bims-necame 2025-10-26 papers

bims-necame

Biomed News

on Metabolism in small cell neuroendocrine cancers

Issue of 2025–10–26
eighteen papers selected by
Grigor Varuzhanyan, UCLA

Preclinical Activity of the DLL3-Targeted T-cell Engager MK-6070 in Neuroendocrine Prostate Cancer.
Enhancing cisplatin therapy for small cell lung cancer via a dual strategy of combining surufatinib and CD47 blockade.
Evaluation of siramesine, β-Lapachone, and palbociclib as novel maintenance therapies after chemotherapy in small cell lung cancer.
Metabolic phenotype and gender may predict treatment outcomes of atezolizumab in extensive-stage small cell lung cancer.
Neuroscience in prostate cancer.
Genetically encoded fluorescent probes to assist in the diagnosis of small cell lung cancer.
Erythrocytosis-inducing PHD2 mutations implicate biological role for N-terminal prolyl-hydroxylation in HIF1α oxygen-dependent degradation domain.
Paltusotine versus octreotide: different effects on radioligand uptake in neuroendocrine tumours.
VRK1 Is a Novel Therapeutic Target for Small Cell Neuroendocrine Carcinoma of the Cervix.
Pre-screening value of serum albumin and the glucose-lymphocyte ratio as the "transport-activation" effectors of immune checkpoint inhibitors in small cell lung cancer.
Netrin-DCC Inhibition Suppresses Neuroendocrine Neoplasms Growth in vivo.
Machine learning-enhanced direct mass spectrometry analysis of non-volatile breath metabolites for rapid and accurate lung cancer screening.
Anatomical-biochemical discordance and prognostic role of bone metastases in advanced MTC treated with [¹⁷⁷Lu]Lu-DOTA-TATE.
Comparison of the averaged biodistribution and pharmacokinetics between [99mTc]Tc-HYNIC-TOC and [177Lu]Lu-DOTA-TATE in neuroendocrine tumor patients.
¹⁸F-AlF-NOTA-octreotide PET/CT in high-grade G3 neuroendocrine tumors and neuroendocrine carcinomas: diagnostic performance and complementarity with ¹⁸F-FDG PET/CT.
Novel radiohybrid PET-Tracers for SST2-targeted imaging of neuroendocrine tumors.
Expression of YAP1 delineates distinct subtypes of pulmonary large cell neuroendocrine carcinoma with divergent therapeutic implications.
An effective and affordable blood test for lung cancer early detection using four protein markers and artificial intelligence.

Mol Cancer Ther. 2025 Oct 24. OF1-OF9

Preclinical Activity of the DLL3-Targeted T-cell Engager MK-6070 in Neuroendocrine Prostate Cancer.

Sheng-Yu Ku, Nishat Manzar, Maria Mica Garcia, Min Jin Kim, David J Einstein, Steven P Balk, Yasutaka Yamada, Himisha Beltran.

Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer with limited therapeutic options. Delta-like ligand 3 (DLL3) is a cell-surface protein and therapeutic target expressed in the vast majority of NEPC tumors. The DLL3-targeted T cell-activating construct MK-6070 (formerly called HPN328) binds to both DLL3 on tumor cells and CD3 on T cells, as well as serum albumin to extend half-life. A phase I/II trial of MK-6070 is currently underway, which includes an NEPC cohort (NCT04471727). In this study, we report the preclinical activity of MK-6070 in prostate cancer models, showing high specificity and antitumor activity in DLL3-expressing NEPC models both in vitro and in vivo, with T-cell activation and tumor infiltration of T cells after treatment. MK-6070 also demonstrates antitumor activity in mixed tumors, affecting DLL3-negative prostate cancer cells after engagement with surrounding DLL3-expressing tumor cells, supporting a potential bystander effect. Overall, these data demonstrate the promising activity of MK-6070 in NEPC preclinical models including heterogeneous tumors, supporting the clinical development of MK-6070.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-0453
J Control Release. 2025 Oct 21. pii: S0168-3659(25)00962-9. [Epub ahead of print]388(Pt 1): 114348

Enhancing cisplatin therapy for small cell lung cancer via a dual strategy of combining surufatinib and CD47 blockade.

Kaiming Li, Ziming Lin, Ting Wu, Jintong Zhou, Jie Wu, Yupeng Zhou, Huimin Gao, Ya Lin, Xufeng Chen, Huae Xu, Xiaolin Li.

  Small cell lung cancer (SCLC) is a highly lethal malignancy with a < 7 % 5-year survival rate. Platinum-based chemotherapy remains the standard treatment; however, its clinical efficacy is limited. There is an urgent need for new therapeutic strategies. In this study, we developed a RGD labeled liposome (CS/RGD-Lipo) encapsulating both cisplatin and surufatinib as a target delivery system against SCLC, aimed at enhancing ferroptosis to improve cisplatin efficacy, inhibiting angiogenesis, and reversing TAM phenotypes to overcome immunosuppression. Additionally, we combined CS/RGD-Lipo with αCD47 to further enhance antitumor activity. In tumor-bearing mice, CS/RGD-Lipo effectively targeted tumor tissues for the delivery of cisplatin and surufatinib. The combination of CS/RGD-Lipo with αCD47 significantly promoted ferroptosis in SCLC, improved anti-angiogenesis, induced the conversion of M2 macrophages to M1 macrophages, and enhanced the M1 macrophages-mediated antitumor immune response, resulting in a marked inhibition of tumor growth in SCLC mouse models. Taken together, this work demonstrates a feasible therapeutic approach to inhibit SCLC by combining cisplatin, surufatinib, and αCD47 to leverage tumor ferroptosis, angiogenesis inhibition and tumor-associated macrophage polarization.

