bims-necame 2025-10-19 papers

bims-necame

Biomed News

on Metabolism in small cell neuroendocrine cancers

Issue of 2025–10–19
ten papers selected by
Grigor Varuzhanyan, UCLA

Tumor Heterogeneity and Plasticity in Small Cell Lung Cancer.
Multiparametric MRI characteristics for differentiating primary cancer origin in brain metastases.
Metabolic Dependency on De Novo Pyrimidine Synthesis is a Targetable Vulnerability in Platinum Resistant Ovarian Cancer.
[Is stereotactic radiotherapy a viable alternative to whole-brain irradiation for one to 10 brain metastases even in small cell lung cancer?]
Ceritinib inhibits growth and ACTH production of PitNETs: Insights from patient-derived organoids.
HER2 aberration is a potential predictive biomarker for extrapulmonary small cell neuroendocrine carcinoma contrary to small cell lung cancer.
PRMT1/PRMT5-Mediated Differential Arginine Methylation of CRIP1 Promotes the Recurrence of Small Cell Lung Cancer after Chemotherapy.
Dynamic Reprogramming of Immune-Related Signaling During Progression to Enzalutamide Resistance in Prostate Cancer.
Options and Considerations in the Management of Peritoneal Disease in Patients with Small Bowel Neuroendocrine Tumors.
Co-occurrence of Ectopic Adrenocorticotropic Hormone (ACTH) Secretion and Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) in Small Cell Lung Cancer: A Case Report.

Lung Cancer (Auckl). 2025 ;16 125-138

Tumor Heterogeneity and Plasticity in Small Cell Lung Cancer.

Gina N Duronio, Julien Sage.

  The heterogeneous nature of cell populations in human tumors is a major contributor to tumor evolution, including and perhaps most importantly in response to treatment. Here, we review current knowledge on tumor heterogeneity and cell state plasticity in small cell lung cancer (SCLC), a fast growing and highly metastatic form of lung cancer which develops rapid resistance to therapy. There is a pressing need to expand treatment options for patients with SCLC, which requires a better understanding of the mechanisms by which this disease is able to rapidly grow and evolve in response to therapy. Our current understanding points to epigenetic rather than genetic factors in defining major aspects of inter- and intra-tumoral heterogeneity in SCLC. SCLC is overall considered to be a neuroendocrine (NE) cancer type but SCLC tumors harbor a wide diversity of cancer cell states, including both NE and non-neuroendocrine (non-NE) states, defined by their mutually exclusive expression of a set of transcription factors such as ASCL1, NEUROD1, and POU2F3. The immune microenvironments of SCLC tumors also contain a great deal of heterogeneity. Here, we discuss the different SCLC cell states associated with their defining transcription factors, as well as the epigenetic mechanisms regulating the ability of SCLC cells to switch from one state to another. We further discuss how the composition of SCLC tumors and the surrounding immune cells may affect the response to chemotherapy and immunotherapy. Being able to control plasticity and heterogeneity in SCLC may in the future offer unique opportunities to improve treatment efficacy in this recalcitrant cancer.

Keywords:  SCLC; neuroendocrine; plasticity; tumor heterogeneity

DOI:  https://doi.org/10.2147/LCTT.S511789
BMC Med Imaging. 2025 Oct 15. 25(1): 415

Multiparametric MRI characteristics for differentiating primary cancer origin in brain metastases.

Ali Salbas, Mehmet Coskun, Yusuf Kenan Cetinoglu, Merve Horoz, Murat Yogurtcu, Anil Huvez, Mustafa Fazil Gelal.

