bims-necame 2025-07-06 papers

bims-necame

Biomed News

on Metabolism in small cell neuroendocrine cancers

Issue of 2025–07–06
seven papers selected by
Grigor Varuzhanyan, UCLA

PET imaging and radionuclide therapy in neuroendocrine prostate cancer: a systematic review.
Comprehensive analysis of a real-world cohort identifies geranylgeranyl diphosphate synthase 1 as a predictor of chemoresistance in small cell lung cancer.
Decoding MUC1 and AR axis in a radiation-induced neuroendocrine prostate cancer cell-subpopulation unveils novel therapeutic targets.
Clinicopathological, Cellular and Molecular Analyses of Pulmonary Neuroendocrine Carcinoma with High Expression of Hepatocyte Nuclear Factor 4 Alpha.
[Targeting NAD metabolism in neuroendocrine carcinoma].
The association between energy-adjusted dietary inflammatory index (E-DII) and lung cancer in 101,755 participants aged 55 years and above: a large prospective cohort.
Inhibition of autophagy enhances the antitumor efficacy of T/CAR T cell against neuroblastoma.

Q J Nucl Med Mol Imaging. 2025 Jun;69(2): 99-117

PET imaging and radionuclide therapy in neuroendocrine prostate cancer: a systematic review.

Ahmed S Abdlkadir, Dhuha Al-Adhami, Ula Al-Rasheed, Mario Jreige, Waleed Mahafza, Khaled Al-Khawaldeh, Enrique Estrada-Lobato, Akram Al-Ibraheem.

INTRODUCTION: Neuroendocrine prostate cancer (NEPC) is a rare cancer subtype with significant prognostic implications. This systematic review aims to explore the current landscape of positron emission tomography (PET) imaging and radionuclide therapy in this rare entity.
EVIDENCE ACQUISITION: The Scopus and PubMed online databases were systemically reviewed to identify relevant studies on the topic of interest.
EVIDENCE SYNTHESIS: A total of 60 studies reporting such evidence in 102 patients were retrieved. A total of 179 PET/CT examinations were performed across all NEPC patients, with [18F]Fluorodeoxyglucose ([18F]FDG) being the most frequently utilized radiotracer (45% of NEPC patients), followed by [68Ga]Ga-DOTA-peptides (22%), [68Ga]Ga-prostate specific membrane antigen ([68Ga]Ga-PSMA) (18%), and other PET tracers (15%). Single-modality PET/CT imaging was mostly employed to evaluate NEPC extent, detect unusual metastatic sites, assess therapy response, and guide for biopsy sites in cases of hormone-secreting NEPC. Multimodal PET/CT utilizing dual- or triple-tracer approaches was employed for collective NEPC interpretation, assessment of heterogeneity, therapy response assessment, and determination of radionuclide therapy eligibly. For treatment, 16 [177Lu]Lu-DOTATATE cycles, administered to 7 patients, produced effective disease control in all patients. One patient received both [177Lu]Lu-PSMA and [177Lu]Lu-DOTATATE, achieving partial response, while another patient receiving 4 [177Lu]Lu-PSMA cycles also showed a partial response.
CONCLUSIONS: The multimodal molecular imaging approach appears to be the most effective for NEPC evaluation and determination of radionuclide therapy eligibility. [177Lu]Lu-based therapies seem to be a compelling treatment approach to be pursued in eligible cases, although larger studies are needed to confirm the current findings.

DOI: https://doi.org/10.23736/S1824-4785.25.03638-6
Int J Cancer. 2025 Jul 04.

Comprehensive analysis of a real-world cohort identifies geranylgeranyl diphosphate synthase 1 as a predictor of chemoresistance in small cell lung cancer.

Yi Deng, Chenchen Guo, Tengfei Zhang, Yuan Chen, Xin Zhang, Hongbin Ji, Liang Hu.

