bims-meluca 2021-10-03 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2021–10–03
nine papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge and Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Glutathione peroxidase 4-dependent glutathione high-consumption drives acquired platinum chemoresistance in lung cancer-derived brain metastasis.
Immunonutritional Indices in Non-small-cell Lung Cancer Patients Receiving Adjuvant Platinum-based Chemotherapy.
Oxamate, an inhibitor of lactate dehydrogenase, can stimulate M2 polarization of peritoneal macrophages in mice with Lewis lung carcinoma.
Cancer cachexia syndrome and clinical outcome in patients with metastatic non-small cell lung cancer treated with PD-1/PD-L1 inhibitors: results from a prospective, observational study.
Novel mitochondria-based targeting restores responsiveness in therapeutically resistant human lung cancer cells.
The Reality of Lung Cancer Paradox: The Impact of Body Mass Index on Long-Term Survival of Resected Lung Cancer. A French Nationwide Analysis from the Epithor Database.
Transcriptome Analyses Identify a Metabolic Gene Signature Indicative of Antitumor Immunosuppression of EGFR Wild Type Lung Cancers With Low PD-L1 Expression.
Identifying metabolic alterations in newly diagnosed small cell lung cancer patients.
Inflammation-nutritional markers of peripheral blood could predict survival in advanced non-small-cell lung cancer patients treated with PD-1 inhibitors.

Clin Transl Med. 2021 Sep;11(9): e517

Glutathione peroxidase 4-dependent glutathione high-consumption drives acquired platinum chemoresistance in lung cancer-derived brain metastasis.

Wenwen Liu, Yang Zhou, Wenzhe Duan, Jing Song, Song Wei, Shengkai Xia, Yingyan Wang, Xiaohui Du, Encheng Li, Caixia Ren, Wei Wang, Qimin Zhan, Qi Wang.

   BACKGROUND: Platinum-based chemotherapy is effective in inducing shrinkage of primary lung cancer lesions; however, it shows finite therapeutic efficacy in patients suffering from brain metastasis (BM). The intrinsic changes of BM cells, which contribute to the poor results remain unknown.
METHODS: Platinum drug-sensitivity was assessed by utilizing a preclinical BM model of PC9 lung adenocarcinoma cells in vitro and in vivo. High consumption of glutathione (GSH) and two associated upregulated proteins (GPX4 and GSTM1) in BM were identified by integrated metabolomics and proteomics in cell lines and verified by clinical serum sample. Gain-of-function and rescue experiments were implemented to reveal the impact and mechanism of GPX4 and GSTM1 on the chemosensitivity in BM. The interaction between GPX4 and GSTM1 was examined by immunoblotting and immunoprecipitation. The mechanism of upregulation of GPX4 was further uncovered by luciferase reporter assay, immunoprecipitation, and electrophoretic mobility shift assay.
RESULTS: The derivative brain metastatic subpopulations (PC9-BrMs) of parental cells PC9 developed obvious resistance to platinum. Radically altered profiles of BM metabolism and protein expression compared with primary lung cancer cells were described and GPX4 and GSTM1 were identified as being responsible for the high consumption of GSH, leading to decreased chemosensitivity by negatively regulating ferroptosis. Besides, GSTM1 was found regulated by GPX4, which was transcriptionally activated by the Wnt/NR2F2 signaling axis in BM.
CONCLUSIONS: Collectively, our findings demonstrated that Wnt/NR2F2/GPX4 promoted acquired chemoresistance by suppressing ferroptosis with high consumption of GSH. GPX4 inhibitor was found to augment the anticancer effect of platinum drugs in lung cancer BM, providing novel strategies for lung cancer patients with BM.

Keywords:  GPX4 inhibitor; brain metastasis; chemotherapeutic resistance; ferroptosis; glutathione metabolism; lung cancer

DOI:  https://doi.org/10.1002/ctm2.517
Anticancer Res. 2021 Oct;41(10): 5157-5163

Immunonutritional Indices in Non-small-cell Lung Cancer Patients Receiving Adjuvant Platinum-based Chemotherapy.

Taichi Matsubara, Fumihiko Hirai, Masafumi Yamaguchi, Motoharu Hamatake.