Keywords:  CD47 blockade; Cisplatin; Ferroptosis; Macrophage repolarization; Small cell lung cancer; Surufatinib

DOI:  https://doi.org/10.1016/j.jconrel.2025.114348
Eur J Pharmacol. 2025 Oct 17. pii: S0014-2999(25)01027-1. [Epub ahead of print] 178273

Evaluation of siramesine, β-Lapachone, and palbociclib as novel maintenance therapies after chemotherapy in small cell lung cancer.

María Ángeles Chico, Kevin Doello, Raul Ortiz, Consolación Melguizo, Cristina Mesas, Jose Prados.

  Small cell lung cancer (SCLC) represents approximately 15% of all lung cancer cases and is characterized by rapid proliferation and a high metastatic potential. In the search for new treatments, drug repurposing has gained increasing attention, particularly with FDA-approved agents such as palbociclib (PB). Other compounds with reported antitumor activity, including siramesine (SR) and β-Lapachone (LP), are also under investigation, although they remain unapproved for clinical use. In this study, we evaluated the antitumor activity and underlying mechanisms of SR, LP, and PB in the H69 cell line. Antiproliferative effects, apoptosis (via PARP1 and Bcl-2), autophagy (via LC3β and p62), and senescence (via p21) were analyzed. Antitumor activity was further investigated using the chick chorioallantoic membrane (CAM) assay in ovo. Additionally, in vivo therapeutic efficacy was evaluated in subcutaneous murine models bearing H69 tumors, both as monotherapy and as maintenance treatment. All three compounds reduced cell proliferation and colony formation. PB increased reactive oxygen species (ROS) levels and induced cellular senescence. In the CAM assay, tumors appeared less dense and showed reduced expression of the proliferation marker Ki-67. Interestingly, SR, LP, and PB significantly reduced tumor volume when administered as monotherapies in murine models of SCLC. Furthermore, when they were used as maintenance therapy following chemotherapy, these drugs enhanced the antitumor response. Therefore, our findings highlight SR, LP, and PB as promising therapeutic candidates for the treatment of SCLC.

Keywords:  Small cell lung cancer; in ovo; in vivo; palbociclib; siramesine; β-Lapachone

DOI:  https://doi.org/10.1016/j.ejphar.2025.178273
Transl Lung Cancer Res. 2025 Sep 30. 14(9): 3836-3846

Metabolic phenotype and gender may predict treatment outcomes of atezolizumab in extensive-stage small cell lung cancer.

Peter May, Christof Winter, Inga Hubrecht, Eva Ortner, Selina Strathmeyer, Roland Geyer, Steffen Heelemann, Jan Stratmann, Folker Schneller, Florian Bassermann, Aaron Becker von Rose.

   Background: Small cell lung cancer (SCLC) is characterized by an aggressive clinical course and poor survival rates. The introduction of immune checkpoint blockade (ICB) into the frontline treatment of extensive-stage (ES)-SCLC with programmed death-ligand 1 (PD-L1) inhibitors such as atezolizumab and durvalumab has improved outcomes. However, median overall survival (OS) is still limited to approximately 12 months, underscoring the need for predictive biomarkers to optimize treatment selection. Notably, recent subgroup analyses suggest potential sex-specific differences in response to ICB, with improved outcomes observed in female patients. However, the biological mechanisms underlying these differences remain unclear. Additionally, metabolic factors may influence response to immunotherapy, yet their roles in ES-SCLC remain underexplored. This study aims to evaluate the impact of sex and metabolic phenotypes on treatment outcomes in ES-SCLC patients receiving atezolizumab and to identify potential metabolic biomarkers of response.
Methods: This retrospective single-center study evaluated the impact of sex and metabolic phenotypes on treatment outcomes in ES-SCLC patients receiving atezolizumab. Seventy patients were analyzed: 33 treated with atezolizumab plus chemotherapy (September 2019 to May 2024) and 37 historical controls who received chemotherapy alone (January 2014 to September 2019). Primary endpoints were OS and progression-free survival (PFS). Additionally, targeted metabolomic profiling was performed using nuclear magnetic resonance (NMR) spectroscopy on serum samples from 12 patients receiving atezolizumab, yielding 55 serum samples for analysis.
Results: Our study replicated the OS benefit of atezolizumab, with the greatest advantage observed in female patients (median OS: 20.2 vs. 11.7 months). Body mass index (BMI) and uric acid levels exhibited an inverse U-shaped relationship with OS, suggesting a possible metabolic influence on immunotherapy efficacy. Multivariate analysis confirmed female sex and lower lactate dehydrogenase levels as independent prognostic factors for improved survival. Additionally, preliminary metabolome analysis identified distinct metabolite profiles in responders (PFS >6 months), including elevated cystine, histidine, and creatine, and reduced phenylalanine levels.
Conclusions: These findings support the hypothesis that both sex and metabolic factors modulate responses to ICB in ES-SCLC. Further research is warranted to validate these biomarkers and explore potential interventions to enhance immunotherapy efficacy in this aggressive malignancy.

Keywords:  Atezolizumab; body mass index (BMI); extensive-stage small cell lung cancer (ES-SCLC); gender; metabolome

DOI:  https://doi.org/10.21037/tlcr-2025-300
Prostate Cancer Prostatic Dis. 2025 Oct 18.

Neuroscience in prostate cancer.

Ziteng Liu, Qiang Peng, Yuliang Wang, Peter Ka-Fung Chiu, Jeremy Yuen-Chun Teoh, Rongjiang Wang, Xiaodong Liu, Dinglan Wu, Chi-Fai Ng.