  A subset of patients with small cell lung cancer (SCLC) exhibit intrinsic resistance to chemotherapy. However, biomarkers that effectively predict this group of patients are still lacking. We previously reported that high geranylgeranyl diphosphate synthase 1 (GGPS1) expression is associated with poor overall survival (OS) in SCLC, and statin combination therapy is effective in overcoming chemoresistance, especially in GGPP-high SCLC. However, the expression patterns of GGPS1 in SCLC subtypes and its relationship with clinical chemotherapy response remain unclear, and whether GGPS1 indicates statin treatment sensitivity in chemoresistant SCLC needs further validation. Through integrative analyses of 146 real-world SCLC cases, we found that approximately 25% exhibited high GGPS1 expression. Subgroup analysis revealed that GGPS1 expression was higher in the ASCL1/NEUROD1/POU2F3 triple-negative subgroup. Moreover, high GGPS1 expression was significantly correlated with reduced objective response rate (ORR) and progression-free survival (PFS) as well as OS. In addition, analysis of seven paired biopsy samples demonstrated that GGPS1 was upregulated in chemoresistant SCLC. We further showed that the combination of etoposide and cisplatin (E/P) with statins had improved efficacy in a patient-derived xenograft (PDX) model derived from a relapsed patient with high GGPS1 expression. Our findings suggest that GGPS1 is a promising biomarker for predicting chemoresistance in SCLC and may be a potential indicator of sensitivity to statin combination therapy in chemoresistant SCLC.

Keywords:  GGPS1; biomarker; chemoresistance; small cell lung cancer; therapeutic response

DOI:  https://doi.org/10.1002/ijc.70036
Cell Death Discov. 2025 Jul 03. 11(1): 306

Decoding MUC1 and AR axis in a radiation-induced neuroendocrine prostate cancer cell-subpopulation unveils novel therapeutic targets.

Catarina Macedo-Silva, Ângela Albuquerque-Castro, Iris Carriço, Joana Lencart, Isa Carneiro, Lucia Altucci, João Lobo, Vera Miranda-Gonçalves, Rui Henrique, Margareta P Correia, Carmen Jerónimo.

Despite the initial efficacy of radiotherapy (RT) in treating prostate adenocarcinoma (PCa), disease progression can lead to the emergence of neuroendocrine prostate cancer (NEPC) - a highly aggressive malignancy for which standard therapies are mostly ineffective. Although oncogenic MUC1-C is a leading driver of NEPC and of PCa lineage plasticity, its putative role in response to RT, including RT-induced neuroendocrine transdifferentiation (tNED), has not been explored. We thus aimed to explore the interplay between androgen receptor (AR) signaling and MUC1 in PCa progression to NEPC. Firstly, using a radioresistant PCa cell line (22Rv1-RR), we demonstrated that epigenetic suppression of AR signaling led to MUC1/MUC1-C upregulation, which seems to be activated through γSTAT3. MUC1 activation is positively associated with increased expression of neuroendocrine-related markers, including CD56, chromogranin A, synaptophysin, and INSM transcriptional repressor 1 (INSM1). In NEPC tissues and compared to prostate adenocarcinoma, MUC1 was upregulated and negatively correlated with AR, which was suppressed. Finally, proteomic analyses revealed that MUC1 activation upon RT selective pressure led to the acquisition of stemness features, induction of epithelial to mesenchymal transition, and enhancement of basal cell-like traits. Notably, MUC1 knockdown significantly boosted response to RT in both 22Rv1-RR and DU145 cell lines. Moreover, AR-induced overexpression in PC3 cell lines entailed MUC1 downregulation, resulting in attenuated neuroendocrine traits and radioresistance, as well as impaired cell migration and invasion capabilities. Collectively, these results highlight MUC1 as a promising radiosensitization target and may ultimately help overcome therapy resistance and NEPC progression.

DOI: https://doi.org/10.1038/s41420-025-02597-4
Lab Invest. 2025 Jul 02. pii: S0023-6837(25)00120-5. [Epub ahead of print] 104210

Clinicopathological, Cellular and Molecular Analyses of Pulmonary Neuroendocrine Carcinoma with High Expression of Hepatocyte Nuclear Factor 4 Alpha.

Kei Asayama, Ryota Matsuoka, Suzuka Tachi, Aya Shiba-Ishii, Yoshihiko Murata, Tomoki Nakagawa, Yosuke Furuhashi, Hitomi Kawai, Ayako Suzuki, Yutaka Suzuki, Naohiro Kobayashi, Yukio Sato, Nobuyuki Hizawa, Yoshinori Murakami, Toshiro Niki, Daisuke Matsubara.

