bims-necame 2025-11-23 papers

bims-necame

Biomed News

on Metabolism in small cell neuroendocrine cancers

Issue of 2025–11–23
nineteen papers selected by
Grigor Varuzhanyan, UCLA

GLP1 Receptor Agonism Alters Growth and Therapeutic Response in Prostate Cancer.
Metabolome-Wide Mendelian Randomization Identifies Maleate as a Mediator of the Effect of Obesity on the Risk of Small Cell Lung Cancer.
Structural basis of DNA-dependent coactivator recruitment by the tuft cell master regulator POU2F3.
Radiosensitization of NET cells by HSP90 inhibitor ganetespib is mediated through pleiotropic stress responses.
[18F]FDG-PET/CT-based evaluation of tumor response kinetics during induction chemotherapy and concurrent radiochemotherapy in stage II - III small-cell lung cancer.
Small cell lung cancer transdifferentiation: not a negligible phenomenon.
NHWD-870 suppresses tumor proliferation via the BRD4/STRADA/CCND1 axis in small cell lung cancer.
Early C-reactive protein reduction predicts survival in real-world extensive-stage small cell lung cancer treated with first-line adebrelimab-based immunotherapy.
Theranostics in surgical oncology.
Clinical Implications of Ki-67 Index, Grade and Hormonal Changes in Pancreatic Neuroendocrine Tumors: Insights Into Tumor Heterogeneity Based on Primary and Secondary Lesions.
Tumor cell-specific loss of GPX4 reprograms triacylglycerol metabolism to escape ferroptosis and impair antitumor immunity in NSCLC.
Ciliogenesis in Pancreatic Neuroendocrine Tumors: Insight into the Role of WDR60.
Phase II trial of cabozantinib in combination with nivolumab for advanced extrapancreatic neuroendocrine tumors (epNET).
Challenges in evaluating high-grade pancreato-hepato-biliary neuroendocrine tumors.
Targeting prostate adenocarcinoma tumor microenvironment via cancer nanotheranostics: a comprehensive update on improved roadmap for disease diagnosis, therapy and management.
A Rare Case of Chemotherapy Combined with Immunotherapy for Dual Primary AFP-Positive Gastric Cancer and Synchronous Small Cell Lung Cancer.
IPI score as a new prognostic index in extensive stage small cell lung cancer.
Validation of the pheochromocytoma of adrenal gland scaled score (PASS) grading system: A retrospective double-centered cross-sectional study.
Delta-Like Ligand 3 Expression and Functional Imaging in Gastroenteropancreatic Neuroendocrine Neoplasms.

Endocr Relat Cancer. 2025 Nov 19. pii: ERC-25-0185. [Epub ahead of print]

GLP1 Receptor Agonism Alters Growth and Therapeutic Response in Prostate Cancer.

Soumen Bera, Lisa Gutgesell, Brynne Darden, Robert M Sargis, Mark Maienschein-Cline, Charles E Gaber, Natalie Reizine, Donald J Vander Griend, Jordan E Vellky.

  The burgeoning metabolic benefits of GLP1 receptor (GLP1R) agonists have led to their widespread use for treatment of type 2 diabetes mellitus and obesity. While the pharmacological GLP1R agonist semaglutide primarily activates GLP1R signaling in the pancreas, GLP1R is also expressed in advanced prostate cancer where GLP1R agonism could directly alter cellular signaling. Because metabolic disorders and their treatment are common among those with prostate cancer, understanding the effects of semaglutide in prostate cells is critical for deciphering its systemic effects and delineating potential impacts on prostate cancer outcomes. In prostate cancer models, semaglutide decreased cell proliferation, glycolytic function, and phospho-kinase-mediated signaling. This overall suppression of signaling downstream of GLP1R is consistent with inhibitory GPCR signaling, which was confirmed by reduced cAMP levels. Further, cell proliferation was decreased with semaglutide alone and in combination with enzalutamide, supporting that GLP1R agonism may provide therapeutic benefit as a standalone treatment or to augment the therapeutic benefits of androgen receptor signaling inhibitors (ARSI). Interestingly, in a trans-differentiation model (n=55), GLP1R and AR expression were negatively correlated, while GLP1R and NEPC markers (DLL3, ASCL1) were positively correlated, suggesting an association between GLP1R and neuroendocrine differentiation. Bioinformatic analyses on publicly-available patient RNA-sequencing data (n=664) identified significantly higher GLP1R expression in advanced prostate cancer vs. benign prostate, where it was associated with negative Notch signaling. Taken together, our data support a model wherein GLP1R agonism blocks oncogenic signaling pathways and growth of prostate cancer cells that could be exploited therapeutically for men with advanced prostate cancer.

Keywords:  Castration-resistant prostate cancer; Neuroendocrine prostate cancer; advanced prostate cancer; incretin mimetics; metabolic co-morbidities

DOI:  https://doi.org/10.1530/ERC-25-0185
Food Sci Nutr. 2025 Nov;13(11): e70918

Metabolome-Wide Mendelian Randomization Identifies Maleate as a Mediator of the Effect of Obesity on the Risk of Small Cell Lung Cancer.

Kui Li, Zhaodi Yang, Haifei Li, Cheng Yan.