BACKGROUND: Emerging evidence in cancer neuroscience indicates that the nervous system interacts directly or indirectly with cancer cells, promoting tumor progression. The prostate gland contains an extensive neural network essential for regulating key physiological functions of prostate cells, and the significant neural distribution observed in prostate cancer highlights its critical role in driving cancer pathogenesis. Unfortunately, Comprehensive reviews systematically summarizing progress in cancer neuroscience for prostate cancer are currently lacking.
METHOD: We synthesize existing research on interactions between the nervous system and prostate cancer cells, explore the neural distribution within the prostate, and evaluate the impact of neural innervation on prostate cancer development and progression. Additionally, we also assess the potential neural regulation mechanisms in neuroendocrine prostate cancer (NEPC).
RESULT: We found that neural interactions significantly influence prostate cancer development. Neural circuitry within the tumor microenvironment drives progression and contributes to the aggressiveness of lethal subtypes like NEPC. Targeting neuromodulation emerges as a promising therapeutic approach, potentially allowing the repurposing of established medications for treating advanced tumors.
CONCLUSION: Neuromodulation offers a promising therapeutic option for advanced prostate cancer, particularly NEPC, which faces limited treatment options. However, further research is necessary to fully understand the neural regulatory mechanisms involved in prostate cancer development and to identify new therapeutic targets and strategies for advanced stages.

DOI: https://doi.org/10.1038/s41391-025-01042-y
Appl Microbiol Biotechnol. 2025 Oct 25. 109(1): 236

Genetically encoded fluorescent probes to assist in the diagnosis of small cell lung cancer.

Dengyue Xu, Hong Yuan, Zhi Li, Qingyun Jiang, Angyang Shang, Jiaqi Liu, Chengyu Xue, Shuai Shao, Hangyu Zhang, Bin Wu, Bo Liu.

  Small cell lung cancer (SCLC) is one of the most aggressive malignancies, with early detection being crucial for improving patient outcomes. Serum biomarkers, neuron-specific enolase (NSE), and pro-gastrin releasing peptide (ProGRP), play significant roles in the early screening and pathological classification of SCLC. In the study, the affinity peptides of NSE and ProGRP were screened by phage display technology, which were then assessed for binding affinity using enzyme-linked immunosorbent assay (ELISA) and biolayer interferometry (BLI). Circularly permuted fluorescent protein (cpFP) probes were constructed by genetically encoding the selected peptides as binding domains. The E1 probe for NSE and the P10 probe for ProGRP demonstrated high sensitivity and specificity in detecting their respective targets. The E1 probe with a concentration of 4 μg/mL reacted well with NSE (1-16,000 ng/mL), and the reaction exhibited a good linear relationship when the NSE concentration was between 1 and 100 ng/mL. The 4 μg/mL P10 probe reacted well with ProGRP (0.01-2000 ng/mL) and showed good linear relationship between 0.01 and 50 ng/mL. Clinical validation revealed that adjusting the upper limit of normal concentrations significantly improved the probes' diagnostic sensitivity and specificity for SCLC. These probes offer a high-sensitivity, specific, rapid, and cost-effective approach to SCLC detection, holding promise for early diagnosis and improved patient management . KEY POINTS: In this study, peptides targeting NSE and ProGRP were selected by phage display technology, and the peptides obtained have good affinity with the corresponding proteins. Based on R-GECO1, cpFP probes were constructed using peptides as binding domains, and E1 probe for NSE and P10 probe for ProGRP were obtained. E1 probe and P10 probe have good sensitivity and specificity for the diagnosis of SCLC.

Keywords:  Circularly permuted fluorescent protein; Neuron-specific enolase; Peptides; Phage display; Pro-gastrin-releasing peptide; Small cell lung cancer

DOI:  https://doi.org/10.1007/s00253-025-13577-0
Elife. 2025 Oct 20. pii: RP107121. [Epub ahead of print]14

Erythrocytosis-inducing PHD2 mutations implicate biological role for N-terminal prolyl-hydroxylation in HIF1α oxygen-dependent degradation domain.

Cassandra C Taber, Wenguang He, Geneviève M C Gasmi-Seabrook, Mia Hubert, Fraser G Ferens, Mitsuhiko Ikura, Jeffrey E Lee, Michael Ohh.

  Mutations in EGLN1, the gene encoding for hypoxia-inducible factor (HIF) prolyl-4-hydroxylase 2 (PHD2), cause erythrocytosis and in rare cases the development of neuroendocrine tumors. In the presence of oxygen, PHD2 hydroxylates one or both conserved prolines in the oxygen-dependent degradation domain (ODD) of HIFα subunits, sufficiently marking HIFα for binding and ubiquitylation via the von Hippel-Lindau (VHL) tumor suppressor protein-containing E3 ubiquitin ligase and subsequent degradation by the 26S proteasome. However, prolyl-hydroxylation in the C-terminal ODD appears to be the predominant and sufficient event in triggering the oxygen-dependent destruction of HIFα, rendering the biological significance of N-terminal ODD proline unclear. Here, we examined seven disease-associated EGLN1 mutations scattered across the catalytic core and showed definitively that all PHD2 mutants have a structural and/or catalytic activity defect as measured by time-resolved nuclear magnetic resonance. Notably, we identified one of the PHD2 mutants, P317R, to retain comparably wild-type capacity to hydroxylate the predominant proline in the C-terminal ODD but had uniquely compromised ability to hydroxylate the N-terminal ODD proline. These findings support the notion that deregulation of HIF ultimately underlies PHD2-driven erythrocytosis and challenge the currently held uncertainty that the N-terminal ODD prolyl-hydroxylation event is dispensable in normal hypoxic signaling pathway.

Keywords:  E. coli; HIF; PHD2; cancer biology; erythrocytosis; hypoxic response

DOI:  https://doi.org/10.7554/eLife.107121
Endocr Oncol. 2025 Jan;5(1): e250041

Paltusotine versus octreotide: different effects on radioligand uptake in neuroendocrine tumours.

