bims-necame 2025-08-03 papers

Issue of 2025–08–03
six papers selected by
Grigor Varuzhanyan, UCLA

Cancers (Basel). 2025 Jul 18. pii: 2385. [Epub ahead of print]17(14):

Impact of Metastatic Microenvironment on Physiology and Metabolism of Small Cell Neuroendocrine Prostate Cancer Patient-Derived Xenografts.

Shubhangi Agarwal, Deepti Upadhyay, Jinny Sun, Emilie Decavel-Bueff, Robert A Bok, Romelyn Delos Santos, Said Al Muzhahimi, Rosalie Nolley, Jason Crane, John Kurhanewicz, Donna M Peehl, Renuka Sriram.

Background: Potent androgen receptor pathway inhibitors induce small cell neuroendocrine prostate cancer (SCNC), a highly aggressive subtype of metastatic androgen deprivation-resistant prostate cancer (ARPC) with limited treatment options and poor survival rates. Patients with metastases in the liver have a poor prognosis relative to those with bone metastases alone. The mechanisms that underlie the different behavior of ARPC in bone vs. liver may involve factors intrinsic to the tumor cell, tumor microenvironment, and/or systemic factors, and identifying these factors is critical to improved diagnosis and treatment of SCNC. Metabolic reprogramming is a fundamental strategy of tumor cells to colonize and proliferate in microenvironments distinct from the primary site. Understanding the metabolic plasticity of cancer cells may reveal novel approaches to imaging and treating metastases more effectively. Methods: Using magnetic resonance (MR) imaging and spectroscopy, we interrogated the physiological and metabolic characteristics of SCNC patient-derived xenografts (PDXs) propagated in the bone and liver, and used correlative biochemical, immunohistochemical, and transcriptomic measures to understand the biological underpinnings of the observed imaging metrics. Results: We found that the influence of the microenvironment on physiologic measures using MRI was variable among PDXs. However, the MR measure of glycolytic capacity in the liver using hyperpolarized 13C pyruvic acid recapitulated the enzyme activity (lactate dehydrogenase), cofactor (nicotinamide adenine dinucleotide), and stable isotope measures of fractional enrichment of lactate. While in the bone, the congruence of the glycolytic components was lost and potentially weighted by the interaction of cancer cells with osteoclasts/osteoblasts. Conclusion: While there was little impact of microenvironmental factors on metabolism, the physiological measures (cellularity and perfusion) are highly variable and necessitate the use of combined hyperpolarized 13C MRI and multiparametric (anatomic, diffusion-, and perfusion- weighted) 1H MRI to better characterize pre-treatment tumor characteristics, which will be crucial to evaluate treatment response.

Keywords: glycolysis; hyperpolarized carbon-13 magnetic resonance imaging; metabolism; metastases; microenvironment; perfusion; physiology; small cell neuroendocrine cancer

DOI: https://doi.org/10.3390/cancers17142385

Cancer Res. 2025 Jul 25.

Dasatinib Remodels the Tumor Microenvironment and Sensitizes Small Cell Lung Cancer to Immunotherapy.

Effective strategies to reinvigorate the immune system are needed to improve outcomes in small cell lung cancer (SCLC). Targeting Src family kinases with dasatinib (Dasa) can elicit immunomodulatory effects in some cancer types. Here, we explored the potential of combining Dasa with immune checkpoint blockade in SCLC. While the SCLC models were refractory to anti-PD-1 or anti-CTLA4 monotherapy, anti-PD-1 and anti-CTLA4 combination immunotherapy (ITc) induced a significant antitumor response. Further, the Dasa+ITc combination was superior to ITc or Dasa alone. Dasa+ITc activity was mediated by CD4+ T cells, MHC-II+ antigen presenting cells (APCs), and natural killer (NK) cells, as depletion of these populations impeded the combination treatment antitumor efficacy. Increased tumor infiltration of CD4+ and CD8+ T cells, NK cells, M1-like macrophages, and CD11c+ APCs and a reduction of regulatory T cells (Tregs) and M2-like macrophages were found in Dasa+ITc-treated mice. Dasa increased CCL5 in NK cells and reduced Treg cell conversion from CD4+ lymphocytes. Dasa+ITc therapy elicited robust antitumor efficacy in 3D co-cultures of immune and SCLC cells. In vivo experiments showed that CCL5 was necessary for the Dasa+ITc response. In SCLC immunotherapy-treated patients, a gene signature including CD4, CIITA, and tumor mutational burden predicted good prognosis. On-treatment CCL5 plasma levels were increased only in patients with long progression-free survival, and pre-treatment secretomics identified cytokines related to myeloid cells significantly associated with poor prognosis. In summary, combining Dasa with immunotherapy represents a strategy to treat SCLC, with CCL5 as a cytokine that could serve to monitor response.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-2772