   BACKGROUND: Accurate identification of primary cancer origin in brain metastases (BMs) is crucial for diagnosis and treatment planning. Identification is challenging, particularly in unknown primary cases. Multiparametric Magnetic Resonance Imaging (MRI) offers non-invasive imaging characteristics as diagnostic clues. This study aimed to investigate the relationship between multiparametric MRI features of BMs and their primary tumor origin.
METHODS: This retrospective study included 125 patients with intra-axial brain metastases, classified as breast cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), malignant melanoma, and other cancers. Multiparametric MRI, including T2-FLAIR, contrast-enhanced 3D T1-weighted imaging, apparent diffusion coefficient (ADC) maps, susceptibility-weighted imaging (SWI), and cerebral blood volume (CBV) maps, was performed. Lesion volume, necrotic volume, necrosis ratio, peritumoral edema volume, and edema ratio were measured. 3D Slicer® software was used for semi-automated volumetric measurements. Quantitative ADC and rCBV values, intratumoral susceptibility signal (ITSS) scores, and metastasis number and location were analyzed to differentiate primary tumor origins.
RESULTS: 291 metastatic lesions from 125 patients were analyzed. NSCLC metastases showed significantly higher necrosis ratios than breast (p < 0.001) and SCLC (p = 0.025) metastases. Malignant melanoma metastases exhibited significantly higher edema ratios than breast (p = 0.001) and SCLC (p = 0.004) metastases. NSCLC metastases also showed a significantly higher edema ratio than breast (p = 0.011) metastases. Mean ADC values were significantly higher in NSCLC metastases compared to all other groups, with an optimal cut-off of ≥ 0.905 mm²/s (AUC: 0.775). Malignant melanoma and SCLC metastases had significantly higher rCBV values than breast cancer metastases. Malignant melanoma metastases consistently showed the highest ITSS scores among all groups, with an optimal cut-off of ≥ 1 (AUC: 0.769). Furthermore, multiple metastases ≤ 0.5 cm³ were significantly associated with breast cancer (p = 0.041). Infratentorial metastases were more prevalent in breast cancer (OR = 2.490, p = 0.001).
CONCLUSION: Brain metastases exhibit distinct multiparametric MRI characteristics by primary cancer origin. Breast cancer metastases tend to be smaller, multiple, and infratentorial. NSCLC metastases show greater necrosis and higher ADC values, while melanoma metastases demonstrate higher intratumoral susceptibility. These features offer valuable diagnostic clues for differentiating primary cancer types in patients with brain metastases.
CLINICAL TRIAL NUMBER: Not applicable.

Keywords:  ADC; Brain metastases; Breast cancer; ITSS; Lung cancer; Malignant melanoma; Necrosis; Perilesional edema; Primary tumor origin; rCBV

DOI:  https://doi.org/10.1186/s12880-025-01925-5
Cancer Res. 2025 Oct 15.

Metabolic Dependency on De Novo Pyrimidine Synthesis is a Targetable Vulnerability in Platinum Resistant Ovarian Cancer.

Horacio Cardenas, Yinu Wang, Guangyuan Zhao, Delan Xingyue Hao, Ana Maria Isac, Vanessa Hernandez, Ujin Kim, Wenan Qiang, Hao F Zhang, Daniela Matei.

Ovarian cancer (OC) is lethal due to near universal development of resistance to platinum-based chemotherapy. Metabolic adaptations can play a pivotal role in therapy resistance. Here, we aimed to identify key metabolic pathways that regulate platinum response and represent potential therapeutic targets. Transcriptomic and metabolomic analyses in cisplatin sensitive and resistant ovarian cancer cells identified enrichment of pyrimidine metabolism related to upregulated de novo pyrimidine synthesis. 15N-glutamine flux analysis confirmed increased de novo pyrimidine synthesis in cisplatin resistant cells. Targeting this pathway using brequinar (BRQ), an inhibitor of the key enzyme dihydroorotate dehydrogenase (DHODH), decreased cell viability, delayed G2/M cell cycle progression, and altered expression of genes related to mitochondrial electron transport in resistant cells. Under basal conditions, cisplatin resistant cells had a lower oxygen consumption rate (OCR) and spare respiratory capacity (SRC) than sensitive cells. BRQ suppressed OCR in both sensitive and resistant but only inhibited SRC in resistant cells. In cell line-derived and patient-derived xenograft models, BRQ attenuated the growth of cisplatin resistant ovarian tumors and enhanced the inhibitory effects of carboplatin. Together, these results identify metabolic reprogramming in cisplatin resistant ovarian cancer that induces an acquired dependency on de novo pyrimidine synthesis, which can be targeted to sensitize tumors to chemotherapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0043
Strahlenther Onkol. 2025 Oct 13.

[Is stereotactic radiotherapy a viable alternative to whole-brain irradiation for one to 10 brain metastases even in small cell lung cancer?]

Yvonne Dzierma, Guido Hildebrandt.