Katharina Wang, Christoph J Auernhammer, Simon Lindner, Mathias Zacherl, Rudolf A Werner, Julian Maurer, Lea Peischer, Julia Hamati, Maximilian P Hungbauer, Thomas Knösel, Astrid Reul, Elena Kuzmenko, Diana Vetter, José Oberholzer, Umberto Maccio, Felix Beuschlein, Martin Reincke, Constanze Hantel, Karel Pacak, Ashley B Grossman, Kathrin Zitzmann, Svenja Nölting.

   Objective: Somatostatin receptor analogues are well-established in the treatment of metastatic gastro-enteropancreatic neuroendocrine tumours (GEP-NETs), especially for symptom control in patients with the carcinoid syndrome, and to control tumour growth. However, they need to be discontinued before peptide receptor radionuclide therapy (PRRT) as they may saturate the somatostatin receptor 2 (SSTR2) and prevent binding of the radioactive ligand.
Design: We evaluated the effects of the novel somatostatin analogue paltusotine on 18F-SiTATE radioligand uptake and on GEP-NET cell viability in comparison to octreotide.
Methods: Paltusotine and octreotide were evaluated in varying concentrations in an 18F-SiTATE uptake assay using stable hSSTR2 over-expressing BON-1 cells, and in a cell viability assay utilising different NET cell lines and human patient-derived GEP-NET primary cultures (n = 13).
Results: Low, clinically-relevant concentrations of paltusotine (7.3-25.4 nM) demonstrated no influence on cellular radioligand uptake compared to the control. In contrast, octreotide reduced radioligand uptake at low, clinically-relevant concentrations (7.3-25.4 nM) and led to a further significant reduction of radioligand uptake at higher concentrations (73-508 nM). Both paltusotine and octreotide showed overall little or no significant anti-tumour effects in vitro in NET cell lines. However, in contrast to octreotide, paltusotine led to a slight decrease in cell viability of patient-derived GEP-NET primary cultures.
Conclusions: Treatment with paltusotine did not significantly reduce radioligand binding of 18F-SiTATE in vitro, indicating no influence on SSTR2 targeting. This might enable a continuation of somatostatin receptor analogue therapy with paltusotine during PRRT, potentially improving symptom control in GEP-NET patients with the carcinoid syndrome.

Keywords:  PRRT; neuroendocrine tumour; octreotide; paltusotine; peptide receptor radionuclide therapy; somatostatin analogue

DOI:  https://doi.org/10.1530/EO-25-0041
Cancer Sci. 2025 Oct 20.

VRK1 Is a Novel Therapeutic Target for Small Cell Neuroendocrine Carcinoma of the Cervix.

Mariya Kobayashi, Satoshi Nakagawa, Yusuke Ishii, Yuji Kamei, Mizuki Kanda, Tatsuo Masuda, Mamoru Kakuda, Kosuke Hiramatsu, Tadashi Iwamiya, Tomomi Egawa-Takata, Shinya Matsuzaki, Hiroyuki Uematsu, Kunishige Onuma, Masahiro Inoue, Yutaka Ueda, Tadashi Kimura, Michiko Kodama.

  Small cell neuroendocrine carcinoma of the cervix (SCNEC) is classified as a high-grade neuroendocrine carcinoma with a worse prognosis than other major histological types of cervical cancer. Identifying novel therapeutic targets based on its molecular characteristics is highly desirable but challenging due to the rarity of SCNEC and the resulting lack of research resources. In this study, we identified vaccinia-related kinase 1 (VRK1) as a potential therapeutic target for SCNEC. VRK1 was prioritized based on our previously reported proteomic analysis of patient-derived organoids. Immunohistochemistry of patient samples consistently revealed high VRK1 expression in SCNEC, as opposed to its variable expression in other cervical carcinomas. Although VRK1 knockdown in SCNEC had only a limited effect on cell proliferation in two-dimensional cultures, it significantly suppressed cell proliferation in three-dimensional cultures and inhibited xenograft tumor growth in vivo. Gene set enrichment analysis of RNA-sequencing data from mouse xenograft models demonstrated that VRK1 is associated with mitochondrial-related pathways. Furthermore, under oxidative stress conditions, VRK1 knockdown resulted in a reduction of mitochondrial membrane potential, an indicator of mitochondrial integrity, and decreased expression of cytochrome c oxidase subunit IV (COX IV), a nuclear-encoded subunit of cytochrome c oxidase, the terminal enzyme complex of the mitochondrial respiratory chain. These findings suggest that VRK1 knockdown indirectly impaired mitochondrial function. Collectively, these anti-tumor effects highlight VRK1 as a promising therapeutic target for SCNEC.

Keywords:  VRK1; cervical cancer; in vivo; mitochondria; small cell neuroendocrine carcinoma

DOI:  https://doi.org/10.1111/cas.70211
Transl Lung Cancer Res. 2025 Sep 30. 14(9): 4037-4050

Pre-screening value of serum albumin and the glucose-lymphocyte ratio as the "transport-activation" effectors of immune checkpoint inhibitors in small cell lung cancer.

Chenxi Wang, Jinhe Xu, Ying Chen, Shuting Lu, Weiwei Xue, Feng Cheng, Yuxin Guo, Wenting Zhang, Ruiying Rao, Xinyu Zhang, Nong Zhou, Liangchong Shi, Masatsugu Hamaji, Hirokazu Taniguchi, Zongyang Yu.