Biomedicines. 2025 Jul 04. pii: 1642. [Epub ahead of print]13(7):

Unlocking the Role of OCT4 in Cancer Lineage Plasticity: A Cross-Cancer Perspective with an Emphasis on Prostate Cancer.

Mohammad Esfini Farahani, Yanquan Zhang, Amos Olalekan Akinyemi, Fatemeh Seilani, Md Rakibul Alam, Xiaoqi Liu.

Prostate cancer (PCa) is a highly heterogeneous disease, with castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC) representing its most aggressive and therapy-resistant forms. Emerging evidence indicates that lineage plasticity-driven by key transcription factors such as Octamer Binding Factor 4 (OCT4)-plays a crucial role in therapeutic resistance and disease progression. OCT4, in coordination with SOX2 and NANOG, acts as a master regulator of stemness and is frequently upregulated in prostate cancer stem cells (PCSCs). This upregulation contributes to tumor initiation, metastasis, and resistance to both androgen deprivation therapy (ADT) and chemotherapy. In this review, we explore the role of OCT4 in mediating lineage plasticity in prostate cancer, with particular emphasis on its involvement in treatment resistance and neuroendocrine differentiation. We also examine therapeutic strategies aimed at targeting OCT4 directly, such as microRNA-mediated suppression, small-molecule inhibitors, and suicide gene therapy, as well as indirect approaches that modulate OCT4 expression via FGFR and NF-κB signaling pathways. While these strategies offer promising avenues, challenges such as adaptive resistance and the intricate signaling networks within PCSCs remain significant hurdles. A deeper understanding of the molecular mechanisms underlying OCT4-driven plasticity may pave the way for novel therapeutic approaches and improved outcomes in advanced prostate cancer.

Keywords: androgen deprivation therapy; castration-resistant prostate cancer; neuroendocrine prostate cancer; octamer-binding transcription factor 4; prostate cancer stem cells

DOI: https://doi.org/10.3390/biomedicines13071642

Discov Oncol. 2025 Jul 30. 16(1): 1445

Alterations in GSH/GSSG and CyS/CySS redox status in small cell lung cancer patients undergoing chemotherapy.

Azra Guzonjić, Milkica Crevar, Ivana Simić, Natalija Samardzić, Vesna Ćeriman Krstić, Jelena Kotur Stevuljević, Dragana Jovanović.

BACKGROUND: In small cell lung cancer (SCLC), oxidative stress disrupts redox balance and contributes to tumor progression and treatment resistance through DNA damage, inflammation, and tumorigenesis. Thiol compounds such as glutathione (GSH) and cysteine (CyS) together with their oxidized forms (GSSG and CySS) serve as markers of oxidative stress. The aim of this study was to investigate changes in GSH/GSSG and CyS/CySS ratios during chemotherapy and evaluate their potential as prognostic indicators in SCLC.
MATERIALS AND METHODS: In this longitudinal study, redox biomarkers (GSH/GSSG and CyS/CySS ratios) were investigated in 60 stage III/IV SCLC patients receiving cisplatin-etoposide chemotherapy. Plasma samples were collected before chemotherapy, after two cycles and after four cycles and analyzed by LC-MS/MS.
RESULTS: Significant redox changes were observed during chemotherapy. The GSH/GSSG ratio decreased after two cycles (p = 0.029) and increased after four cycles (p = 0.002). The same trend was observed for CyS/CySS dynamics (p = 0.031 and p = 0.030, respectively). The Survivors showed a recovery of the redox balance, while the deceased patients showed persistently lower ratios. Kaplan-Meier analysis showed that a higher GSH/GSSG ratio before treatment (p = 0.037) predicted better survival. A positive correlation was found between GSH/GSSG and CyS/CySS ratios (ρ = 0.306, p = 0.019).
CONCLUSIONS: This study demonstrates that redox imbalance reflected in GSH/GSSG and CyS/CySS ratios is an important factor for SCLC treatment response and survival. Higher GSH/GSSG ratios before treatment are associated with improved survival, indicating the potential of redox markers as prognostic tools in SCLC.