  Obesity is a well-established risk factor for numerous types of cancer, including small cell lung cancer (SCLC). However, the underlying mechanisms remain largely unclear. This research explores the causal relationships between obesity, circulating metabolites, and the risk of SCLC, aiming to identify potential metabolic intermediaries. To achieve this, a two-step Mendelian randomization (MR) approach was employed to examine metabolites mediating the effect of obesity on the risk of SCLC. In Step 1, MR identified metabolites causally associated with SCLC, confirmed with an independent SCLC genome-wide association study (GWAS) as the outcome. In Step 2, whole-body fat mass was examined as the exposure to assess its causal effects on the metabolites identified in Step 1, with further validation using body mass index (BMI) as an alternative exposure. Sensitivity analyses confirmed robust causal inference. The product of coefficients approach for testing mediation quantified the role of specific metabolites in linking obesity to the risk of SCLC. In the initial screening, 1400 circulating metabolites were tested for their association between obesity and the risk of SCLC, and 55 metabolites with significant causal associations were identified. Subsequent MR analyses showed that whole-body fat mass had an effect on 12 of these metabolites, and maleate levels were associated with both obesity and increased SCLC risk. Validation using BMI as an alternative exposure confirmed the causal association between obesity and maleate levels. Further validation using independent GWAS datasets for SCLC confirmed the causal association between maleate levels and the risk of SCLC. Mediation analysis revealed that maleate partially mediated the relationship between obesity and the risk of SCLC, accounting for 14.9% of the effect when using whole-body fat mass as the exposure and 5.23% when using BMI as the exposure. This study highlights maleate as a key metabolic mediator in the obesity-SCLC pathway, which may offer novel insights into the metabolic mechanisms underlying the increased risk of obesity-related cancer.

Keywords:  MR; SCLC; maleate; obesity

DOI:  https://doi.org/10.1002/fsn3.70918
Cell Rep. 2025 Nov 18. pii: S2211-1247(25)01344-0. [Epub ahead of print] 116572

Structural basis of DNA-dependent coactivator recruitment by the tuft cell master regulator POU2F3.

Aktan Alpsoy, Jonathan J Ipsaro, Damianos Skopelitis, Sujay Pal, Frank S Chung, Shannon Carpenter, John J Desmarais, Xiaoli S Wu, Kenneth Chang, Matthew T DiMare, Erin Harten, Staci Bergman, Justin B Kinney, Jeffrey A Engelman, Hyo-Eun C Bhang, Leemor Joshua-Tor, Christopher R Vakoc.

  The transcription factor POU2F3 defines the identity of tuft cells and underlies a distinct molecular subtype of small cell lung cancer (SCLC). Although POU2F3 is considered undruggable, its activity critically depends on the coactivators OCA-T1 and OCA-T2. Here, we demonstrate that acute suppression of either POU2F3 or OCA-T1 induces regression of tuft cell-like SCLC xenografts in vivo. To explore the structural basis and druggability of this dependency, we determine crystal structures of POU2F3 bound to OCA-T1 or OCA-T2 in complex with DNA, revealing a tripartite, DNA-dependent interface. We further employ deep mutational scanning to assess the functional impact of 4,218 missense variants in POU2F3 and OCA-T1, uncovering both mutation-sensitive hotspots and structurally constrained regions critical for tumor cell fitness. These findings define a transcriptional complex that integrates DNA recognition with coactivator recruitment and nominate POU2F3-OCA-T as a structurally tractable vulnerability in tuft cell-like carcinomas.

Keywords:  CP: cancer; CP: molecular biology; OCA-T1; OCA-T2; POU2AF2; POU2AF3; POU2F3; X-ray crystallography; deep mutational scanning; small cell lung cancer; tuft cell

DOI:  https://doi.org/10.1016/j.celrep.2025.116572
EJNMMI Res. 2025 Nov 21.

Radiosensitization of NET cells by HSP90 inhibitor ganetespib is mediated through pleiotropic stress responses.

Pleun A M Engbers, Thom G A Reuvers, José María Heredia-Genestar, Jiang Chang, Nicole S Verkaik, Mariangela Sabatella, Julie Nonnekens.

   BACKGROUND: Peptide receptor radionuclide therapy (PRRT) employing [177Lu]Lu-[DOTA-Tyr3]octreotate has been established as treatment for patients with metastatic neuroendocrine tumors (NETs) that overexpress the somatostatin receptor (SSTR). While PRRT improves survival and quality of life, curative responses remain rare. One way to enhance PRRT efficacy is to combine it with radiosensitizing agents such as heat shock protein 90 (HSP90) inhibitors. HSP90 is a highly conserved molecular chaperone essential for the maturation and stabilization of over a hundred proteins, including proteins involved in the DNA damage response and oncogenic signaling. HSP90-inhibition has been shown to potentiate PRRT, however the mechanism behind this radiosensitizing effect remains unknown. This study aimed to elucidate mechanisms involved in the radiosensitizing effect of HSP90 inhibition.
RESULTS: The radiosensitizing effect of HSP90 inhibitor ganetespib in the context of PRRT and external beam radiotherapy (EBRT) was tested using viability assays for NET cell models GOT1 and BON1-SSTR2. Ganetespib significantly enhanced radiation-induced cytotoxicity in both models. To explore underlying mechanisms, we assessed DNA double-strand break (DSB) repair by quantifying 53BP1 foci numbers, and functionally evaluated DSB repair pathways by RAD51 foci quantification and end-joining assay. Although HSP90 inhibition reduced RAD51 foci numbers, its effect on non-homologous end joining and overall DSB persistence was limited. Finally, potential DSB repair-independent mechanisms of radiosensitization were assessed for GOT1 cells using RNA sequencing. Transcriptomic analysis revealed enrichment of pathways related to loss of HSP90 function, such as protein folding and response to heat stress, following combination treatment. This was consistent with effects observed after HSP90 inhibitor monotherapy.
CONCLUSIONS: Given the lack of significant effects on direct DNA repair or transcriptomic responses, our findings suggest that HSP90 inhibition radiosensitizes NET cells by inducing a pleiotropic effect on multiple stress-related pathways at the protein level, rather than solely through disruption of DNA damage response mechanisms. This effect is likely driven by loss of HSP90 function and subsequent cumulated unfolded protein and proteotoxic stress.

