2025.108812
  8. JCO Oncol Pract. 2025 Nov 06. OP2501109
    Management of Neuroendocrine Tumors: Making Strides or Inching Forward?
    Kanika G Nair.
      
    DOI:  https://doi.org/10.1200/OP-25-01109
  9. Front Oncol. 2025 ;15 1636533
    Real-world survival patterns and multimodal therapy utilization in small cell lung cancer: a retrospective cohort study in a Chinese countryside hospital.
    Taosheng Huang, Linjie Ma, Mingfang Wang, Xumei Pang, Jiying Xu, Xi Chen, Yutao Xia, Min Yan, Wenxiang Zhao, Congcong Cheng, Runqing Wang, Kai Sun, Peng Wang.
       Introduction: Small cell lung cancer (SCLC) accounts for 13-15% of all lung malignancies and remains a highly aggressive disease with limited therapeutic progress, particularly in rural settings. Despite advances such as immune checkpoint inhibitors and multimodal therapy, real-world evidence on treatment utilization and survival outcomes in developing regions is scarce. This retrospective cohort study aimed to evaluate survival patterns and multimodal therapy use in SCLC patients from a Chinese countryside hospital.
    Methods: A total of 132 patients diagnosed with SCLC at Weifang Yidu Central Hospital between 2014 and 2023 were retrospectively analyzed. Patients were classified as limited-stage (LS) or extensive-stage (ES) using the Veterans Administration Lung Study Group (VALG) system. Clinical data, including demographics, treatment regimens, and outcomes, were collected. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method, and subgroup analyses assessed the effects of platinum sensitivity, prophylactic cranial irradiation (PCI), concurrent chemoradiotherapy (CCRT), and palliative radiotherapy.
    Results: Of 132 patients (64 LS-SCLC, 68 ES-SCLC), most received first-line platinum-etoposide regimens, with diminishing treatment continuity in later lines due to cumulative toxicities. Median OS was significantly longer in LS-SCLC than ES-SCLC (50.2 vs. 16.8 months, p<0.05). PCI reduced brain metastases (0% vs. 27%) and improved OS (50.2 vs. 36.4 months; HR=0.47), though not statistically significant. CCRT achieved longer OS than sequential chemoradiotherapy (54.9 vs. 50.2 months; HR=0.54). In second-line therapy, platinum-sensitive patients benefited from platinum rechallenge (median OS 17.7 vs. 12.5 months, p<0.05), whereas platinum-resistant patients showed no improvement. Palliative radiotherapy in ES-SCLC prolonged PFS (16.1 vs. 7.8 months) and OS (30.2 vs. 16.1 months) with near-significant trends (HR≈0.5).
    Discussion: This real-world study confirms that concurrent chemoradiotherapy (CCRT) and prophylactic cranial irradiation (PCI) confer survival advantages in LS-SCLC, while palliative radiotherapy yields potential benefits in ES-SCLC. Platinum sensitivity remains a crucial predictor of second-line treatment efficacy, supporting reintroduction of platinum in sensitive relapses per guideline recommendations. Conversely, irinotecan-lobaplatin combinations provided limited benefit. Findings emphasize the need for personalized treatment sequencing and improved access to standardized multimodal care in rural healthcare settings.
    Keywords:  CCRT; SCLC - small cell lung cancer; chemotherapy; prophylactic cranial irradiation (PCI); radiotherapy
    DOI:  https://doi.org/10.3389/fonc.2025.1636533
  10. Cancer Res Treat. 2025 Nov 05.
    Real World Efficacy and Safety of First Line Chemo Immunotherapy in Extensive Stage Small Cell Lung Cancer and its association with molecular subtype.
    Miran Han, Sehhoon Park, Se-Hoon Lee, Junkyu Kim, Jin-Yong Kim, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn.
       Purpose: Small cell lung cancer (SCLC) is an aggressive malignancy with poor outcomes. IMpower133 and CASPIAN established platinum-etoposide plus anti-PD-L1 antibody as standard first-line therapy for extensive-stage SCLC (ES-SCLC). Real-world data in Korean patients are scarce. We evaluated the effectiveness and safety of first-line chemo-immunotherapy in ES-SCLC and compared outcomes with pivotal trials.
