bims-meluca 2025-03-02 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2025–03–02
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Prognostic value of the lactate dehydrogenase to albumin ratio in advanced non-small cell lung cancer patients treated with the first-line PD-1 checkpoint inhibitors combined with chemotherapy.
Lineage plasticity of the integrated stress response is a hallmark of cancer evolution.
Role of guanylate-binding protein 1 in the proliferation of invasive lung adenocarcinoma cells.
Multi-omics analysis reveals the sensitivity of immunotherapy for unresectable non-small cell lung cancer.
Novel post-translational modification learning signature reveals B4GALT2 as an immune exclusion regulator in lung adenocarcinoma.
Predictive Value of Circulatory Total VEGF-A and VEGF-A Isoforms for the Efficacy of Anti-PD-1/PD-L1 Antibodies in Patients with Non-Small-Cell Lung Cancer.
Discovery of Key Candidate Protein Biomarkers in Early-Stage Nonsmall Cell Lung Carcinoma through Quantitative Proteomics.
Anamorelin Efficacy in Non-Small-Cell Lung Cancer Patients With Cachexia: Insights From ROMANA 1 and ROMANA 2.

Front Immunol. 2025 ;16 1473962

Prognostic value of the lactate dehydrogenase to albumin ratio in advanced non-small cell lung cancer patients treated with the first-line PD-1 checkpoint inhibitors combined with chemotherapy.

Meifeng Luo, Huiting Wei, Moqin Qiu, Cuiyun Su, Ruiling Ning, Shaozhang Zhou.

   Background: This study aimed to investigate the prognostic value of pretreatment lactate dehydrogenase to albumin ratio (LAR) in advanced non-small cell lung cancer (NSCLC) patients treated with first-line programmed cell death protein 1 (PD-1) checkpoint inhibitors and chemotherapy.
Methods: A retrospective cohort study was conducted on advanced NSCLC patients treated with first-line PD-1 checkpoint inhibitors plus chemotherapy at Guangxi Medical University Cancer Hospital. The receiver operating characteristic (ROC) analysis determined the optimal LAR cutoff values for prediction. Univariate and multivariate analyses identified independent prognostic factors, and survival curves were estimated using the Kaplan-Meier method. Subgroup analysis evaluated the association between high LAR and disease progression and death risk.
Results: A total of 210 patients were enrolled, with a mean age of 58.56 ± 10.61 years and a male proportion of approximately 79.05%. ROC analysis found the optimal LAR cutoff value was 5.0, resulting in a sensitivity of 78.87% and a specificity of 44.6% (area under the ROC curve 0.622; P = 0.001). Multivariate analysis revealed a significant positive association between LAR and overall survival (OS) after adjusting for confounders (HR = 2.22, 95% CI = 1.25-3.96, P = 0.007). Subgroup analysis confirmed the relationship between high LAR and the risk of disease progression and death across all patient subgroups.
Conclusions: Pretreatment LAR may be a potential independent prognostic marker for advanced NSCLC patients receiving PD-1 checkpoint inhibitors plus chemotherapy. A large-scale, prospective study is necessary to confirm these findings.

Keywords:  LAR; PD-1 checkpoint inhibitors; chemotherapy; non-small cell lung cancer; prognosis

DOI:  https://doi.org/10.3389/fimmu.2025.1473962
bioRxiv. 2025 Feb 13. pii: 2025.02.10.637516. [Epub ahead of print]

Lineage plasticity of the integrated stress response is a hallmark of cancer evolution.

Shiqi Diao, Jia Yi Zou, Shuo Wang, Nour Ghaddar, Jason E Chan, Hyungdong Kim, Nicolas Poulain, Constantinos Koumenis, Maria Hatzoglou, Peter Walter, Nahum Sonenberg, John Le Quesne, Tuomas Tammela, Antonis E Koromilas.