Keywords:   177Lu-DOTA-TATE; Ganetespib; HSP90; Neuroendocrine tumors; Peptide receptor radionuclide therapy; Radiosensitization

DOI:  https://doi.org/10.1186/s13550-025-01346-z
Eur J Nucl Med Mol Imaging. 2025 Nov 17.

[18F]FDG-PET/CT-based evaluation of tumor response kinetics during induction chemotherapy and concurrent radiochemotherapy in stage II - III small-cell lung cancer.

Christian Hoffmann, Hubertus Hautzel, Marcel Wiesweg, David Kersting, Nika Guberina, Christoph Pöttgen, Martin Metzenmacher, Martin Schuler, Thomas Gauler, Benedikt Höing, Cornelius Kürten, Fabian Doerr, Servet Bölükbas, Natalie Baldes, Marcel Opitz, Aleksandar Milosevic, Felix Nensa, Lale Umutlu, Faustina Funke, Wolfgang P Fendler, Ken Herrmann, Martin Stuschke, Maja Guberina.

   PURPOSE: Evaluation of interim-[18F]FDG-PET/CT as a prognostic tool in limited disease small cell lung cancer (SCLC).
METHODS: We included 35 patients with limited disease SCLC from a prospective institutional registry in this retrospective study. Patients received induction chemotherapy (3-4 cycles) followed by concurrent radiochemotherapy. Baseline [18F]FDG-PET/CT was performed before or shortly after start of induction chemotherapy, interim PET/CT was acquired during late induction or concurrent chemoradiotherapy. Maximum standardized uptake value (SUVmax), metabolic target volume (MTV), and total lesion glycolysis values (TLG) were determined. An exponential decay model with an asymptotic offset was used to describe treatment response over time. Deviations > 2 standard deviations (SD) above model-predicted means after day 30 were considered poor response. Progression-free survival (PFS) was analyzed.
RESULTS: All patients underwent twice-daily radiotherapy to a base dose of 45 Gy. SUVmax showed greater inter-patient variability than MTV. Poor treatment response was observed in 17%, 31%, or 14% at the SUVmax, MTV and TLG endpoints. Deviations > 2 SD from the model in SUVmax and TLG were significantly associated with shorter PFS (p = 0.0003, p = 0.0014); MTV was not prognostic (p = 0.2630). Leave-one-out cross-validation (LOOCV) could confirm the prognostic value of the standardized residual SUVmax larger than 2 standard deviations above model estimate as negative PFS predictor (p = 0.0152, Fishers exact test).
CONCLUSION: Our decay model enables the characterization of [18F]FDG-PET/CT response parameters from scans acquired at variable time points during induction chemotherapy and at start of concurrent radiochemotherapy. Poor SUVmax or TLG response was predictive of PFS. Interim-[18F]FDG-PET/CT response may guide individualized treatment adaptation.

Keywords:  Prognostic; Radiotherapy; Small cell lung cancer; Treatment response; [18F]FDG-PET/CT

DOI:  https://doi.org/10.1007/s00259-025-07658-5
Curr Opin Oncol. 2025 Nov 21.

Small cell lung cancer transdifferentiation: not a negligible phenomenon.

Lilla Horvath, Kristiina Boettiger, Zsolt Megyesfalvi, Balázs Döme, Clemens Aigner, Anita Horváth-Rózsás, Judit Berta.

   PURPOSE OF REVIEW: Small cell lung cancer (SCLC), particularly its transdifferentiated form, is highly aggressive and has a poor prognosis. The diagnosis of SCLC transdifferentiation is challenging, as repeat biopsies are often not clinically feasible and few noninvasive predictors of this neuroendocrine transformation have been identified to date.
RECENT FINDINGS: Some retrospective studies and case reports have investigated this phenomenon. These studies indicate that it can occur in nonsmall cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangements, or rearranged during transfection (RET) fusions, typically following treatment with tyrosine kinase inhibitors. However, it has also been observed in cases of EGFR-wild type NSCLC after immunotherapy or radiation therapy.
SUMMARY: Several molecular mechanisms that can drive SCLC transdifferentiation have been identified. The treatment of transdifferentiated SCLC remains a significant challenge, although promising new strategies are currently under investigation. This review summarizes the current understanding of SCLC transdifferentiation.

Keywords:  molecular drivers; small cell lung cancer; therapeutic approaches; transdifferentiation

DOI:  https://doi.org/10.1097/CCO.0000000000001205
Lung Cancer. 2025 Nov 12. pii: S0169-5002(25)00733-0. [Epub ahead of print]210 108841

NHWD-870 suppresses tumor proliferation via the BRD4/STRADA/CCND1 axis in small cell lung cancer.

Linrui Ma, Xiangyu Zhang, Shidong Xu, Jiacheng Dai, Zhe Huang, Zhaohui Ruan, Yuda Zhang, Xuexue Zhou, Yuanze Sun, Yahui Chen, Huan Yan, Chun Zou, Si Qi Xiang, Jingyi Li, Yangqian Chen, Tian Xu, Renzhi Zhang, Dan Yang, Fang Tian, Nachuan Zou, Yi Liao, Jie Zou, Wenjuan Jiang, Xue Chen, Jin Zhang, Jun Deng, Hua Xiang, Liang Zeng, Yongchang Zhang.