   BACKGROUND/AIM: Adjuvant platinum-based chemotherapy (APC) has been the standard of care for patients with non-small-cell lung cancer (NSCLC) who have undergone complete pulmonary resection. This study analyzed the clinical and prognostic significance of immunonutritional indices in NSCLC patients receiving APC.
PATIENTS AND METHODS: We retrospectively reviewed 110 patients from 2008 to 2016. Three immunonutritional indices were calculated: neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and prognostic nutritional index (PNI).
RESULTS: The median age was 64 years, and 66 patients were males. Each index showed a significant correlation with primary tumor length. NLR and PLR were significantly correlated with vascular invasion. Prognostic analyses revealed that each index was significantly correlated with postoperative recurrence-free survival (RFS) and overall survival (OS). On multivariate analyses, PNI was an independent predictor of RFS and OS.
CONCLUSION: Host immunonutritional status may have a significant effect on the postoperative prognosis of NSCLC in patients receiving APC.

Keywords:  Non-small-cell lung cancer; neutrophil-to-lymphocyte ratio; platelet-to-lymphocyte ratio; prognostic factor; prognostic nutritional index

DOI:  https://doi.org/10.21873/anticanres.15333
Exp Oncol. 2021 09;43(3): 270-273

Oxamate, an inhibitor of lactate dehydrogenase, can stimulate M2 polarization of peritoneal macrophages in mice with Lewis lung carcinoma.

G I Solyanik, О М Karaman, Y R Yakshibaeva, O N Pyaskovskaya, D L Kolesnik.

BACKGROUND: Inhibition of aerobic glycolysis of cancer cells is considered a promising therapeutic strategy for the treatment of neoplasms. Some inhibitors of energy metabolism can affect not only tumor cells but also the functional polarization of tumor-associated macrophages, which may either enhance the antitumor effect of such agents or impair their antitumor efficacy.
AIM: To investigate the effect of oxamate, a lactate dehydrogenase (LDH) inhibitor, on the polarization of peritoneal macrophages (PMP) in both intact mice and mice with transplanted Lewis lung carcinoma (LLC).
MATERIALS AND METHODS: The low-metastatic LLC variant, LLC/R9, was transplanted to female C57Bl/6 mice. Sodium oxamate was used as the test agent at concentrations of 0.02, 0.2, and 2 mg/ml. Macrophage polarization in tumor-bearing mice was estimated on day 23 after tumor transplantation by assessing nitric oxide (NO) production and arginase activity as functional indices of PMPs polarization.
RESULTS: Oxamate can affect the functional polarization of PMPs in both intact mice and animals with transplanted LLC/R9. Oxamate in all studied concentrations changed the markers of PMPs polarization in intact mice (decreasing NO levels and activating arginase activity) that indicated the stimulation of M2 polarization. In tumor-bearing animals, stimulation of M2 polarization is observed at low concentrations of oxamate (0.02 mg/ml), but its high concentrations (2.0 mg/ml) causes M1 polarization, which is characterized by three-fold increase in the level of NO and a decrease in the level of arginase activity.
CONCLUSION: Oxamate, an inhibitor of LDH, can stimulate M2 polarization of peritoneal macrophages of mice bearing LLC in a dose-dependent manner.
Transl Lung Cancer Res. 2021 Aug;10(8): 3538-3549

Cancer cachexia syndrome and clinical outcome in patients with metastatic non-small cell lung cancer treated with PD-1/PD-L1 inhibitors: results from a prospective, observational study.

Konstantinos Rounis, Dimitrios Makrakis, Alexandros-Pantelis Tsigkas, Alexandra Georgiou, Nikolaos Galanakis, Chara Papadaki, Alexia Monastirioti, Lambros Vamvakas, Konstantinos Kalbakis, Nikolaos Vardakis, Meropi Kontogianni, Ioannis Gioulbasanis, Dimitrios Mavroudis, Sofia Agelaki.

   Background: Cancer cachexia syndrome (CCS) is an adverse prognostic factor in cancer patients undergoing chemotherapy or surgical procedures. We performed a prospective study to investigate the effect of CCS on treatment outcomes in patients with non-oncogene driven metastatic non-small cell lung cancer (NSCLC) undergoing therapy with programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors.
Methods: Patients were categorized as having cancer cachexia if they had weight loss >5% in the last 6 months prior to immunotherapy (I-O) initiation or any degree of weight loss >2% and body mass index (BMI) <20 kg/m2 or skeletal muscle index at the level of third lumbar vertebra (LSMI) <55 cm2/m2 for males and <39 cm2/m2 for females. LSMI was calculated using computed tomography (CT) scans of the abdomen at the beginning of I-O and every 3 months thereafter.
Results: Eighty-three patients were included in the analysis and the prevalence of cancer cachexia at the beginning of I-O was 51.8%. The presence of CCS was associated with inferior response rates to ICIs (P≤0.001) and consisted an independent predictor of increased probability for developing disease progression as best response to treatment, OR =8.11 (95% CI: 2.95-22.40, P≤0.001). In the multivariate analysis, the presence of baseline cancer cachexia consisted an independent predictor for inferior survival, HR =2.52 (95% CI: 1.40-2.55, P=0.002). Reduction of LSMI >5% during treatment did not affect overall survival (OS; P=0.40).
Conclusions: CCS is associated with reduced PD-1/PD-L1 inhibitor efficacy in NSCLC patients and should constitute an additional stratification factor in future I-O clinical trials. Further research at a translational and molecular level is required to decipher the mechanisms of interrelation of metabolic deregulation and suppression of antitumor immunity.