The link between the "stress phenotype"-a well-established hallmark of cancer-and its role in tumor progression and intratumor heterogeneity remains poorly defined. The integrated stress response (ISR) is a key adaptive pathway that enables tumor survival under oncogenic stress. While ISR has been implicated in promoting tumor growth, its precise role in driving tumor evolution and heterogeneity has not been elucidated. In this study, using a genetically engineered mouse models, we demonstrate that ISR activation-indicated by elevated levels of phosphorylated eIF2 (p-eIF2) and ATF4-is essential for the emergence of dedifferentiated, therapy-resistant cell states. ISR, through the coordinated actions of ATF4 and MYC, facilitates the development of tumor cell populations characterized by high plasticity, stemness, and an epithelial-mesenchymal transition (EMT)-prone phenotype. This process is driven by ISR-mediated expression of genes that maintain mitochondrial integrity and function, critical for sustaining tumor progression. Importantly, genetic, or pharmacological inhibition of the p-eIF2-ATF4 signaling axis leads to mitochondrial dysfunction and significantly impairs tumor growth in mouse models of lung adenocarcinoma (LUAD). Moreover, ISR-driven dedifferentiation is associated with poor prognosis and therapy resistance in advanced human LUAD, underscoring ISR inhibition as a promising therapeutic strategy to disrupt tumor evolution and counteract disease progression.

DOI: https://doi.org/10.1101/2025.02.10.637516
Front Oncol. 2025 ;15 1434249

Role of guanylate-binding protein 1 in the proliferation of invasive lung adenocarcinoma cells.

Takashi Kumada, Takahiro Mimae, Norifumi Tsubokawa, Kei Kushitani, Yukio Takeshima, Yoshihiro Miyata, Morihito Okada.

   Background: Guanylate-binding protein 1 (GBP1) is involved in the malignant progression of lung adenocarcinoma, particularly in the acquisition of invasive potential. However, its role in tumor proliferation and therapeutic viability in invasive lung adenocarcinomas remains unclear.
Methods: This study included 99 patients with invasive lung adenocarcinoma, excluding those with non-invasive lepidic components, who had undergone complete pulmonary resection. Immunohistochemical staining was performed to examine the presence of GBP1, and its prognostic significance was assessed using uni- and multi-variable Cox regression analyses. Additionally, the expression levels of GBP1 gene and protein levels were evaluated in lung adenocarcinoma cell lines (PC-9, A549, NCI-H322, NCI-H441, NCI-H820, and ABC-1), and its proliferative role in these cell lines was analyzed using specific inhibitors targeting GBP1.
Results: GBP1 expression was detected in 45 (45.5%) patients. The 5-year overall survival rates for GBP1-positive and -negative patients were 66.0% (95% confidence interval (CI): 46.3-80.0%) and 85.7% (95% CI: 72.0-93.0%), respectively (P = 0.029). The multivariable analysis demonstrated that GBP1 positivity was an independent factor for poor overall survival (hazard ratio [HR] = 2.52 [95% CI: 1.02-6.22], P = 0.045). GBP1 gene and protein were markedly expressed in NCI-H820 than in NCI-H322 and ABC-1. The inhibitor targeting GBP1 significantly suppressed the growth of NCI-H820 but not that of NCI-H322 or ABC-1.
Conclusions: GBP1 is a prognostic factor that may be involved in the proliferation of invasive lung adenocarcinoma, suggesting that inhibiting GBP1 activity may be a promising therapeutic approach for lung adenocarcinoma patients expressing GBP1.

Keywords:  GBP1; cell growth; inhibitor; lung adenocarcinoma; prognostic factor; therapy

DOI:  https://doi.org/10.3389/fonc.2025.1434249
Front Immunol. 2025 ;16 1479550

Multi-omics analysis reveals the sensitivity of immunotherapy for unresectable non-small cell lung cancer.

Rui Wu, Kunchen Wei, Xingshuai Huang, Yinge Zhou, Xiao Feng, Xin Dong, Hao Tang.