  Pulmonary neuroendocrine carcinoma (NEC), including small cell carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC), is highly aggressive and have a poor prognosis. The molecular subtyping of NECs has recently attracted attention, and we identified a new NEC subtype, the hepatocyte nuclear factor 4α (HNF4α) subtype. HNF4α, a transcription factor associated with gastrointestinal differentiation, and TTF-1 are mutually and exclusively expressed in lung adenocarcinomas; however, the characteristics of HNF4α-high NEC and TTF-1-high NEC have yet to be compared. We immunohistochemically examined the characteristics of HNF4α-high NEC in 83 surgically resected specimens (37 SCLCs and 46 LCNECs) and revealed that HNF4α-high and TTF-1-high NEC accounted for 15% (12/83) and 47% (39/83), respectively. In SCLCs, HNF4α-high cases (n=3) and TTF-1-high cases (n=20) were almost confined to the neuroendocrine phenotype with high ASCL1 expression, and the expressions of HNF4α, TTF-1, and POU2F3 were mutually exclusive. Similar results were obtained for LCNECs; however, some HNF4α-high cases were positive for TTF-1 or YAP1, possibly due to the heterogeneity of LCNEC. Therefore, we investigated the heterogeneity of LCNEC and performed a spatial transcriptome analysis of one HNF4α-high LCNEC case, which revealed a mutually exclusive mixture of different subgroups characterized by HNF4A and NKX2-1 (TTF-1) expression. A whole-genome analysis of 10 LCNECs showed that NFE2L2/KEAP1 mutations were characteristic of HNF4α-positive LCNECs. A prognostic analysis revealed a significantly worse prognosis in HNF4α-high LCNECs than in HNF4α-low LCNECs. A cell line analysis showed that TTF-1-high-expressing (Lu139/H889/H510A) and HNF4α-high-expressing (VMRC-LCD/H810) lines were consistent with ASCL1-high-expressing lines. HNF4α knockdown/knock-in experiments in VMRC-LCD and SBC5 (HNF4α-negative) revealed that HNF4α promoted cell proliferation by inhibiting apoptosis. The HNF4α-subtype of pulmonary NEC is a unique subtype, characterized by a neuroendocrine phenotype with high ASCL1 expression and mutual exclusivity with the TTF-1/POU2F3 subtypes. NFE2L2/KEAP1 mutations and HNF4α itself are potential therapeutic targets for this subtype.

Keywords:  Hepatocyte nuclear factor 4 alpha; large cell neuroendocrine carcinoma; neuroendocrine carcinoma; small cell carcinoma; thyroid transcription factor 1

DOI:  https://doi.org/10.1016/j.labinv.2025.104210
Nihon Yakurigaku Zasshi. 2025 ;160(4): 261-267

[Targeting NAD metabolism in neuroendocrine carcinoma].

Nobuhiro Tanuma.

NAD is an important metabolite that functions as a cofactor in various metabolic reactions, and its biosynthesis is known to be upregulated during malignant transformation. The NAD salvage, in which NAMPT is a rate-limiting enzyme, is a predominant pathway for NAD synthesis in most tissues including cancer. However, less is known about how cancer sensitivity against NAMPT inhibition (NAMPTi) is dictated. Here we report that lung and prostate neuroendocrine carcinomas (NECs) are extremely vulnerable to NAMPTi and that the therapeutic effect of NAMPTi is markedly enhanced by dietary restriction of the NAD precursor, niacin. We found that de novo NAD synthesis is inactivated during neuroendocrine differentiation of tumor cells, leading to a high dependence of NEC cells on NAD salvage. Further investigations in mouse transplantation models showed that lowering blood levels of nicotinic acid riboside (NAR), one of the non-classical niacin, dramatically increases the therapeutic effect of NAMPTi on NEC. Metabolic studies showed that dietary nicotinic acid is converted to NAR and then released into the circulation, and NAD synthesis using NAR substrates can compensate for the effects of NAMPTi in tumor cells. These findings reveal that niacin restriction with NAMPTi is synthetic lethal to NECs.

DOI: https://doi.org/10.1254/fpj.24068
BMC Public Health. 2025 Jul 03. 25(1): 2373

The association between energy-adjusted dietary inflammatory index (E-DII) and lung cancer in 101,755 participants aged 55 years and above: a large prospective cohort.

Yangpiaoyi Shi, Wanhao Tan, Yi Xiao, Linglong Peng, Zhiquan Xu, Hang Liu, Qi Wei, Yaxu Wang, Ling Xiang, Haitao Gu.