Keywords:  Cancer cachexia; PD-1/PD-L1 inhibitors; immunotherapy; non-small cell lung cancer (NSCLC); outcome; response rate; survival

DOI:  https://doi.org/10.21037/tlcr-21-460
Mol Cancer Ther. 2021 Sep 28. pii: molcanther.MCT-20-1095-A.2020. [Epub ahead of print]

Novel mitochondria-based targeting restores responsiveness in therapeutically resistant human lung cancer cells.

Liyuan Yin, Yi Zhang, Lijuan Yin, Yan Ou, Michael S Lewis, Ruoxiang Wang, Haiyen E Zhau, Qinghua Zhou, Leland W K Chung.

Cisplatin and tyrosine kinase inhibitors (TKIs) are recommended to treat non-small-cell lung cancer (NSCLC). However, ubiquitously acquired drug resistance in NSCLC patients diminishes their therapeutic efficacy. Strategies for overcoming cisplatin and TKI resistance are an unmet medical need. We previously described a group of near-infrared heptamethine carbocyanine fluorescent dyes, referred to as DZ, with tumor-homing properties via differentially expressed organic anion-transporting polypeptides on cancer cells. This group of organic dyes can deliver therapeutic payloads specifically to tumor cells in the form of a chemical conjugate. We synthesized DZ-SIMvastatin (DZ-SIM) initially to target cell membrane cholesterol biosynthesis in lung cancer cells. DZ-SIM induced apoptosis in both cisplatin-sensitive and resistant as well as EGFR TKI-sensitive and resistant lung cancer cells. This conjugate specifically accumulated in and effectively inhibited the growth of xenograft tumors formed by NSCLC cells resistant to first (H1650) and third (PC9AR) generation EGFR TKIs. DZ-SIM induced cell death by targeting mitochondrial structure and function. We concluded that DZ-SIM could be a promising novel therapy for overcoming drug resistance in NSCLC patients.

DOI: https://doi.org/10.1158/1535-7163.MCT-20-1095
Cancers (Basel). 2021 Sep 12. pii: 4574. [Epub ahead of print]13(18):

The Reality of Lung Cancer Paradox: The Impact of Body Mass Index on Long-Term Survival of Resected Lung Cancer. A French Nationwide Analysis from the Epithor Database.

Marco Alifano, Elisa Daffré, Antonio Iannelli, Laurent Brouchet, Pierre Emmanuel Falcoz, Françoise Le Pimpec Barthes, Alain Bernard, Pierre Benoit Pages, Pascal Alexandre Thomas, Marcel Dahan, Raphael Porcher.

  Obesity could have a protective effect in patients with lung cancer. We assessed the prognostic role of preoperative BMI on survival in patients who underwent lung resection for NSCLC. A total of 54,631 consecutive patients with resectable lung cancer within a 15-year period were extracted from Epithor (the French Society of Thoracic and Cardiovascular Surgery database). Patient subgroups were defined according to body mass index (BMI): underweight (BMI < 18.5 kg/m2), normal weight (18.5 ≤ BMI < 25 kg/m2), overweight (25 ≤ BMI < 30 kg/m2), and obese (BMI ≥ 30 kg/m2). Underweight was associated with lower survival (unadjusted HRs 1.24 (1.16-1.33)) compared to normal weight, whereas overweight and obesity were associated with improved survival (0.95 (0.92-0.98) and 0.88 (0.84-0.92), respectively). The impact of BMI was confirmed when stratifying for sex or Charlson comorbidities index (CCI). Among patients with obesity, a higher BMI was associated with improved survival. After adjusting for period of study, age, sex, WHO performance status, CCI, side of tumor, extent of resection, histologic type, and stage of disease, the HRs for underweight, overweight, and obesity were 1.51 (1.41-1.63), 0.84 (0.81-0.87), and 0.80 (0.76-0.84), respectively. BMI is a strong and independent predictor of survival in patients undergoing surgery for NSCLC.