   BACKGROUND: Small cell lung cancer (SCLC) is a highly aggressive malignancy with poor prognosis and limited therapeutic options. The lack of effective targeted therapies for SCLC is a major limitation of this field. Bromodomain and Extra-Terminal (BET) inhibitors have emerged as a promising class of anticancer agents. This study aimed to evaluate the preclinical efficacy and mechanism of action of NHWD-870, a novel BET inhibitor targeting BRD4, in SCLC.
METHOD: The therapeutic effects of NHWD-870 on SCLC have been validated through compassionate use. The anti-tumor effects of NHWD-870 were explored using in vitro and in vivo models. CCK-8 assays and flow cytometry were utilized to examine cell viability, apoptosis, and mechanisms of cell cycle arrest. The in vivo effectiveness of NHWD-870 was evaluated using cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of SCLC. Mechanistic studies involving RNA sequencing, Western blotting, qPCR, and transfection were conducted to investigate and confirm the underlying mechanisms of NHWD-870.
RESULT: Our study observed the efficacy of NHWD-870 in a patient with SCLC. NHWD-870 demonstrated robust anti-tumor activity against SCLC in both in vitro and in vivo models, effectively halting tumor growth, inducing apoptosis, and disrupting the cell cycle. RNA sequencing confirmed that the cell cycle is its primary pathway of action, with BRD4, STRADA, and CCND1 identified as key targets.
CONCLUSION: NHWD-870 exhibits anti-tumor activity both in vitro and in vivo against SCLC, primarily by regulating the BRD4/STRADA/CCND1 axis and inhibiting the transition of the cell cycle from the G1 phase to the S phase. These findings highlight the therapeutic potential of NHWD-870 as a novel BET inhibitor for SCLC treatment and provide a molecular basis for further clinical development.

Keywords:  BRD4; Cell cycle; NHWD-870; Small cell lung cancer

DOI:  https://doi.org/10.1016/j.lungcan.2025.108841
Front Oncol. 2025 ;15 1709336

Early C-reactive protein reduction predicts survival in real-world extensive-stage small cell lung cancer treated with first-line adebrelimab-based immunotherapy.

Jian Wang, Xueli Zhang, Qijia Gao, Jianxin Chen.

   Background: Extensive-stage small cell lung cancer (ES-SCLC) remains an aggressive malignancy with limited biomarkers for predicting outcomes in real-world settings. While baseline systemic inflammation correlates with prognosis, the role of longitudinal inflammation dynamics during PD-L1 inhibitor-based therapy is unexplored. This study investigated whether early changes in systemic inflammation markers, particularly C-reactive protein (CRP), predict clinical efficacy in ES-SCLC patients receiving first-line adebrelimab plus chemotherapy.
Methods: In this retrospective, single-center study, 35 ES-SCLC patients (median age: 72 years) treated with adebrelimab plus platinum-etoposide or platinum-irinotecan chemotherapy were analyzed. Ten systemic inflammation markers (NLR, PLR, LMR, PAR, SII, NPR, CAR, CLR, CRP, LDH) were assessed at baseline and after 2 months of therapy. Inflammatory trends were quantified as the ratio of 2-month to baseline values. Associations between inflammation dynamics and survival (OS from 2 months, OS2) or radiologic response (RECIST 1.1) were evaluated using Kaplan-Meier analysis, Cox regression, and Spearman's correlation.
Results: The cohort showed robust real-world efficacy (median OS: 15.0 months; ORR: 62.8%). Among ten inflammation markers analyzed, only CRP dynamics were significantly associated with OS in univariate analysis. Patients achieving CRP reduction (trend ratio <1) at 2 months had significantly longer median OS (16.2 months) versus those without reduction (8.1 months; HR = 3.492, 95% CI:1.239-9.847, P = 0.011). No other inflammatory trend correlated with OS. Inflammation dynamics (including CRP) showed no association with best overall response or tumor regression (P>0.05 for all markers).
Conclusion: Early reduction in CRP levels during adebrelimab-based chemoimmunotherapy is an potentially predictor of improved survival in ES-SCLC, despite dissociation from initial radiologic response. This suggests that CRP kinetics could serve as a practical, real-world biomarker for prognostication and early efficacy assessment in ES-SCLC. Prospective validation in larger cohorts is essential to confirm these findings.

Keywords:  C-reactive protein; adebrelimab; extensive-stage small cell lung cancer; prognostic biomarker; real-world evidence

DOI:  https://doi.org/10.3389/fonc.2025.1709336
Eur J Surg Oncol. 2025 Nov 13. pii: S0748-7983(25)01615-4. [Epub ahead of print]52(1): 111187

Theranostics in surgical oncology.

S Stättner, Kjetil Soreide, Julie Hallet, Chiara Maria Grana, Stefan Partelli, Ken Herrmann, Andreas Brandl.

  Theranostics is a method where molecules that target surface structures in tumors are coupled with different radioisotopes, allowing them to bind to tumor cells for detection (diagnostic) and elimination (therapeutic). In the case of neuroendocrine tumors (NET), peptides targeting somatostatin receptors (SSTR) are most commonly used for this purpose. These peptides are, for example, coupled with 68Ga for diagnostic and 177Lu for therapeutic purposes. This allows SSTR-positive tumors to be detected with high sensitivity and treated effectively, which is particularly beneficial in cases where surgery (alone) is not feasible. However, theranostic procedures can also be used to guide surgical procedures or - in the context of a neoadjuvant approach - increase resectability. Other therapies currently in development aim to increase antitumor effectiveness or aim to combat tumors which are resistant to other radiopharmaceutical therapies (RPT) using new isotopes and SSTR-targeting peptides or combining RPT with other drugs. Modern radiological diagnostics, as well as the production and use of radiopharmaceuticals, require costly equipment and specialized procedures and are therefore not accessible to most patients around the world. However, the expansion of the repertoire of studied and approved theranostics promises to make these highly effective treatments available to more patients. The following review intends to provide an overview of current questions about theranostics with relevance to surgical oncology.