    Materials and Methods: We retrospectively reviewed patients diagnosed with ES-SCLC between 2018 and 2021. Overall survival (OS), progression-free survival (PFS), and time to next treatment (TTNT) were analyzed using Kaplan-Meier methods. Multivariate Cox regression identified prognostic factors. Objective response rate (ORR) was assessed by RECIST v1.1, and histological subtypes evaluated.
    Results: Among 177 patients, median age was 66 years (range, 42-91), with 63.8% aged ≥65; most were male (92.7%) and ECOG 0-1 (91.5%). Smoking history was present in 80.8%. Baseline brain and liver metastases occurred in 27.7% and 26%. Median follow-up was 27.2 months (range, 3.9-43.2). ORR was 74.5% (95% CI, 67.1-81.1). Median OS, PFS, and TTNT were 12.4 (95% CI, 11.6-14.9), 5.3 (95% CI, 5.1-5.87), and 5.6 months (95% CI, 1.43-38.27). In 49 patients with brain metastases, ORR was 63.2%, with no difference in efficacy. Local therapy for brain metastases improved OS (HR 0.42; p=0.012), while PFS was not different. Treatment-related adverse events occurred in 90%, primarily grade ≥2 cytopenias; the most common immune-related event was grade 1 rash.
    Conclusion: In this real-world Korean cohort, first-line chemo-immunotherapy achieved outcomes comparable to pivotal trials, supporting its role as standard care for ES-SCLC in clinical practice.
    Keywords:  Chemo-Immunotherapy; Clinical trials; Real-World data; Small Cell Lung Cancer
    DOI:  https://doi.org/10.4143/crt.2025.971
  11. Cell Commun Signal. 2025 Nov 07. 23(1): 480
    Integrated circulating tumor DNA-based prognostic algorithm for limited stage small-cell lung cancer under definitive chemoradiotherapy and utility in consolidation immunotherapy benefit prediction.
    Yao Fu, Jianming Zhou, Xiaoxi Chen, Naiqing Ding, Xiaotian Zhao, Hua Bao, Yang Yang, Ning Xia.
       BACKGROUND: Reliable biomarkers to identify inoperable limited stage small-cell lung cancer (LS-SCLC) benefiting from post-definitive chemoradiotherapy (dCRT) immunotherapy is valuable. This study aims to develop a circulating tumor DNA (ctDNA)-based algorithm to stratify progression risk and predict survival benefit from consolidation immunotherapy.
    METHODS: Baseline tumor tissues from 203 consecutive LS-SCLC receiving dCRT and a cBioPortal LS-SCLC cohort (n = 218) were analyzed to identify tissue-based prognostic genetic alterations. Plasma ctDNA after induction chemotherapy initiation (post-ICT) and/or during subsequent thoracic radiotherapy (TRT) were collected from two independent dCRT-only cohorts (training, n = 49; test, n = 32) and from 86 patients receiving post-dCRT consolidation immunotherapy, for prognostic algorithm development and utility investigation.
    RESULTS: Tissue-based prognostic biomarkers were generally rare except for PTEN, whose mutations were associated with antigen processing and presentation pathway enrichment (p.adjust = 0.008), and better progression-free survival (PFS, p = 0.047) and overall survival (p = 0.040). A Bayesian inference prognostic algorithm, combining post-ICT and TRT ctDNA detection, receipt of prophylactic cranial irradiation, and post-ICT shrinkage, accurately predicted 3-year progression (time-dependent AUC = 0.796) and stratified the training cohort into two subgroups exhibiting significantly different PFS (p = 0.008), with consistent performance in the test cohort (time-dependent AUC = 0.745; PFS, p = 0.098). The posterior Bayesian algorithm involving the test cohort revealed ctDNA-based risk classification as an independent predictor of PFS (p < 0.001). Notably, significantly improved PFS under consolidation immunotherapy was exclusively observed in patients predicted as high-risk (p = 0.004), with increasing benefit observed at higher high-risk thresholds.
    CONCLUSIONS: Serial ctDNA monitoring during dCRT is a critical approach to predicting inoperable LS-SCLC progression and consolidation immunotherapy benefit identification.
    Keywords:  Bayesian inference; CtDNA; LS-SCLS; NGS
    DOI:  https://doi.org/10.1186/s12964-025-02462-y
  12. Discov Oncol. 2025 Nov 07. 16(1): 2052
    Efficacy and safety of anlotinib maintenance therapy in limited-stage small cell lung cancer.