   Background: Small cell lung cancer (SCLC), a therapy-resistant neuroendocrine carcinoma, shows variable responses to immune checkpoint inhibitors (ICIs) and chemotherapy regimens. This study aimed to evaluate the pre-screening utility of peripheral blood serum albumin (ALB) and the glucose-to-lymphocyte ratio (GLR) as biomarkers for identifying populations of SCLC patients likely to benefit from ICIs.
Methods: A retrospective cohort of SCLC patients receiving ICIs between 2018 and 2023 was analyzed. The optimal prognostic thresholds for ALB and the GLR were determined using maximally selected rank statistics. The survival outcomes were assessed via Kaplan-Meier analysis and Cox regression. A propensity score matching (PSM) analysis adjusted for confounders was performed. A prognostic nomogram integrating ALB, the GLR, and clinical variables was developed. Model performance was assessed using the concordance index (C-index) and time-dependent receiver operating characteristic (ROC) curves.
Results: Among 126 eligible patients, 93 (73.8%) had extensive-stage SCLC at diagnosis, and 33 (26.2%) presented with brain metastasis. The optimal cut-off values of ALB and the GLR for predicting overall survival (OS) were 40.9 g/L and 5.02, respectively. Multivariable Cox regression identified ALB [hazard ratio (HR) =0.415, 95% confidence interval (CI): 0.247-0.696] and GLR (HR =0.560, 95% CI: 0.315-0.994) as independent prognostic factors favoring longer OS, with ALB showing stronger protective association. Patients with both high ALB and a high GLR demonstrated the most favorable OS among the four subgroups (P<0.001). The prognostic model, which incorporated ALB, the GLR, carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and clinical stage, had a C-index of 0.752 [area under the curve (AUC) values: 0.804 at 12 months and 0.781 at 24 months].
Conclusions: Pre-treatment serum ALB and the GLR represent cost-effective, readily accessible biomarkers for stratifying SCLC patients who may derive survival benefits from ICI-based regimens. These findings warrant validation in prospective multicenter studies.

Keywords:  Small cell lung cancer (SCLC); biomarkers; glucose-to-lymphocyte ratio (GLR); immunotherapy; serum albumin (serum ALB)

DOI:  https://doi.org/10.21037/tlcr-2025-825
Endocr Relat Cancer. 2025 Oct 21. pii: ERC-25-0226. [Epub ahead of print]

Netrin-DCC Inhibition Suppresses Neuroendocrine Neoplasms Growth in vivo.

Liav Sela Peremen, Alona Telerman, Yuval Kahan Yossef, Naama Peshes Yaloz, Amit Tirosh.

  DCC protein functions as a tumor suppressor and is altered in various tumors, including neuroendocrine neoplasms. Netrin (NTN)-1 serves as the primary ligand for DCC. Acting as a dependence receptor, DCC induces apoptosis in the absence of NTN and promotes cell survival when NTN is present. In certain cancers, such as small-cell lung cancer and neuroblastoma, the upregulation of NTN-3 has been observed instead of NTN-1. However, the exact role of NTNs and DCC in PNEN remains unclear. We assessed DCC and netrin expression in pancreatic neuroendocrine neoplasms (PNEN) cells (BON-1). We examined the effect of netrin on cell viability using DCC knockdown and NP137, a netrin-inhibiting antibody. In vivo, PNEN cells were injected into nude mice and treated with NP137 or PBS. Tumor RNA sequencing was performed. A population-based analysis using TCGA data evaluated the impact of DCC and NTN3 expression on survival. BON-1 cells exhibited elevated expressions of DCC and NTN-3. The addition of NTN-1 augmented BON1 viability, a response that was lessened upon NTN blockade using NP137. Furthermore, DCC siRNA negated the effect of NTN-1 on cell viability. Mice bearing PNEN BON-1 xenografts treated with NP137 exhibited markedly diminished xenograft growth. RNA sequencing revealed upregulation of small nucleolar RNAs (SNORs) in NP137-treated tumors, with enriched pathways related to RNA processing. TCGA analysis showed a negative correlation between NTN3 expression and survival. In conclusion, our data suggest that NTN-3, NTN-1, and DCC have interdependent oncogenic roles in PNENs, which can be reversed by blocking NTN binding to DCC.

Keywords:  DCC; Netrin; Neuroendocrine neoplasms; Pancreas

DOI:  https://doi.org/10.1530/ERC-25-0226
Anal Methods. 2025 Oct 20.

Machine learning-enhanced direct mass spectrometry analysis of non-volatile breath metabolites for rapid and accurate lung cancer screening.

Ran Zheng, Jiaxin Dong, Ying Zhang, Bo Pang, Cong Hu, Rui Su.

Breath analysis by direct mass spectrometry faces significant challenges due to the inherent complexities in sample collection, low analyte concentrations, and accurate compound identification. While current breath analysis primarily focuses on volatile organic compounds (VOCs) for disease research, non-volatile organic compounds (nVOCs) remain largely unexplored despite their diagnostic potential. Here, we present a novel breath analysis method for lung cancer diagnosis based on nVOCs, integrating non-invasive breath analysis with machine learning algorithms for comprehensive characterization of 98 clinical breath samples. This study leverages a machine learning-driven database docking methodology to overcome the bottleneck of metabolite direct mass spectrometry conventional identification. This approach enables rapid and precise screening of non-volatile differential metabolites while effectively excluding exogenous confounders (e.g., pharmacological or environmental interference), enhancing nVOC detection in breath. The approach identified 29 statistically significant nVOC biomarkers, including fatty acids and amino acids, achieving a 0.9878 prediction accuracy for lung cancer detection. For distinguishing between NSCLC and SCLC, the area under the curve (AUC) value can reach 0.9, and the out-of-bag error of random forest is 0.00402. Notably, specific nVOCs including fatty acids and amino acids have high diagnostic potential, with an AUC of up to 0.67 of individual metabolites for the differentiation of SCLC from NSCLC. Finally, significantly altered metabolic pathways were explored by metabolite pathway and transcriptome analysis, showing that the fatty acid metabolism is a potentially regulatable pathway. Our approach facilitates rapid, non-invasive discrimination of NSCLC and SCLC in metabolic analysis, showing promise as an efficient, low-cost clinical test.