Keywords:  For submission; NET; Neuroendocrine tumor; Nuclear medicine; Oncologic surgery; Radiopharmaceutic therapy; Surgical oncology; Theranostics

DOI:  https://doi.org/10.1016/j.ejso.2025.111187
J Hepatobiliary Pancreat Sci. 2025 Nov 16.

Clinical Implications of Ki-67 Index, Grade and Hormonal Changes in Pancreatic Neuroendocrine Tumors: Insights Into Tumor Heterogeneity Based on Primary and Secondary Lesions.

Masatoshi Murakami, Nao Fujimori, Kazuhide Matsumoto, Keijiro Ueda, Kohei Nakata, Masafumi Nakamura, Takeo Yamamoto, Yoshinao Oda, Tetsuhide Ito, Yoshihiro Ogawa.

   BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) show heterogeneity, including temporal shifts in proliferation and hormone production; however, their clinical implications remain uncertain.
METHODS: This retrospective study included 114 patients with metastatic or recurrent PanNETs at Kyushu University Hospital. Paired specimens from 46 patients (27 synchronous metastases and 19 recurrences) were evaluated for Ki-67 index and tumor grade. Proliferation change was defined as grade progression or a ≥ 10% absolute Ki-67 increase. Hormonal phenotype changes were assessed in all patients.
RESULTS: In metastases, mean Ki-67 increased from 12.3% to 16.4% (p = 0.0043); 22.2% showed a ≥ 10% increase, and 33.3% progressed in grade. In recurrences, Ki-67 increased from 8.8% to 9.3% (p = 0.8256); 15.8% showed a ≥ 10% increase, and 21.1% progressed in grade. Median progression-free survival was 7.8 months in metastases and 17.1 months in recurrences. Median overall survival was significantly longer in the recurrence group (124.8 vs. 32.5 months, p = 0.003). Hormonal transformation occurred in six patients (5.3%), mostly during progressive hepatic disease.
CONCLUSION: A subset of PanNETs exhibited increased proliferation of metastases or recurrence without detrimental survival effects, possibly because of timely treatment adjustments. Rebiopsy may be useful for detecting proliferative changes, whereas hormonal shifts highlight tumor heterogeneity and warrant continued clinical and biochemical monitoring.

Keywords:  grade change; hormonal phenotype; metastasis and recurrence; pancreatic neuroendocrine tumors; tumor heterogeneity

DOI:  https://doi.org/10.1002/jhbp.70028
Protein Cell. 2025 Nov 19. pii: pwaf101. [Epub ahead of print]

Tumor cell-specific loss of GPX4 reprograms triacylglycerol metabolism to escape ferroptosis and impair antitumor immunity in NSCLC.

Peng Wang, Shengdan Zhang, Xin Chen, Xu-Dong Yang, Shi Huang, Huiyong Yin, Hao-Yu Duan, Fuling Zhou, Jia Yu, Bo Zhong, Dandan Lin.

  Glutathione peroxidase 4 (GPX4) is a master regulator of ferroptosis, a process that has been proposed as a potential therapeutic strategy for cancer. Here we have unexpectedly found that inducible knockout of GPX4 in tumor cells significantly promotes non-small cell lung cancer (NSCLC) progression in the autochthonous Kras LSL-G12D/+ Lkb1 fl/fl (KL) and Kras LSL-G12D/+ Tp53 fl/fl (KP) mouse models, whereas inducible overexpression of GPX4 in tumor cells exerts the opposite effect. GPX4-deficient tumor cells evade ferroptosis by upregulating the expression of DGAT1/2 to promote the synthesis of triacylglycerol (TAG) and oxidized TAG (oxTAG) and the formation of lipid droplets in cells. In addition, GPX4-deficient tumor cells secrete TAG and oxTAG into the extracellular space to induce dysfunction of antitumor CD8+ T cells, thereby coordinating an immunoinhibitory tumor microenvironment (TME). Consistently, treatment with DGAT1/2 inhibitors or inducible overexpression of GPX4 in tumor cells significantly resensitizes tumor cells to ferroptosis and ignites the activation of T cells in the TME to inhibit NSCLC progression. These findings highlight a previously uncharacterized role of tumor cell-specific GPX4 in NSCLC progression and provide potential therapeutic strategies for NSCLC.

Keywords:  GPX4; lipid droplets; lipid release; non-small cell lung cancer; triacylglycerol; tumor microenvironment

DOI:  https://doi.org/10.1093/procel/pwaf101
Endocr Relat Cancer. 2025 Nov 21. pii: ERC-25-0218. [Epub ahead of print]

Ciliogenesis in Pancreatic Neuroendocrine Tumors: Insight into the Role of WDR60.

Cristina Grassi, Alice Laffi, Alessandro Zerbi, Elisabetta Lavezzi, Gherardo Mazziotti, Silvia Uccella, Andrea Gerardo Lania, Eleonora Vitali.