    Sha Li, Zhonghua Chen, Jie Lv, Xiaohong Zhou.
       BACKGROUND: Effective maintenance therapy options after first-line chemoradiotherapy for limited-stage small cell lung cancer (LS-SCLC) remain limited. Anlotinib, a multi-target tyrosine kinase inhibitor, was evaluated for its efficacy and safety in this setting.
    METHODS: In this single-center, prospective, randomized controlled trial, 60 LS-SCLC patients who had completed first-line chemoradiotherapy were enrolled and randomly assigned (1:1) to receive either anlotinib maintenance therapy or best supportive care. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints included objective response rate (ORR), safety, and quality of life (QoL).
    RESULTS: The anlotinib group demonstrated a significantly prolonged median PFS compared to the control group. Furthermore, patients in the anlotinib group experienced earlier and more significant improvement in QoL, and a strong positive correlation was observed between QoL scores and OS. The safety profile of anlotinib was consistent with its known characteristics, with hypertension and proteinuria being the most common adverse events, which were manageable through dose modifications.
    CONCLUSION: Anlotinib as maintenance therapy significantly improved PFS and QoL in patients with LS-SCLC, with a manageable safety profile. This study provides initial evidence supporting the potential role of anlotinib in this treatment paradigm.
    Keywords:  Anlotinib; Maintenance therapy; Progression-free survival; Prospective randomized controlled trial; Quality of life; Small cell lung cancer
    DOI:  https://doi.org/10.1007/s12672-025-03895-0
  13. Expert Rev Anticancer Ther. 2025 Nov 06.
    Prognostic and clinicopathological value of myeloid-derived suppressor cells in lung cancer: a comprehensive systematic review and meta-analysis.
    Fateme Sheida, Nadia Alipour, Aida Naseri, Sepideh Razi, Gita Manzari Tavakoli, Seyed Javad Moghaddam, Nastaran Karimi, Nima Rezaei.
       INTRODUCTION: Lung cancer remains the leading cause of cancer-related mortality, and reliable prognostic biomarkers are needed. The prognostic significance of myeloid-derived suppressor cells (MDSCs) in lung cancer is aim of the current systematic review and meta-analysis.
    METHODS: A systematic search was conducted in PubMed, Scopus, Web of Science, and Embase, and eligible studies included patients with lung cancer reporting survival/progression outcomes by MDSCs level. Study quality was assessed using the Joanna Briggs Institute (JBI) checklist. The Comprehensive Meta-Analysis (CMA) software version 3 was used to estimate pooled hazard ratios (HRs) with 95% confidence intervals (CIs).
    RESULTS: Twenty-five studies (1,679 patients) were included. Elevated baseline monocytic MDSCs (M-MDSCs) were significantly associated with worse overall survival (OS) in non-small cell lung cancer (NSCLC) (HR = 1.89, 95% CI: 1.39-2.59) and small cell lung cancer (SCLC) (HR = 2.72, 95% CI: 1.62-4.59), and with shorter progression/recurrence-free survival in NSCLC (HR = 1.86, 95% CI: 1.44-2.40). Associations for polymorphonuclear MDSCs (PMN-MDSCs) were weaker and inconsistent, showing significance only in HR for OS based on univariable data (HR = 1.76, 95% CI: 1.32-2.35).
    CONCLUSIONS: High M-MDSCs predict adverse outcomes in lung cancer, supporting their role as prognostic biomarkers and potential therapeutic targets.
    REGISTRATION: PROSPERO (CRD420251026405).
    Keywords:  Lung neoplasms; Non-small-cell lung carcinomas; prognostic biomarkers; survival outcomes; systematic review; tumor microenvironment
    DOI:  https://doi.org/10.1080/14737140.2025.2586691
  14. Clin Chim Acta. 2025 Oct 30. pii: S0009-8981(25)00566-2. [Epub ahead of print]579 120687
    Cancer-testis antigens (CTAs) in lung cancer.
    Chitrali Talele, Chintan Aundhia, Dipali Talele, Niyati Shah, Mamta Kumari, Surya Nath Pandey, Nardev Singh, Gaurav Gupta, Moayad Al Shahwan, Kamal Dua.