DOI: https://doi.org/10.1039/d5ay01304f
BMC Cancer. 2025 Oct 24. 25(1): 1644

Anatomical-biochemical discordance and prognostic role of bone metastases in advanced MTC treated with [¹⁷⁷Lu]Lu-DOTA-TATE.

S Bilgic, A Nazari, M S Sağer, K Sonmezoglu.

   BACKGROUND: Medullary thyroid carcinoma (MTC) is a rare malignancy with limited treatment options in the metastatic setting. While peptide receptor radionuclide therapy (PRRT) with [¹⁷⁷Lu]Lu-DOTA-TATE has been well established in gastroenteropancreatic neuroendocrine tumors, its clinical utility in MTC remains under investigation.
METHODS: We retrospectively analyzed 18 patients with advanced, somatostatin receptor-positive MTC treated with [¹⁷⁷Lu]Lu-DOTA-TATE. Treatment decisions-including in patients with low somatostatin receptor (SSTR) expression or first-line PRRT indication-were made by a multidisciplinary tumor board. Anatomical response was assessed using RECIST 1.1 on [⁶⁸Ga]Ga-DOTA-TATE PET/CT after two cycles. Biochemical and clinical outcomes were also recorded. Progression-free survival (PFS) was evaluated using Kaplan-Meier and Cox regression.
RESULTS: Median PFS was 37.0 months. Radiologic disease control -defined as partial response (PR) or stable disease (SD) -was achieved in 78%, and biochemical response (≥ 50% decrease in calcitonin) in 44% of patients. Patients with bone metastases had significantly shorter PFS (24.6 vs. 47.0 months, p = 0.027). Longer PFS was also observed in those receiving higher cumulative dose, those with larger solitary tumors, and those treated in the first-line setting, although these trends did not reach statistical significance. Discordance between anatomical and biochemical response was observed in 50% of cases, highlighting limitations of calcitonin-based monitoring.
CONCLUSION: PRRT with [¹⁷⁷Lu]Lu-DOTA-TATE is a well-tolerated treatment option for selected patients with advanced MTC, including those receiving first-line therapy and those with low SSTR expression. In our limited cohort, bone metastases were associated with shorter PFS, and discordant imaging/biochemical responses are common. Functional imaging-guided selection and individualized response assessment are essential for optimal management.

Keywords:  177Lu-DOTATATE; Calcitonin response; Medullary thyroid cancer; Peptide receptor radionuclide therapy; Treatment personalization

DOI:  https://doi.org/10.1186/s12885-025-15101-z
Nucl Med Rev Cent East Eur. 2025 ;28(0): 82-89

Comparison of the averaged biodistribution and pharmacokinetics between [99mTc]Tc-HYNIC-TOC and [177Lu]Lu-DOTA-TATE in neuroendocrine tumor patients.

Sara Kurkowska, Bozena Birkenfeld, Hanna Piwowarska-Bilska.

   BACKGROUND: Accurate pre-therapeutic dosimetry can potentially help optimize peptide receptor radionuclide therapy in patients with neuroendocrine tumors. While positron emission tomography (PET) imaging with [68Ga]Ga-DOTA-peptides has been previously studied for predicting therapeutic absorbed dose, it is limited by its single-time-point nature. In contrast, [99mTc]Tc-HYNIC-TOC offers advantages such as lower cost and multi-time-point imaging capability, but its potential to predict [177Lu]Lu-DOTA-TATE biodistribution remains underexplored. The study objective was to evaluate pharmacokinetics, isolating biological clearance from physical decay effects, and compare relative organ uptake ratios between the compounds. This work lays the foundation for future studies exploring [99mTc]Tc-HYNIC-TOC as a predictive tool for treatment planning - particularly in regions where [68Ga] Ga-DOTA-peptides are less accessible.
MATERIAL AND METHODS: The study compared the biodistribution and pharmacokinetics of [99mTc]Tc-HYNIC-TOC and [177Lu]Lu-DOTA-TATE in neuroendocrine tumor (NET) patients by modeling pharmacokinetics, analyzing time-integrated activity coefficients, and biological half-lives in the kidneys, liver, spleen, and lesions from 11 diagnostic and 8 therapeutic studies.
RESULTS: [177Lu]Lu-DOTA-TATE showed significantly higher kidney-to-spleen and lesion-to-spleen uptake ratios compared to [99mTc]Tc-HYNIC-TOC, indicating greater relative accumulation in these organs. There was no statistically significant difference in liver-to-spleen uptake between the two compounds. The biological half-life in the kidneys was longer for [99mTc]Tc-HYNIC-TOC than for [177Lu]Lu-DOTA-TATE, suggesting faster renal clearance of the therapeutic agent. Liver and spleen kinetics were comparable between the two tracers.
CONCLUSIONS: While [99mTc]Tc-HYNIC-TOC and [177Lu]Lu-DOTA-TATE show similar biodistribution patterns in the liver and spleen, they differ in renal and lesion uptake and clearance kinetics. The ability of [99mTc]Tc-HYNIC-TOC to capture dynamic behavior through multi-time-point imaging may offer improved prediction of [177Lu]Lu-DOTA-TATE absorbed dose.

Keywords:  [177Lu]Lu-DOTA-TATE; [99mTc]Tc-HYNIC-TOC; biodistribution; dosimetry; pharmacokinetics

DOI:  https://doi.org/10.5603/nmr.107203
Eur J Nucl Med Mol Imaging. 2025 Oct 24.

¹⁸F-AlF-NOTA-octreotide PET/CT in high-grade G3 neuroendocrine tumors and neuroendocrine carcinomas: diagnostic performance and complementarity with ¹⁸F-FDG PET/CT.