  Primary cilia have emerged as key regulators in cancer biology, influencing tumor progression and therapeutic response through diverse signaling pathways. In this study, we identify WDR60, a component of the dynein-2 complex essential for retrograde intraflagellar transport, as a novel modulator of pancreatic neuroendocrine tumor (Pa-NET) behavior. Transcriptomic analysis of the GEO dataset GSE73338 revealed that WDR60 is significantly upregulated in both primary and metastatic Pa-NETs compared to normal pancreatic islets. Moreover, WDR60 expression is higher in G2 compared to G1 Pa-NETs. Functional analyses in QGP-1 cells following WDR60 silencing demonstrated broad transcriptional reprogramming, with enrichment of pathways related to cell adhesion and extracellular matrix (ECM) remodeling. Notably, WDR60 knockdown reduced cell migration and enhanced adhesion, without affecting cell viability or proliferation. Among the key upregulated genes were PIK3AP1, RAP1B, and RFLNA, suggesting that WDR60 is involved in regulating PI3K/AKT signaling and cytoskeletal dynamics. To explore potential therapeutic implications, we examined the effects of Ciliobrevin A (HPI-04), an inhibitor of Hedgehog signaling and ciliogenesis. HPI-04 significantly reduced WDR60 expression, impaired cell migration, and increased adhesion. RT-qPCR confirmed overlapping gene expression changes between HPI-04 treatment and WDR60 silencing, although some differences, such as CD164 regulation, suggest WDR60-independent mechanisms. Collectively, these findings identify WDR60 as a critical regulator of cell motility and adhesion in Pa-NETs via ciliary signaling and cytoskeletal remodeling. They also support the therapeutic potential of targeting cilia-associated pathways, including WDR60 and Hedgehog signaling, in the treatment of Pa-NETs.

Keywords:  Ciliogenesis; Pancreatic Neuroendocrine Tumors; WD Repeat Domain 60; ciliobrevin A

DOI:  https://doi.org/10.1530/ERC-25-0218
Clin Cancer Res. 2025 Nov 20.

Phase II trial of cabozantinib in combination with nivolumab for advanced extrapancreatic neuroendocrine tumors (epNET).

Kimberly J Perez, Nora Horick, Joanna Baginska, Anita Giobbie-Hurder, Ilana Gomez Diaz, Allison N Nau, Ian D Dryg, Kathleen Pfaff, Scott J Rodig, F Stephen Hodi, Mark Redston, Alexandra Bird, Marta Holovatska, Thomas Abrams, Anuj Patel, Douglas A Rubinson, Benjamin L Schlechter, Matthew H Kulke, Jennifer A Chan.

BACKGROUND: Cabozantinib, a multi-kinase inhibitor, improves progression-free survival (PFS) in patients with advanced extrapancreatic NET (epNET). Cabozantinib alters the tumor microenvironment to be more permissive to immune cells by reducing the presence of regulatory T cells and CD14+ monocytes. This trial investigated the efficacy and safety of cabozantinib in combination with nivolumab in patients with advanced epNET.
METHODS: Open-label, single-arm, phase II trial, which enrolled patients with advanced epNET. Patients received nivolumab 240 mg intravenously on days 1 and 15 and cabozantinib 40 mg orally once daily on a 28-day cycle. The primary endpoint was objective response rate (ORR) by RECIST v1.1. Using a Simon's two-stage design 19 patients were enrolled in the first stage. Secondary objectives included ORR by immune-related response criteria (irRECIST), PFS, and safety. Exploratory objectives included correlation between immune and angiogenic proteomic profile, and clinical outcomes.
RESULTS: Eighteen of the 19 enrolled patients were evaluable for response. Best response was partial response 1(5%), stable disease 16 (90%), and progressive disease 1 (5%). ORR did not meet goal for the first stage, so enrollment was terminated. Median PFS was 5.6 months (95% CI, 3.5 to 9.9). Grade 3 toxicities attributed to the combination included tumor lysis (n= 1, 5%), elevated transaminases (n= 1, 5%), and fatigue (n= 2, 10%). Immune and angiogenic proteomic profiles demonstrated trends associated with longer time on therapy.
CONCLUSION: Cabozantinib and nivolumab was associated with limited response in patients with epNET. Alternative strategies to enhance the immune response in epNET are needed.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-2337
World J Gastrointest Endosc. 2025 Oct 16. 17(10): 111259

Challenges in evaluating high-grade pancreato-hepato-biliary neuroendocrine tumors.

Payila Satya Raghava Aneesh, Venkatesh Vaithiyam.

  We read with great interest and commend Tasneem et al for their valuable study on pancreato-hepatobiliary neuroendocrine tumors diagnosed via endoscopic ultrasound-guided biopsy. While the study offers important insights, we raise concerns regarding lesion classification, the lack of correlation between tumor size and aggressiveness, and the limited predictive value of individual clinical factors. Notably, many extra-pancreatic lesions may represent metastases rather than primary tumors. We advocate for a more comprehensive risk stratification approach and suggest incorporating novel molecular markers and analysis of the tumor microenvironment. Larger prospective studies are essential to enhance understanding and management of these rare and heterogeneous neoplasms.

Keywords:  Endoscopic ultrasound; Malignant transformation; Pancreatic tumors; Pancreato-hepatobiliary neuroendocrine tumors; Screening

DOI:  https://doi.org/10.4253/wjge.v17.i10.111259
Clin Transl Oncol. 2025 Nov 19.

Targeting prostate adenocarcinoma tumor microenvironment via cancer nanotheranostics: a comprehensive update on improved roadmap for disease diagnosis, therapy and management.

Abdul Wasai, Adhiraj Roy, Deepti Pandita.