      The predominant cause of cancer-related death worldwide is lung cancer. Poor survival rates are mainly due to late diagnosis due to the lack of sensitive and specific biomarkers and analytical tools. In this review, we examine the use of cancer-testis antigens (CTAs) as potential biomarkers due to their increased expression in malignancy. For example, the diagnostic potential of New York esophageal squamous cell carcinoma 1 (NY-ESO-1) autoantibodies was low for sensitivity (48.3%) but higher for specificity (90.9%) in small cell lung cancer (SCLC). In contrast, A-kinase anchoring protein 4 (AKAP4) peripheral blood mononuclear cell (PBMC) quantitative polymerase chain reaction (qPCR) was 92.8% (sensitivity) and 92.6%, (specificity) in non-small cell lung cancer (NSCLC). We assess existing knowledge regarding CTAs and compare their effectiveness vs other markers such as NY-ESO-1, melanoma-associated antigen A (MAGE-A), sperm-associated antigen 9 (SPAG9), AKAP4, X antigen family member 1 (XAGE-1) and B-cell receptor-associated protein 31 (BCAP31). We also discuss the incorporation of CTA testing in lung cancer diagnostic workflows with focus on its analytical performance, preanalytical factors as well as comparative value vs existing markers. Finally, we outline the role of CTAs as companion diagnostics in immunotherapy and targeted treatment plans, and indicate the main challenges and research priorities towards the clinical translation of CTAs.
    Keywords:  Biomarkers; Cancer/Testis Antigens; Diagnosis; Lung Cancer; Treatment
    DOI:  https://doi.org/10.1016/j.cca.2025.120687
  15. Cancer Rep (Hoboken). 2025 Nov;8(11): e70394
    TGFβ1 and SMAD3 Expression Are Associated With Survival After the Immune Checkpoint Inhibitor Therapy for Small Cell Lung Cancer.
    Zenta Seto, Minehiko Inomata, Akira Noguchi, Tomonobu Kado, Nozomu Murayama, Naoki Takata, Kotaro Tokui, Seisuke Okazawa, Shingo Imanishi, Tosihiro Miwa, Ryuji Hayashi, Kenichi Hirabayashi, Kazuyuki Tobe.
       BACKGROUND: Tumor immunity is involved in the progression of malignant tumors. However, there are few reports on the relationship between the immunological environment and the efficacy of immune checkpoint inhibitors in small cell lung cancer (SCLC). We analyzed the relationship between tumor-infiltrating immune cells and protein expression and survival in patients with SCLC treated with combined therapy with immune checkpoint inhibitors plus chemotherapy.
    METHODS: Patients with SCLC who received combined therapy with immune checkpoint inhibitors plus chemotherapy between 2019 and 2023 were enrolled. Immune cell infiltration levels, including CD4, CD8, FOXP3, CD163-positive cells and expression levels of TGFβ1 and SMAD3 proteins in tumor tissue were evaluated by immunohistochemistry. Progression-free survival (PFS) and overall survival (OS) were evaluated as endpoints.
    RESULTS: Data from 22 patients were analyzed. The high CD4-positive T lymphocyte (p = 0.008, log-rank test) and the high CD8-positive T lymphocyte infiltration group (p = 0.031, log-rank test) showed statistically significantly longer OS than the low infiltration group. On the other hand, the low TGFβ1 expression group showed significantly longer PFS (p = 0.026, log-rank test) and the low SMAD3 expression group showed significantly longer OS (p = 0.042, log-rank test) than the high expression group.
    CONCLUSION: In conclusion, it is suggested that infiltration of T lymphocytes and expression of TGFβ1 and SMAD3 may be related to the efficacy of the combined therapy with immune checkpoint inhibitors plus chemotherapy in patients with SCLC.
    Keywords:  SMAD3; TGFβ; immune checkpoint inhibitor; small cell lung cancer
    DOI:  https://doi.org/10.1002/cnr2.70394
  16. Lung Cancer. 2025 Nov 01. pii: S0169-5002(25)00703-2. [Epub ahead of print]210 108811
    Plasma proteomics profiling identifies predictive biomarkers for immunotherapy response in small-cell lung cancer.
    Guang-Ling Jie, Jia-Xin Zhong, Jing-Ze Wang, Zheng-Qi Cao, Xiao-Min Niu, Li-Liang Xia, Shun Lu.
       INTRODUCTION: Immune checkpoint inhibitors have improved clinical outcomes for small-cell lung cancer (SCLC), but patient responses vary widely, and predictive biomarkers remain inadequate.