Guozhu Hou, Yuanyuan Jiang, Yi Yang, Susheng Shi, Yihebali Chi, Rong Zheng, Hong Zhao, Jingjing Zhang, Xuejuan Wang.

  Radiolabeled somatostatin receptor (SSTR) analogues are widely utilized for both imaging (PET or scintigraphy) and peptide receptor radionuclide therapy (PRRT) in the management of neuroendocrine neoplasms (NENs). These approaches have been extensively validated in low- to intermediate-grade gastroenteropancreatic neuroendocrine tumors (NET G1 - G2). However, data on the use of SSTR imaging - particularly SSTR PET imaging - in patients with high-grade NETs (G3) and neuroendocrine carcinomas (NECs) remain limited. This study aimed to evaluate the diagnostic performance of ¹⁸F-AlF-NOTA-octreotide (¹⁸F-AlF-OC) PET/CT in patients with high-grade NENs and assess its complementarity with ¹⁸F-FDG PET/CT.
METHODS: Out of 426 patients who underwent ¹⁸F-AlF-OC PET/CT between January 2023 and October 2024, 42 patients with histologically confirmed high-grade NENs (28 with G3 NETs and 14 with NECs) were retrospectively analyzed. 36 patients also underwent 18F-FDG PET/CT. Lesions were classified as positive on PET/CT if their uptake exceeded organ background activity and could not be explained by physiologic biodistribution. Tumor uptake higher than normal liver was considered high uptake.
RESULTS: On a per-patient basis, ¹⁸F-AlF-OC PET/CT was positive in 39 of 42 patients, yielding a detection rate of 92.9%. Among all patients, 28 (66.7%, 28/42) exhibited high ¹⁸F-AlF-OC uptake, and 19 (45.2%, 19/42) demonstrated positivity in all lesions. Of the 36 patients who underwent both scans, detection rates were 91.7% (33/36) for ¹⁸F-AlF-OC and 88.9% (32/36) for ¹⁸F-FDG PET/CT. Discordant findings were observed in 11 patients (30.6%) with¹⁸F-AlF-OC-negative/¹⁸F-FDG-positive lesions and in 13 patients (36.1%) with ¹⁸F-AlF-OC-positive/¹⁸F-FDG-negative lesions. On a per-lesion basis, ¹⁸F-AlF-OC PET/CT showed a higher detection rate than ¹⁸F-FDG PET/CT (80.7% [547/678] vs. 72.9% [494/678]). Specifically, ¹⁸F-AlF-OC identified 109 lesions missed by ¹⁸F-FDG, while ¹⁸F-FDG identified 56 lesions missed by ¹⁸F-AlF-OC. The combined use of both tracers improved the detection rate to 89.1% (604/678), surpassing either modality alone.
CONCLUSION: ¹⁸F-AlF-OC PET/CT demonstrated high detection rates in patients with high-grade NENs, with a substantial proportion showing strong SSTR expression and lesion-wide positivity, supporting its potential role in guiding PRRT eligibility. The complementary nature of ¹⁸F-AlF-OC and ¹⁸F-FDG PET/CT enhances overall diagnostic accuracy, making dual-tracer imaging a valuable approach in this setting.

Keywords:   18F-AlF-NOTA-octreotide; 18F-FDG; G3 NETs; High-grade NENs; PET; PRRT

DOI:  https://doi.org/10.1007/s00259-025-07584-6
Eur J Nucl Med Mol Imaging. 2025 Oct 23.

Novel radiohybrid PET-Tracers for SST2-targeted imaging of neuroendocrine tumors.

Lennard Wendlinger, Mara Parzinger, Alexandra Litvinenko, David Viertl, Philipp Spatz, Alexander Wurzer, Hans-Jürgen Wester, Margret Schottelius.

   PURPOSE: 68Ga- and 177Lu-labeled theranostic companion tracers have become a mainstay in the clinical management of SST2 overexpressing neuroendocrine tumors. Despite the excellent radionuclide characteristics of [18F]fluorine for PET imaging, 18F-labeled SST2-targeted tracers remain underrepresented. Novel radiohybrid SST2-tracers with DOTA as a bridging unit were designed, allowing radiolabeling with either 18F or 68Ga.
METHODS: Seven DOTA-TATE derivatives (rhTATE1/2: N-SiFAlin-N, N-Me2-Gly-D-Dap/Lys(trans-DOTA-TATE)-OH and (rhTATE2.1-2.5: H-AA1-AA2-AA3-D-Dap(N-SiFAlin-N, N-Me2-Gly)-D-Lys(trans-DOTA-TATE)-OH) with different linkers and hydrophilic modifiers (AA1-AA3) were synthesized and compared to [18F]SiTATE. Competitive binding studies (IC50) were performed using hSST2-CHO cells and [125I]TOC. Internalization was investigated using AR42J cells. Biodistribution and PET/CT studies were performed using AR42J xenograft bearing CD1 nu/nu mice. SST2 specificity was confirmed in a blocking study (+/- co-injection of octreotide).
RESULTS: While the first-generation compounds showed good affinity (IC50: [natGa]rhTATE1: 5.6 ± 1.4 nM, [natGa]rhTATE2: 5.7 ± 0.2 nM) but high lipophilicity (LogDpH=7.4 = -1.03 and - 1.19), the inclusion of hydrophilic modifiers ([natGa]rhTATE2.1-[natGa]rhTATE2.5) improved affinity (IC50: 2.6 to 3.7 nM) and hydrophilicity (LogDpH=7.4 = -2.30 to -2.12). The compounds demonstrated efficient internalization (357% to 841% compared to [125I]TOC), and variable human serum albumin affinity (84.8% to 98.8%). [18F][natGa]rhTATE2.2 showed the highest tumor accumulation (27.9 ± 4.8%iD/g), while [18F][natGa]rhTATE2.5 showed lower tumor uptake (18.6 ± 6.2%iD/g), but substantially lower background accumulation, providing improved tumor-to-organ ratios.
CONCLUSION: This study demonstrates a SST2-targeted radiohybrid concept using bifunctionalized DOTA as a bridging unit. N-terminal modifications with hydrophilic tripeptides improved the pharmacokinetic properties. [18F][natGa]rhTATE2.5 (D-Glu-D-Glu-D-Glu) compares particularly well to [18F]SiTATE regarding background clearance and tumor accumulation, with the additional advantage of radiohybrid radiolabeling.