   Background: To construct a prediction model consisting of metabolites and proteins in peripheral blood plasma to predict whether patients with unresectable stage III and IV non-small cell lung cancer can benefit from immunotherapy before it is administered.
Methods: Peripheral blood plasma was collected from unresectable stage III and IV non-small cell lung cancer patients who were negative for driver mutations before receiving immunotherapy. Then we classified samples according to the follow-up results after two courses of immunotherapy and non-targeted metabolomics and proteomics analyses were performed to select different metabolites and proteins. Finally, potential biomarkers were picked out by applying machine learning methods including random forest and stepwise regression and prediction models were constructed by logistic regression.
Results: The presence of metabolites and proteins in peripheral blood plasma was causally associated with both non-small cell lung cancer and PD-L1/PD-1 expression levels. A total of 2 differential metabolites including 5-sulfooxymethylfurfural and Anthranilic acid and 2 differential proteins including Immunoglobulin heavy variable 1-45 and Microfibril-associated glycoprotein 4 were selected as reliable biomarkers. The area under the curve (AUC) of the prediction model built on clinical risks was merely 0.659. The AUC of metabolomics prediction model was 0.977 and the AUC of proteomics was 0.875 while the AUC of the integrative-omics prediction model was 0.955.
Conclusions: Metabolic and protein biomarkers in peripheral blood both have high efficacy and reliability in the prediction of immunotherapy sensitivity in unresectable stage III and IV non-small cell lung cancer, but validation in larger population-based cohorts is still needed.

Keywords:  immune checkpoint inhibitors; metabolomics; non-small cell lung cancer; prediction models; proteomics

DOI:  https://doi.org/10.3389/fimmu.2025.1479550
J Immunother Cancer. 2025 Feb 25. pii: e010787. [Epub ahead of print]13(2):

Novel post-translational modification learning signature reveals B4GALT2 as an immune exclusion regulator in lung adenocarcinoma.

Pengpeng Zhang, Dingli Wang, Guangyao Zhou, Shuai Jiang, Ge Zhang, Lianmin Zhang, Zhenfa Zhang.

   BACKGROUND: Lung adenocarcinoma (LUAD) presents significant challenges in prognosis and treatment efficacy evaluation. While post-translational modifications are known to influence tumor progression, their prognostic value in LUAD remains largely unexplored.
METHODS: We developed a post-translational modification learning signature (PTMLS) using machine learning techniques, analyzing data from 1231 LUAD patients across seven global cohorts. The signature's efficacy in predicting immunotherapy response was evaluated using 12 immunotherapy cohorts spanning multiple cancer types (n=1201). An in-house LUAD tissue cohort (n=171) was used to validate beta-1,4-galactosyltransferase 2's (B4GALT2's) prognostic significance. The role of B4GALT2 in immune exclusion was investigated through in vivo and in vitro experiments.
RESULTS: The established PTMLS exhibited exceptional predictive capabilities in LUAD patient outcomes, surpassing the efficacy of 98 existing LUAD prognostic indicators. The system's predictive value was validated across diverse malignancy categories for immunotherapeutic response assessment. From a biological perspective, significant correlations were observed between PTMLS and immunological parameters, whereby elevated PTMLS levels were characterized by attenuated immune responses and immunologically cold neoplastic features. Within the PTMLS framework, B4GALT2 was identified as a crucial molecular component (r=0.82, p<0.05), and its heightened expression was linked to unfavorable clinical outcomes in LUAD cases, particularly in specimens exhibiting CD8-depleted phenotypes. The spatial distribution patterns between B4GALT2 and immune cell populations, specifically CD8+ T lymphocytes and CD20+ B lymphocytes, were elucidated through multiplexed immunofluorescence analysis. Laboratory investigations subsequently established B4GALT2's regulatory influence on LUAD cellular expansion in both laboratory cultures and animal models. Significantly, suppression of B4GALT2 was found to enhance CD8+ T lymphocyte populations and their functional status, thereby potentiating anti-programmed cell death protein 1 immunotherapeutic efficacy in animal studies. This phenomenon was characterized by reduced CD62L+CD8 T lymphocyte levels alongside elevated GZMB+/CD44+/CD69+CD8 T cell populations.
CONCLUSION: The developed PTMLS system represents an effective instrument for individualized prognostic evaluation and immunotherapy stratification in both LUAD and diverse cancer populations. The identification of B4GALT2 as a previously unrecognized oncogenic factor involved in immune exclusion presents a novel therapeutic avenue for LUAD treatment and immunotherapy optimization.