    METHODS: Longitudinal plasma samples were collected from SCLC patients before and during chemo-immunotherapy treatment, and quantified using mass spectrometry. Machine learning models were used to identify predictive biomarkers of chemo-immunotherapy response in both discovery and validation cohorts.
    RESULTS: A total of 118 SCLC patients treated with anti-programmed death-ligand 1 (anti-PD-L1) antibodies plus chemotherapy were enrolled. Proteomic profiling revealed that responders exhibited upregulation of proteins associated with IL-17 and JAK-STAT signaling pathways, while non-responders showed enrichment in PI3K-Akt and HIF-1 pathways. A least absolute shrinkage and selection operator (LASSO)-based machine learning model incorporating three proteins-vasorin (VASN), par-3 family cell polarity regulator (PARD3), and prostaglandin E synthase 3 (PTGES3) (termed VPP model)-was developed to predict treatment response. In the training cohort (N = 42), the VPP model achieved an area under the curve (AUC) of 0.846 (95 % confidence interval (CI): 0.723-0.968, P < 0.001). In the validation cohort (N = 40), the model yielded an AUC of 0.821 (95 % CI: 0.686-0.955, P < 0.001), indicating robust predictive performance. Based on the VPP model, the response rates were 80 % in the low-risk group and 20 % in the high-risk group (χ2 = 12.1, P < 0.001), with median progression-free survival of 6.87 and 3.97 months, respectively (hazard ratio = 0.39; 95 % CI: 0.19-0.81; P = 0.004). In an external independent cohort (N = 36) using the enzyme-linked immunosorbent assay method, the model also demonstrated excellent predictive performance, with an AUC of 0.859 (95 % CI: 0.730-0.981; P < 0.001).
    CONCLUSIONS: Our findings demonstrate that the VPP model, identified through plasma proteomics profiling, serves as a predictive biomarker for response to anti-PD-L1 plus chemotherapy in SCLC patients.
    Keywords:  Biomarker; Immunotherapy; Plasma; Proteomic; Small-cell lung cancer
    DOI:  https://doi.org/10.1016/j.lungcan.2025.108811
  17. Drugs Context. 2025 ;pii: 2025-7-9. [Epub ahead of print]14
    Place in therapy of key treatments for platinum-sensitive, relapsed, extensive-stage small cell lung cancer with a focus on lurbinectedin: a narrative review with case studies.
    Leonid Shunyakov, Firas B Badin, Judith Hafer, David König, Patrizia Froesch, Laurent Greillier.
       Background: Virtually all patients with extensive-stage small cell lung cancer (SCLC) develop resistance to first-line platinum-based chemoimmunotherapy and experience relapse. Second-line therapy is therefore an integral part of the treatment paradigm.
    Methods: Evidence was reviewed for key second-line regimens recommended in major guidelines for treatment of patients with platinum-sensitive relapse (chemotherapy-free interval ≥90 days), focusing on recent prospective clinical trials and post hoc analyses. Case studies of second-line lurbinectedin are presented as examples of the current management approach to platinum-sensitive relapsed SCLC.
    Results: Subject to the limitations of cross-trial comparisons, the evidence review allowed us to draw broad conclusions about the place in therapy of approved options for platinum-sensitive relapse. Platinum rechallenge is more effective and better tolerated than topotecan and is a reasonable second-line choice in suitable patients. Topotecan provides modest clinical benefit and has the potential to cause dose-limiting haematological toxicities. Cyclophosphamide-doxorubicin-vincristine combination therapy offers no clear advantages over topotecan. Efficacy outcomes with second-line lurbinectedin are similar or better than those reported with platinum rechallenge, and lurbinectedin has a more favourable safety profile and simpler administration schedule. Second-line lurbinectedin preserves platinum rechallenge for later use and may resensitize tumour cells to platinum with potential survival advantages. Lurbinectedin safety is not affected by advanced age (≥65 years). Case studies highlight objective and durable responses to second-line lurbinectedin, along with good tolerability and quality of life.
    Conclusions: Available evidence supports second-line lurbinectedin as a useful alternative to platinum rechallenge, topotecan and cyclophosphamide-doxorubicin-vincristine in patients with platinum-sensitive relapsed SCLC.
    Keywords:  extensive-stage small cell lung cancer; lurbinectedin; platinum rechallenge; second-line chemotherapy; topotecan
    DOI:  https://doi.org/10.7573/dic.2025-7-9
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