  Prostate adenocarcinoma (PAC) ranks second as most lethal malignancy in men worldwide with significant economic burden on public health management. Despite of cytoreductive surgery of visible tumor mass followed by administration of chemotherapies including androgen deprivation therapy (ADT) using several drugs including enzalutamide, patients develop therapy resistance displaying metastatic, castration-resistant PAC (mCRPC). Furthermore, mCRPC patients fail to respond to neoadjuvant chemotherapies (NACT) such as androgen receptor-targeted agents (ARTAs) and develop a lethal, highly aggressive, therapy-induced neuroendocrine PAC (NEPC). Hence, identification of novel, targetable drivers and therapeutic interventions are highly warranted to manage this lethal pathology. Recently, nanotheranostics, an approach combining cancer diagnostics and therapeutics via nanotechnology is emerging as a promising intervention strategy towards early detection, disease remission and improved PAC patient survival outcomes. It frequently targets interacting components between cancer cells and tumor microenvironment (TME) which play critical role in disease progression and chemoresistance. For example, multimodal peptide-based imaging probes (peptides complexed with Cu64 etc.) combined with PET-MRI improved early PAC detection and patient survival. In this review, we have comprehensively discussed recent developments in cancer nanotheranostics-their targets in PAC TME, mode of actions and potential therapeutic strategies.

Keywords:  Nano formulation; Nanotheranostics; Precision medicine; Prostate adenocarcinoma; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12094-025-04121-7
Cancer Manag Res. 2025 ;17 2785-2791

A Rare Case of Chemotherapy Combined with Immunotherapy for Dual Primary AFP-Positive Gastric Cancer and Synchronous Small Cell Lung Cancer.

Jiangyu Bian, Yuxing Sun, Tong Zhang.

   Background: Alpha-fetoprotein-positive gastric cancer (AFPGC) is a rare subtype of gastric cancer characterized by high invasiveness and extremely poor prognosis. According to relevant studies, the median overall survival of such patients is significantly shorter than that of AFP-negative gastric cancer patients (14 months vs 40 months). Small cell lung cancer (SCLC), the most malignant type of lung cancer, has a median survival time of only 8-12 months in patients with extensive disease. To date, there have been no reported cases of dual primary cancers involving both AFPGC and SCLC, and the therapeutic role of immunotherapy in such dual primary tumors remains unclear.
Case Presentation: This paper reports a case of a 72-year-old male patient who was diagnosed via imaging and pathology as having concurrent AFPGC (moderately to poorly differentiated adenocarcinoma, PD-L1 positive, Tumor mutation burden(TMB) 10.03Muts/Mb, PD-L1 Combined Positive Score (CPS)<1) combined with primary extensive-stage SCLC. The patient received CAPEOX regimen (capecitabine plus oxaliplatin) combined with tislelizumab therapy. After 4 cycles, partial response (PR) was observed in the gastric lymph nodes, and stable disease (SD) was noted in the pulmonary lesions. Following pathological confirmation of dual primary cancers, treatment continued with the original regimen, followed by maintenance therapy with tegafur gimeracil oteracil potassium capsule (teysuno) plus tislelizumab. During treatment, serum AFP levels decreased from baseline 502 μg/L to 1.56 μg/L. Both primary tumor lesions remained stably controlled for over 33 months, and the patient currently tolerates treatment well with an Eastern Cooperative Oncology Group (ECOG) performance status of 0.
Conclusion: Through the long-term treatment course of this case, we validated the therapeutic efficacy of chemotherapy combined with immunotherapy (CAPEOX plus tislelizumab) for the rare aggressive dual primary tumors AFPGC and SCLC, demonstrating significant long-term maintenance benefits from the immunotherapy. Concurrently, this case confirmed the efficacy and safety of tislelizumab during the maintenance therapy phase for both tumors, offering a new treatment option for managing such complex clinical presentations.

Keywords:  AFPGC; SCLC; case report; immunotherapy; tislelizumab

DOI:  https://doi.org/10.2147/CMAR.S548762
PeerJ. 2025 ;13 e20343

IPI score as a new prognostic index in extensive stage small cell lung cancer.

Ahmet Burak Ağaoğlu, Ferhat Ekinci, Mustafa Şahbazlar, Atike Pınar Erdoğan.

   Background: Personalized prognostic assessment in extensive-stage small cell lung cancer (ES-SCLC) necessitates a comprehensive understanding of systemic inflammatory markers and their impact on survival outcomes. This study aimed to evaluate the prognostic significance of a novel Inflammatory Prognostic Index (IPI) score, derived from four inflammation-related biochemical markers-albumin, C-reactive protein (CRP), neutrophils, and lymphocytes-in patients with ES-SCLC.
Methods: Patients diagnosed with ES-SCLC were eligible if adequate clinical, pathological, and follow-up data were available. The IPI score was derived using the formula: C-reactive protein × neutrophil-to-lymphocyte ratio (NLR)/serum albumin. The threshold value for the IPI score was identified using receiver operating characteristic (ROC) curve analysis within the cohort and was applied in an exploratory manner. Based on the predefined cut-off, patients were stratified into low- and high-IPI groups. The log-rank test was used to compare survival times, while Kaplan-Meier curves and Cox regression analyses assessed variables associated with long-term survival. Overall survival (OS) served as the primary endpoint, and progression-free survival (PFS) was evaluated as a secondary endpoint.
Results: Patients with a high IPI score had a mean OS of 9 months (95% CI [4.8-13.2]), while those with a low IPI score had a mean OS of 23 months (95% CI [11.4-34.6]), a statistically significant difference (p = 0.005). The prognostic significance of IPI was confirmed in both univariate (p = 0.003) and multivariate (p = 0.012) analyses.
Conclusion: The IPI score in ES-SCLC patients was associated with prognosis, with a high IPI score indicating poorer OS. These findings should be considered hypothesis-generating and warrant validation in larger prospective cohorts.