Keywords:  Biomarker; Immunotherapy; Tumor Microenvironment

DOI:  https://doi.org/10.1136/jitc-2024-010787
Cancers (Basel). 2025 Feb 07. pii: 572. [Epub ahead of print]17(4):

Predictive Value of Circulatory Total VEGF-A and VEGF-A Isoforms for the Efficacy of Anti-PD-1/PD-L1 Antibodies in Patients with Non-Small-Cell Lung Cancer.

Tetsu Hirakawa, Kakuhiro Yamaguchi, Kunihiko Funaishi, Kiyofumi Shimoji, Shinjiro Sakamoto, Yasushi Horimasu, Takeshi Masuda, Taku Nakashima, Hiroshi Iwamoto, Hironobu Hamada, Shingo Yamada, Noboru Hattori.

   BACKGROUND/OBJECTIVES: Vascular endothelial growth factor (VEGF)-A promotes an immunosuppressive tumor microenvironment, potentially affecting the efficacy of anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibody therapy. VEGF121 and VEGF165, VEGF-A isoforms, promote and inhibit tumor growth, respectively. Additionally, VEGF-A levels differ depending on whether they are measured in serum or plasma. However, whether the serum or plasma levels of total VEGF-A (tVEGF-A) or its isoforms are the most suitable for predicting anti-PD-1/PD-L1 antibody therapy efficacy remains unclear.
METHODS: Eighty-six patients with non-small-cell lung cancer (NSCLC) who were treated with anti-PD-1/PD-L1 antibody monotherapy between December 2015 and December 2023 were retrospectively enrolled. The association between the serum and plasma levels of tVEGF-A and its isoforms (VEGF121 and VEGF165) and treatment outcomes was analyzed.
RESULTS: The median progression-free survival (PFS) was 2.9 months, and the objective response rate (ORR) was 23.3%. PFS was significantly shorter in patients with higher tVEGF-A serum levels (≥484.2 pg/mL) than in those without (median PFS 2.1 vs. 3.7 months, p = 0.004). In contrast, plasma tVEGF-A levels could not be used to stratify PFS. Therefore, the serum levels of VEGF-A isoforms were measured. Patients with higher VEGF121 serum levels (≥523.5 pg/mL) showed both significantly shorter PFS (median PFS 2.3 vs. 3.3 months, p = 0.022) and a lower ORR (9.7% vs. 30.9%, p = 0.033) than those without. Multivariate Cox and logistic regression analyses showed that higher levels of serum VEGF121 were significantly associated with shorter PFS and a lower ORR.
CONCLUSIONS: Serum VEGF121 levels may be useful in predicting anti-PD-1/PD-L1 antibody monotherapy efficacy.

Keywords:  VEGF121; anti-PD-1/PD-L1 antibody; biomarker; non-small cell lung cancer; vascular endothelial growth factor-A

DOI:  https://doi.org/10.3390/cancers17040572
J Proteome Res. 2025 Feb 27.

Discovery of Key Candidate Protein Biomarkers in Early-Stage Nonsmall Cell Lung Carcinoma through Quantitative Proteomics.

Baby Rorielyn T Dimayacyac-Esleta, Ferdinand D Mira, Lorenzo M Zarate, Ben Joshua O Porras, Dave Laurence A Juntilla, Lara Beatrice L Suñga, Venus B Pondevida, Sullian S Naval, Treah May S Sayo, Herdee Gloriane C Luna, Eloise I Prieto.