DOI: https://doi.org/10.1007/s00066-025-02467-z
Pharmacol Res. 2025 Oct 11. pii: S1043-6618(25)00418-9. [Epub ahead of print]221 107993

Ceritinib inhibits growth and ACTH production of PitNETs: Insights from patient-derived organoids.

Haoying Yu, Tingcheng Zhang, Jiaqian Chen, Xueying Li, Huarong Zhang, Rongrong Guo, Chengdong Wu, Li Zhang, Jun Fan, Chaohu Wang, Songtao Qi, Yi Liu.

  ACTH-secreting pituitary neuroendocrine tumors (PitNETs), also known as Cushing's disease (CD), are a rare condition lacking effective pharmacological treatments. Drug development for CD has been limited by the absence of suitable preclinical research models. Here, we established a patient-derived organoid (PDO) model and used it for screening tyrosine kinase inhibitors for CD. Ceritinib emerged as a promising therapeutic candidate due to its potent and consistent efficacy across PDOs from different patients in vitro, as well as in vivo in a xenograft mouse model. Multi-omics analyses and molecular validation revealed that Ceritinib exerts its effects by inhibiting phosphorylation within the PI3K-Akt signaling pathway. Specifically, Akt1 was identified as a key mediator, as its knockdown attenuated the suppressive potency of Ceritinib on both tumor growth and ACTH synthesis. Furthermore, Akt1-mediated regulation of ACTH was found to occur via Nur77, the transcriptional activator of POMC. In conclusion, Ceritinib effectively suppresses tumor growth and ACTH production in PDOs of both functioning and silent CD, positioning it as a promising therapeutic agent for CD.

Keywords:  Akt1; Ceritinib; Cushing’s disease; Nur77; PI3K-Akt pathway; Patient-derived organoid; PitNETs; Therapeutic target

DOI:  https://doi.org/10.1016/j.phrs.2025.107993
Virchows Arch. 2025 Oct 14.

HER2 aberration is a potential predictive biomarker for extrapulmonary small cell neuroendocrine carcinoma contrary to small cell lung cancer.

Nikola Hájková, Klára Pavlíčková, Jiří Dvořák, Jan Hojný, Eva Krkavcová, Petr Waldauf, Pavel Dundr, Marie Drösslerová, Marián Švajdler, Pavel Fabian, Miroslava Flídrová, Jan Hrudka, Radoslav Matěj.

  In this study, we investigated human epidermal growth factor receptor 2 (HER2) aberrations, including gene amplification and mutation, and protein expression in 123 small cell lung carcinomas (SCLC) and 128 extrapulmonary small cell neuroendocrine carcinomas (EP-SCNC) samples. Among the EP-SCNC cohort, HER2 mutations were found in 5.5% of samples (7/128); urinary bladder (4 cases), and one case each in samples from the colon, anal canal, and uterine cervix. In SCLCs, HER2 mutations were rare, detected in only 0.8% (1/119) of cases. We also identified eight EP-SCNCs and five SCLC cases with HER2 gene variants of uncertain significance (VUS). HER2 gene amplification was detected in 2.3% (3/128) of EP-SCNCs, but no amplification was found in SCLCs. The differences in HER2 mRNA expression were not statistically significant among tumor groups in the EP-SCNCs and SCLCs cohorts. RNA-seq analysis revealed high HER2 mRNA expression in seven EP-SCNCs and four SCLCs. An immunohistochemistry (IHC) analysis of 10 available tumors with high mRNA expression revealed HER2 protein positivity in 8 cases. The prognostic value of HER2 overexpression in EP-SCNC patients was not established in our study. Furthermore, EP-SCNC patients with high HER2 mRNA expression were generally younger, with a mean age of 60 years. These findings highlight the potential of HER2 as a therapeutic target in EP-SCNC, warranting further investigation into its clinical implications.

Keywords:   HER2 mRNA; HER2 mutation; Anti-HER2; Extrapulmonary small cell neuroendocrine carcinomas; HER2 protein; Small cell lung carcinomas

DOI:  https://doi.org/10.1007/s00428-025-04285-1
Int J Biol Sci. 2025 ;21(13): 5956-5974

PRMT1/PRMT5-Mediated Differential Arginine Methylation of CRIP1 Promotes the Recurrence of Small Cell Lung Cancer after Chemotherapy.