Keywords: Lung cancer; Oxidative stress; Prognostic biomarkers; Redox imbalance

DOI: https://doi.org/10.1007/s12672-025-03251-2

Front Oncol. 2025 ;15 1545101

Efficacy and safety of Cadonilimab plus anlotinib in small cell lung cancer with brain metastases.

Hai-Zhen Yi, Wei Lv, Jin-Jing Chen, Zhan Lin.

Purpose: This study aimed to evaluate the efficiency and safety of Cadonilimab and Anlotinib pairing in individuals diagnosed with small cell lung cancer (SCLC) and brain metastases (BMs).
Methods: A review was performed on individuals who were diagnosed with small cell lung cancer (SCLC) and had central nervous system (CNS) metastases confirmed via magnetic resonance imaging (MRI) of the brain.We assessed the treatment response of Cadonilimab plus Anlotinib using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and Response assessment in neuro-oncology brain metastases (RANO-BM) for evaluating solid tumors and neuro-oncology brain metastases, respectively.The patients' prognosis was determined using Kaplan-Meier analysis and Cox regression analysis.
Findings: The study initially included 46 patients diagnosed with SCLC who presented with brain metastases (BMs). According to the RANO-BM criteria, intracranial lesions showed an objective response rate (ORR) of 41.3%. The median overall survival (OS) was observed to be 19.3 months (95% CI, 17.4-21.1 months). Multivariate Cox regression analysis showed that having a PD1 level below 50% (HR=4.83, P <0.001) or having two or more metastatic organs (HR = 2.71, P = 0.036) were independent factors that positively predicted overall survival of all the patients, 86.9% experienced treatment-related adverse events (TRAEs) associated with the treatment, while 17.4% reported severe TRAEs of grade3-4.
Implications: According to our results, the combination of Cadonilimab and Anlotinib appears to be a promising treatment option for SCLC patients with brain metastases.

Keywords: Cadonilimab; PD-1; anlotinib; brain metastases; small cell lung cancer

DOI: https://doi.org/10.3389/fonc.2025.1545101

Thorax. 2025 Jul 29. pii: thorax-2024-222100. [Epub ahead of print]

Association between ultra-processed food consumption and lung cancer risk: a population-based cohort study.

Kanran Wang, Junhan Zhao, Dingyi Yang, Mao Sun, Wei Zhou, Yongzhong Wu.

BACKGROUND: The evidence on associations between ultra-processed foods (UPF) and lung cancer risk is limited and inconsistent.
RESEARCH QUESTION: Are UPF associated with an increased risk of lung cancer, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)？ METHODS: Data of participants in this study were collected from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Dietary intakes were assessed through a validated diet history questionnaire. These foods were categorised using the NOVA classification according to the degree of processing in the PLCO Cancer Screening Cohort. All cases of incident lung cancer were pathologically verified. Multivariable Cox regression was used to assess the association between consumption of UPF and lung cancer after adjustment for various potential confounders, including key risk factors related to lung cancer and overall diet quality.
RESULTS: A total of 1706 cases of lung cancer cases, including 1473 NSCLC and 233 SCLC, were identified during a mean follow-up of 12.2 years among 101 732 adults (mean age 62.5 years). After multivariable adjustments, individuals in the highest quarters for UPF consumption had a higher risk of lung cancer (HR=1.41, 95% CI 1.22 to 1.60), NSCLC (HR=1.37, 95% CI 1.20 to 1.58) and SCLC (HR=1.44, 95% CI 1.03 to 2.10) compared with those in the lowest quarter. These results remained statistically significant after a large range of subgroup and sensitivity analyses.
CONCLUSIONS: Higher consumption of UPF is associated with an increased risk of lung cancer, NSCLC and SCLC. Although additional research in other populations and settings is warranted, these findings suggest the healthy benefits of limiting UPF.

Keywords: Lung Cancer

DOI: https://doi.org/10.1136/thorax-2024-222100