Keywords:  Extensive; IPI score; Lung cancer; Overall survival

DOI:  https://doi.org/10.7717/peerj.20343
Cancer Treat Res Commun. 2025 Nov 07. pii: S2468-2942(25)00167-4. [Epub ahead of print]45 101031

Validation of the pheochromocytoma of adrenal gland scaled score (PASS) grading system: A retrospective double-centered cross-sectional study.

Maha Ahmad Faraman, Ammar Albostani, Rufaida Ahmad Faraman, Walid Al-Saleh.

   BACKGROUND: Pheochromocytomas are adrenal medullary tumors with unpredictable malignant potential. The Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) stratifies risk based on histology, but its reliability is debated. This study evaluates PASS performance in a contemporary cohort.
METHODS: We retrospectively reviewed adrenal tumor archives from two tertiary hospitals (2014-2021). Among 286 adrenalectomies, 50 pheochromocytomas with complete clinical and histological data met inclusion criteria. Two pathologists independently applied the 12 PASS criteria; discrepancies were resolved by consensus. Tumors were classified as lower-risk (PASS <4) or higher-risk (PASS ≥4). Demographic and clinicopathologic data were analyzed and compared with published series.
RESULTS: Of 50 cases, 27 (54 %) were lower-risk and 23 (46 %) higher-risk. Groups did not differ significantly by age or sex, though both showed female predominance (∼70 %). Right-sided tumors were more common. Higher-risk tumors more frequently exhibited necrosis, capsular invasion, and mitotic activity, whereas these features were rare in lower-risk tumors. Subjective features such as pleomorphism demonstrated inter-observer variability. Compared with Thompson's original series, our patients were younger and had larger tumors.
CONCLUSION: PASS reliably identifies a low-risk subgroup, supporting its use as a screening tool to reduce unnecessary surveillance. However, its ability to predict malignant behavior is limited by subjective criteria and inter-observer variation. PASS should therefore be applied within a multimodal framework incorporating molecular markers. Prospective studies are needed to refine prognostic accuracy.

Keywords:  Adrenal tumors; Histopathological grading; Neuroendocrine tumors; PASS scoring system; Pheochromocytoma; Risk stratification

DOI:  https://doi.org/10.1016/j.ctarc.2025.101031
JCO Precis Oncol. 2025 Nov;9 e2500724

Delta-Like Ligand 3 Expression and Functional Imaging in Gastroenteropancreatic Neuroendocrine Neoplasms.

Rohit Thummalapalli, Salomon Tendler, Joanne F Chou, Zeynep C Tarcan, Courtney Porfido, Jonathan Willner, Irina Linkov, Umesh Bhanot, Alissa J Cooper, Jierui Xu, James J Harding, Natasha Rekhtman, Laura H Tang, Charles M Rudin, Yelena Y Janjigian, Heiko Schöder, John T Porier, Jinru Shia, Olca Basturk, Diane Reidy-Lagunes, Marinela Capanu, Jason S Lewis, Lisa Bodei, Mark P Dunphy, Nitya Raj.

PURPOSE: Delta-like ligand 3 (DLL3) is an emerging target across neuroendocrine cancers, but remains underexplored in gastroenteropancreatic neuroendocrine neoplasms (GEP NENs), including poorly differentiated gastroenteropancreatic neuroendocrine carcinomas (GEP NECs) and well-differentiated neuroendocrine tumors (NETs). We aimed to define the landscape of DLL3 expression and feasibility of DLL3-targeted imaging in this population.
PATIENTS AND METHODS: We completed DLL3 immunohistochemistry (IHC) on 379 tumor samples from patients with GEP NENs, analyzing associations between DLL3 IHC positivity, clinicopathologic features, and outcomes. [89Zr]Zr-DFO-SC16.56 DLL3 immuno-positron emission tomography-computed tomography (immunoPET-CT) imaging was performed in six patients with DLL3 IHC-positive advanced GEP NENs.
RESULTS: Among GEP NECs, DLL3 expression was identified in 55/78 (71%) tumors, was enriched for small cell histology, and did not demonstrate prognostic significance. Among well-differentiated gastroenteropancreatic neuroendocrine tumors, DLL3 expression was identified in 5/235 (2%) of grade 1-2 and 25/66 (40%) grade 3 (G3) tumors, most commonly G3 pancreatic NETs (PanNETs; 22/52, 43%), with univariate analysis revealing increased mortality risk among patients with DLL3-positive advanced G3 PanNETs (hazard ratio 3.27 [95% CI, 1.09 to 9.78]). Between May 28, 2024, and February 10, 2025, six patients with DLL3 IHC-positive GEP NENs underwent [89Zr]Zr-DFO-SC16.56 immunoPET-CT imaging, which delineated DLL3-avid tumor lesions in five of six patients (two of two GEP NECs, three of four G3 PanNETs). Tumor-specific uptake of [89Zr]Zr-DFO-SC16.56 varied between patients, with maximum standard uptake values ranging from 7.4 to 36.7, with four of six cases demonstrating DLL3 avidity in ≥50% of tumor lesions.
CONCLUSION: DLL3 is expressed on a majority of GEP NECs and on a subset of high-grade PanNETs marked by poor outcomes. Functional imaging suggests DLL3 as a promising therapeutic target in both GEP NECs and high-grade PanNETs.

DOI: https://doi.org/10.1200/PO-25-00724