Yu Han, Lie Ma, Xiaolei Zhang, Qingyuan Ren, Qingxia Yuan, Jiawen Zhou, Yanjing Ren, Na Wan, Xin Jin, Jingyao Hou, Yanbo Wang, Baiqu Huang, Yu Zhang, Jun Lu.

  Arginine methylation, a critical epigenetic modification, plays a vital role in tumor initiation and progression; however, the mechanism by which arginine methylation regulates tumor recurrence remains unclear. Here, we found the differential changes between arginine methyltransferase PRMT1 and PRMT5 in small cell lung cancer (SCLC) cells after cisplatin and etoposide treatment. PRMT5 increased at the early stage and then decreased at the later stage, while PRMT1 first decreased and then increased, which was regulated by an inflammation activated E3 ubiquitin ligase PELI1. Both PRMT5 and PRMT1 could modify the same substrate CRIP1. At the early stage, PRMT5-mediated CRIP1 R26/68 methylation activated the Wnt/β-catenin pathway to facilitate the acquisition of a stemness phenotype in senescent cells. At the later stage, PRMT1-mediated CRIP1 R16 methylation accelerated the proliferation of stem-like cells by suppressing the p38 pathway, thereby driving rapid recurrence of SCLC post-chemotherapy. Notably, combination therapy using PRMT5 inhibitor GSK3326595 along with cisplatin and etoposide significantly delayed the recurrence of SCLC. Our findings reveal the promoting effect of post-chemotherapy inflammation on tumor recurrence from an epigenetic perspective and provide a potential therapeutic strategy for SCLC treatment.

Keywords:  CRIP1; arginine methylation modification; chemotherapy; inflammation; recurrence; small cell lung cancer

DOI:  https://doi.org/10.7150/ijbs.115225
Cancers (Basel). 2025 Sep 30. pii: 3187. [Epub ahead of print]17(19):

Dynamic Reprogramming of Immune-Related Signaling During Progression to Enzalutamide Resistance in Prostate Cancer.

Pengfei Xu, Huan Qu, Joy C Yang, Fan Wei, Junwei Zhao, Menghuan Tang, Leyi Wang, Christopher Nip, Henson Li, Allen C Gao, Kit Lam, Marc Dall'Era, Yuanpei Li, Chengfei Liu.

   BACKGROUND: Treatment with androgen receptor (AR) signaling inhibitors, such as enzalutamide, can induce neural lineage plasticity in prostate cancer, potentially progressing to t-NEPC. However, the molecular mechanisms underlying this enzalutamide-driven plasticity, particularly the contribution of immune signaling pathways, remain poorly understood.
METHODS: We analyzed transcriptomic profiles of patient samples and prostate cancer cell lines to investigate changes in immune signaling pathways. Interferon gamma (IFNγ), interferon alpha (IFNα), and interleukin 6 (IL6)-Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signaling were assessed in enzalutamide-sensitive and -resistant prostate cancer cells. Functional assays were conducted to examine cell responsiveness to cytokine stimulation and susceptibility to STAT1 inhibition using fludarabine.
RESULTS: Immune-related pathways, including IFNγ, IFNα, IL6-JAK-STAT3, and inflammatory responses, were significantly suppressed in NEPC patient samples compared to those with castration-resistant prostate cancer (CRPC). Enzalutamide-resistant and NEPC cells exhibited markedly impaired IFNγ and IL6 signaling. In contrast, early-stage enzalutamide treatment paradoxically enhanced IFNγ and IL6 responsiveness. Transcriptomic profiling revealed coordinated upregulation of E2F target genes and activation of IFNα/IFNγ and JAK/STAT signaling pathways during early treatment. Importantly, these early-stage cells remained highly sensitive to IFNγ and IL6 stimulation and showed increased susceptibility to STAT1 inhibition by fludarabine, a sensitivity that was lost in resistant cells.
CONCLUSIONS: Early enzalutamide treatment enhances immune responsiveness, while the development of resistance is associated with suppressed immune signaling and increased lineage plasticity. These results suggest a therapeutic window where combining enzalutamide with STAT inhibitors may delay or prevent lineage plasticity and resistance.

Keywords:  JAK/STAT; enzalutamide resistance; immune-related signaling; lineage plasticity; prostate cancer

DOI:  https://doi.org/10.3390/cancers17193187
Curr Treat Options Oncol. 2025 Oct 13.