  Difficulties in early-stage diagnosis are among the factors contributing to the high mortality of nonsmall cell lung carcinoma (NSCLC) patients. Unfortunately, diagnostic biomarkers are currently lacking, limiting options in the clinic. To discover proteins that have potential for biomarker applications, we performed an in-depth quantitative proteomic analysis on a cohort of Filipino early-stage NSCLC lung adenocarcinoma (LUAD) patients. Differentially expressed proteins (DEPs) were obtained by using tandem mass tag (TMT) labeling and mass spectrometry (MS)-based quantitative proteomics. A total of 6240 quantified proteins were identified with 3155 significantly upregulated and 1248 significantly downregulated. Integration of the proteomic result with curated transcriptome data allowed the identification of 33 proteins with biomarker potential. This study also provided insights into relevant pathways in NSCLC LUAD, such as protein translation and metabolic pathways. Interestingly, all of the enzymes in the hexosamine biosynthetic pathway (HBP) are found to be upregulated, suggesting its important role in NSCLC LUAD. It is worthwhile to look at the potential of targeting the metabolic vulnerability of NSCLC LUAD as a new strategy in drug development. All MS data were deposited into ProteomeXchange with the identifier PXD050598.

Keywords:  LUAD; NSCLC; biomarker; hexosamine biosynthetic pathway; proteomics

DOI:  https://doi.org/10.1021/acs.jproteome.4c00764
J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13732

Anamorelin Efficacy in Non-Small-Cell Lung Cancer Patients With Cachexia: Insights From ROMANA 1 and ROMANA 2.

Barry J A Laird, Richard Skipworth, Philip D Bonomi, Marie Fallon, Stein Kaasa, Ruben Giorgino, Donald C McMillan, David C Currow.

   BACKGROUND: Cancer cachexia presents a significant challenge, but the ghrelin agonist anamorelin shows promise as a potential treatment. This study examined whether the baseline systemic inflammatory response (SIR) (measured by the modified Glasgow Prognostic Score [mGPS]), low BMI or greater weight loss, was associated with a differential treatment effect of anamorelin in people with cachexia and non-small-cell lung cancer (NSCLC).
METHODS: ROMANA 1 and ROMANA 2 were double-blind, placebo-controlled, randomised Phase 3 trials that enrolled people with inoperable stage III/IV NSCLC with cachexia (≥ 5% weight loss within 6 months or body mass index [BMI] < 20 kg/m2). Patients were randomised 2:1 to anamorelin 100 mg once daily or placebo, for 12 weeks. This is a post hoc analysis of efficacy endpoints (body weight and body composition: lean body mass [LBM] and fat mass [FM]), stratified by baseline mGPS, BMI and weight loss and measured in the modified intent-to-treat pooled population.
RESULTS: Seven hundred ninety-five patients had available data. Anamorelin improved body weight (p < 0.001) and body composition parameters (LBM and FM, p < 0.01) in all mGPS groups. In patients with mGPS = 2, anamorelin increased weight > 5% and improved hand grip strength (HGS) and the Functional Assessment of Anorexia/Cachexia Therapy Anorexia/Cachexia Subscale (FAACT A/CS). In patients with BMI < 20 kg/m2 at baseline or weight loss ≥ 10% in the prior 6 months, anamorelin led to significant increases in body weight from baseline (p < 0.001) versus placebo. Patients with weight loss ≥ 10% in the prior 6 months showed the highest improvements in LBM (p < 0.001). Patients with BMI < 20 kg/m2 at baseline showed the highest improvements in FM (p < 0.001).
CONCLUSION: Anamorelin improved body composition parameters in all patients, as well as physical function and symptom burden, particularly in patients with systemic inflammation, BMI < 20 kg/m2 and weight loss ≥ 10%. These results highlight that the anabolic mechanisms of anamorelin are more effective in high-risk groups.
TRIAL REGISTRATION: NCT identifiers: ROMANA 1: NCT01387269; ROMANA 2: NCT01387282.

Keywords:  ROMANA 1; ROMANA 2; cachexia; cancer; modified Glasgow Prognostic Score; systemic inflammatory response; trials

DOI:  https://doi.org/10.1002/jcsm.13732