   BACKGROUND: The association between the Dietary Inflammatory Index (DII) and lung cancer incidence remains unclear. This inconsistency may be attributed to not considering total energy intake and dietary supplement use adequately. To provide reliable evidence, we conducted a secondary analysis of data from the prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to examine the association between lung cancer incidence and E-DII (Energy-adjusted DII) derived from both food and supplements as well as from food only.
METHODS: The data of participants were retrieved from the PLCO Cancer Screening Trial. Cox regression analysis was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the incidence of lung cancer and its subtypes, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Additionally, Restricted Cubic Spline (RCS) were used to describe the linear dose-response relationship between lung cancer and its subtypes across the entire EDII score range, subgroup analyses were conducted to identify potential modifiers, and sensitivity analyses were performed to strengthen the stability of our results.
RESULTS: Over a median follow-up duration of 9.40 years, totally 1,706 incident cases of lung cancer were identified. Our analyses demonstrated that both higher E-DII from food and supplements (HR Q4 vs. Q1: 1.31, 95%CI: 1.14, 1.52, Ptrend = 0.002) and E-DII from food only (HR Q4 vs. Q1: 1.39, 95%CI: 1.22, 1.58, Ptrend <0.001) were associated with an elevated lung cancer incidence. RCS revealed a linear dose-response relationship between both overall lung cancer incidence (Pnonlinearity = 0.509) and NSCLC incidence (Pnonlinearity = 0.489) and E-DII from food and supplements. However, a significant inverse U-shaped association between E-DII from food and supplements SCLC was exhibited (Pnonlinearity = 0.016). The results of the subgroup analyses showed that smoking quantity reveals significant interactions between lung cancer and E-DII from food only (Pinteraction = 0.039). Finally, sensitivity analyses reinforced the robustness of our findings.
CONCLUSION: Our findings revealed a positive association between E-DII and lung cancer incidence among U.S. adults aged 55 years and older, particular in populations with higher smoking exposure, which suggesting dietary inflammatory potential may represent an important modifiable risk factor for lung cancer prevention. Furthermore, our analyses demonstrated that SCLC and NSCLC exhibit distinct inflammatory response patterns, indicating potential differences in their biological mechanisms.

Keywords:  Chronic inflammation; Dietary inflammatory index; Dietary pattern; Epidemiology; Lung cancer

DOI:  https://doi.org/10.1186/s12889-025-22801-5
J Exp Clin Cancer Res. 2025 Jul 03. 44(1): 185

Inhibition of autophagy enhances the antitumor efficacy of T/CAR T cell against neuroblastoma.

Francesca De Mitri, Manuela Giansanti, Ombretta Melaiu, Dorothee Haas, Stefan Ebert, Nicola Tumino, Elisabetta Vulpis, Francesca Gatto, Beatrice Martuscelli, Manuela Antonioli, Elisabetta Sangiuliano, Simona Caruso, Scarsella Marco, Cristiano De Stefanis, Veronica Marabitti, Silvia Campello, Doriana Fruci, Paola Vacca, Ignazio Caruana, Francesca Nazio.

  Neuroblastoma (NB) is the most common extracranial solid tumor in children characterized by poor immune infiltration and resistance to adaptive immunity, contributing to its limited response to immunotherapy. A key mechanism underlying immune evasion in cancer is autophagy, a cellular process that plays many roles in cancer by supporting tumor survival and regulating immune interactions. In this study, we investigate the impact of autophagy inhibition on NB tumor growth, immune modulation, and the efficacy of immunotherapy. Using both murine and human NB cell lines, we demonstrate that genetic and pharmacological inhibition of autophagy significantly reduces 3D spheroid growth and upregulates major histocompatibility complex class I (MHC-I) expression. In vivo studies further confirm that targeting autophagy suppresses tumor progression and promotes immune infiltration into the tumor. Notably, we observe a significant increase in CD8+ T cell recruitment and activation, suggesting that autophagy inhibition reshapes the immune landscape of NB, rendering it more susceptible to immune-mediated clearance. Crucially, autophagy inhibition also sensitizes NB cells to T cell-mediated cytotoxicity and enhances the therapeutic efficacy of GD2.CAR T-cell therapy. In vitro co-culture assays reveal increased CAR T cell-mediated tumor killing upon autophagy blockade, while in vivo models show prolonged tumor control and improved survival in treated mice compared to CAR T-cell therapy alone. These findings highlight autophagy as a key regulator of immune evasion in NB and suggest that its inhibition could serve as a promising therapeutic strategy to enhance immune recognition and improve the efficacy of immunotherapy.

Keywords:  Chloroquine; GD2.CAR T; Immune cells; Neuroblastoma; ULK1 inhibitor

DOI:  https://doi.org/10.1186/s13046-025-03453-0