Options and Considerations in the Management of Peritoneal Disease in Patients with Small Bowel Neuroendocrine Tumors.

Jeremy Chang, Udhayvir S Grewal, Scott K Sherman, James R Howe.

   OPINION STATEMENT: Peritoneal metastases (PM) in small bowel neuroendocrine tumors (SBNET) are challenging. These patients have worse oncologic outcomes and may have symptoms related to mechanical obstruction and hormone production. Difficult decisions apply in diagnosis, surgical selection, postoperative systemic therapy, and surveillance. To aid in these decisions, we routinely recommend obtaining somatostatin receptor based functional imaging (i.e. DOTA PET/CT) and arterial and venous phase CT preoperatively to evaluate disease burden and guide surgical planning. Disease biology should also guide surgical management. The presence of synchronous liver metastases should not exclude patients from surgery. For patients with PM and grade 1 or 2 well differentiated SBNETs, we recommend aggressive surgical cytoreduction with the goal of a completeness of cytoreduction (CC) of 0 or 1 and > 70% cytoreduction of liver metastases. For high grade (G3) well differentiated SBNETs, surgical intervention may still be considered. In patients where the extent of disease does not allow for effective cytoreduction, or where patient comorbidities preclude extensive surgery, palliative surgeries or interventions may be preferred. Postoperatively, radiologic surveillance is important to evaluate for disease progression. Some SBNET patients presenting without PM are at risk of developing PM in follow-up, especially those with liver metastases or high T stage. In patients with progression or inoperable disease, systemic therapy including somatostatin analogs (SSAs), chemotherapy or peptide receptor radionuclide therapy (PRRT) may be potential options, although the latter may pose increased risk of bowel obstruction. When cytoreducton and systemic therapy are no longer options, palliative measures should be employed. Because of this complexity, management of PM in SBNET patients is a multidisciplinary collaborative effort.

Keywords:  Cytoreductive surgery; Peptide receptor radionuclide therapy; Peritoneal metastases; Small bowel neuroendocrine tumor; Somatostatin analogs

DOI:  https://doi.org/10.1007/s11864-025-01364-y
Cureus. 2025 Sep;17(9): e92128

Co-occurrence of Ectopic Adrenocorticotropic Hormone (ACTH) Secretion and Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) in Small Cell Lung Cancer: A Case Report.

Zhan Rong, Anisha Mahat, Jordan Barnett Kradjian, Viraj Modi, Imran Baig.

  Small cell lung cancer (SCLC) is a neuroendocrine malignancy often associated with paraneoplastic syndromes, such as syndrome of inappropriate antidiuretic hormone secretion (SIADH) and ectopic Cushing's syndrome (ECS). While each is individually recognized, their concurrent presentation is exceptionally rare and poses diagnostic and management challenges. A 49-year-old male with a complex medical history presented with back pain, profound hyponatremia (sodium 119 mmol/L), and hypokalemia (potassium 2.5 mmol/L). Imaging revealed a large right hilar mass with mediastinal lymphadenopathy and hepatic lesions. Biopsy confirmed high-grade neuroendocrine carcinoma consistent with SCLC. Persistent electrolyte abnormalities and treatment-resistant hypertension prompted an endocrinologic workup, revealing elevated cortisol (> 64 μg/dL) and adrenocorticotropic hormone (ACTH) (377 pg/mL), consistent with ectopic ACTH production. Concurrent SIADH was diagnosed based on low serum osmolality, high urine osmolality, and urine sodium > 30 mmol/L. The patient was treated with carboplatin and etoposide as per oncology recommendations. Management of SIADH and ECS was challenging due to the complex interplay of fluid retention, cortisol excess, and risks associated with vasopressin antagonists and cortisol-lowering agents. Chemotherapy was prioritized to address the underlying tumor and paraneoplastic processes. This rare case of concurrent SIADH and ECS in SCLC underscores the importance of early recognition and multidisciplinary management. Awareness of overlapping paraneoplastic syndromes is critical for timely diagnosis and effective treatment, which can prevent life-threatening complications and improve outcomes.

Keywords:  ectopic cushing syndrome; hypokalemia; hyponatremia; paraneoplastic syndrome; small cell lung cancer; small cell lung cancer induced-siadh

DOI:  https://doi.org/10.7759/cureus.92128