Keywords:  DOTA-TATE; Fluorine-18; Gallium-68; PET imaging; Radiohybrid

DOI:  https://doi.org/10.1007/s00259-025-07638-9
Transl Lung Cancer Res. 2025 Sep 30. 14(9): 3673-3689

Expression of YAP1 delineates distinct subtypes of pulmonary large cell neuroendocrine carcinoma with divergent therapeutic implications.

Yanli Zhu, Haiyue Wang, Jingjing Wang, Youjun Cao, Jianghua Wu, Kaiwen Chi, Xinting Diao, Xiaozheng Huang, Minglei Zhuo, Dongmei Lin.

   Background: Molecular subtyping [Type I (non-small cell lung carcinoma-like, NSCLC-like) and Type II (small cell lung carcinoma-like, SCLC-like)] and YAP1 expression analysis show promise for precision oncology in pulmonary large cell neuroendocrine carcinoma (LCNEC). However, their clinical utility and prognostic value remain unvalidated, and the aim of this study is to evaluate the disparity of clinicopathologic features, survival outcomes and treatment-relevant biomarkers between these two classifications.
Methods: We retrospectively analyzed 42 surgically resected pulmonary LCNECs. Using next-generation sequencing (NGS) and immunohistochemistry on archival specimens, we classified tumors by molecular subtype and YAP1 protein expression. Clinicopathological features, survival outcomes, and therapeutic biomarkers were compared between these classifications.
Results: Molecular subtyping stratified 61.5% (24/39) as Type I and 38.5% (15/39) as Type II LCNECs. YAP1 immunoreactivity was positive in 71.4% (30/42) of specimens, defining YAP1-negative (n=12) and YAP1-positive (n=30) cohorts. No significant association existed between YAP1 status and molecular subtypes (P=0.15). ASCL1 overexpression (P=0.02) and diffuse prominent nucleoli (P=0.04) were enriched in YAP1-negative tumors, whereas NEUROD1-positive tumors favored YAP1 expression (P=0.04). Type II tumors exhibited elevated POU2F3 expression (vs. Type I, P=0.04) and higher tumor mutation burden (TMB) (P=0.002). YAP1 negativity correlated with upregulated ASCL1 (P=0.003) and DLL3 (P=0.003), whereas positivity associated with major histocompatibility complex class II (MHC II) overexpression (P=0.04). Quantitative analysis revealed that YAP1 expression level correlated positively with NEUROD1 (rho=0.349, P=0.02) but inversely with ASCL1/MHC I (rho=-0.326, P=0.04; rho=-0.338, P=0.03). Neither molecular subtype nor YAP1 status significantly impacted survival.
Conclusions: YAP1 expression was independent of molecular subtypes. YAP1-positive tumors may exhibit enhanced responsiveness to immunotherapy/NEUROD1-targeted therapy, while YAP1-negative tumors could benefit from ASCL1/DLL3-targeted approaches. Prospective validation is warranted.

Keywords:  DLL3; Pulmonary large cell neuroendocrine carcinoma (pulmonary LCNEC); biomarkers; immunotherapy; molecular subtype

DOI:  https://doi.org/10.21037/tlcr-2025-491
Transl Lung Cancer Res. 2025 Sep 30. 14(9): 3444-3456

An effective and affordable blood test for lung cancer early detection using four protein markers and artificial intelligence.

Bing Wei, Wenjian Wang, Shuaipeng Geng, Wei Wu, Chenyu Ding, Dandan Zhu, Shuoyao Cheng, Qiurong Zhao, Yi Luan, Shiyong Li, Mao Mao.

   Background: Lung cancer constitutes the leading cause of cancer mortality globally. This study assessed LungCanSeek, a novel blood-based protein test for lung cancer early detection.
Methods: This retrospective study enrolled 1,814 participants (1,095 lung cancer, 719 non-cancer) from three different cohorts. Blood samples were analyzed for four protein tumor markers (PTMs) using Roche cobas. Artificial intelligence (AI) algorithms were developed for lung cancer detection and subtype classification: lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and small cell lung cancer (SCLC). A two-step approach was modeled, using LungCanSeek for initial screening, followed by low-dose computed tomography (LDCT) for LungCanSeek's positive cases.
Results: LungCanSeek achieved 83.5% sensitivity, 90.3% specificity, and 86.2% accuracy overall. Sensitivities of LUAD, LUSC, and SCLC were 83.3%, 81.4%, and 91.9%. Sensitivity increased with clinical stage in non-small cell lung cancer (NSCLC): 59.5% (I), 69.8% (II), 86.5% (III), and 91.3% (IV). Sensitivities of limited-stage and extensive-stage SCLC were 91.3% and 93.0%, respectively. The subtype classification accuracy was 77.4%. Simulation model analysis showed that the two-step approach reduced 10.3-fold false positives and 2.5-fold cost compared to LDCT for lung cancer screening in high-risk population.
Conclusions: LungCanSeek is a non-invasive and cost-effective test for lung cancer early detection. The two-step approach offers a cost-effective strategy for population-wide lung cancer screening.

Keywords:  LungCanSeek; Protein tumor markers (PTMs); lung cancer early detection; subtype classification; two-step approach

DOI:  https://doi.org/10.21037/tlcr-2025-317