Keywords:  BMI; lung cancer; obesity

DOI:  https://doi.org/10.3390/cancers13184574
Front Oncol. 2021 ;11 643503

Transcriptome Analyses Identify a Metabolic Gene Signature Indicative of Antitumor Immunosuppression of EGFR Wild Type Lung Cancers With Low PD-L1 Expression.

Min Wang, Jie Zhu, Fang Zhao, Jiani Xiao.

   Purpose: With the development and application of targeted therapies like tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), non-small cell lung cancer (NSCLC) patients have achieved remarkable survival benefits in recent years. However, epidermal growth factor receptor (EGFR) wild-type and low expression of programmed death-ligand 1 (PD-L1) NSCLCs remain unmanageable. Few treatments for these patients exist, and more side effects with combination therapies have been observed. We intended to generate a metabolic gene signature that could successfully identify high-risk patients and reveal its underlying molecular immunology characteristics.
Methods: By identifying the bottom 50% PD-L1 expression level as PD-L1 low expression and removing EGFR mutant samples, a total of 640 lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) tumor samples and 93 adjacent non-tumor samples were finally extracted from The Cancer Genome Atlas (TCGA). We identified differentially expressed metabolic genes (DEMGs) by R package limma and the prognostic genes by Univariate Cox proportional hazards regression analyses. The intersect genes between DEMGs and prognostic genes were put into the least absolute shrinkage and selection operator (LASSO) penalty Cox regression analysis. The metabolic gene signature contained 18 metabolic genes generated and successfully stratified LUAD and LUSC patients into the high-risk and low-risk groups, which was also validated by the Gene Expression Omnibus (GEO) database. Its accuracy was proved by the time-dependent Receiver Operating Characteristic (ROC) curve, Principal Components Analysis (PCA), and nomogram. Furthermore, the Single-sample Gene Set Enrichment Analysis (ssGSEA) and diverse acknowledged methods include XCELL, TIMER, QUANTISEQ, MCPcounter, EPIC, CIBERSORT-ABS, and CIBERSORT revealed its underlying antitumor immunosuppressive status. Besides, its relationship with somatic copy number alterations (SCNAs) and tumor mutational burden (TMB) was also discussed.
Results: It is noteworthy that metabolism reprogramming is associated with the survival of the double-negative LUAD and LUSC patients. The SCNAs and TMB of critical metabolic genes can inhibit the antitumor immune process, which might be a promising therapeutic target.

Keywords:  GEO; The Cancer Genome Atlas Program (TCGA); epidermal growth factor receptor (EGFR) wild-type; low expression of programmed death-ligand 1 (PD-L1); lung adenocarcinoma; lung squamous carcinoma

DOI:  https://doi.org/10.3389/fonc.2021.643503
Metabol Open. 2021 Dec;12 100127

Identifying metabolic alterations in newly diagnosed small cell lung cancer patients.

Shona Pedersen, Joachim Bavnhøj Hansen, Raluca Georgiana Maltesen, Weronika Maria Szejniuk, Trygve Andreassen, Ursula Falkmer, Søren Risom Kristensen.

   Background: Small cell lung cancer (SCLC) is a malignant disease with poor prognosis. At the time of diagnosis most patients are already in a metastatic stage. Current diagnosis is based on imaging, histopathology, and immunohistochemistry, but no blood-based biomarkers have yet proven to be clinically successful for diagnosis and screening. The precise mechanisms of SCLC are not fully understood, however, several genetic mutations, protein and metabolic aberrations have been described. We aim at identifying metabolite alterations related to SCLC and to expand our knowledge relating to this aggressive cancer.
Methods: A total of 30 serum samples of patients with SCLC, collected at the time of diagnosis, and 25 samples of healthy controls were included in this study. The samples were analyzed with nuclear magnetic resonance spectroscopy. Multivariate, univariate and pathways analyses were performed.
Results: Several metabolites were identified to be altered in the pre-treatment serum samples of small-cell lung cancer patients compared to healthy individuals. Metabolites involved in tricarboxylic acid cycle (succinate: fold change (FC) = 2.4, p = 0.068), lipid metabolism (LDL triglyceride: FC = 1.3, p = 0.001; LDL-1 triglyceride: FC = 1.3, p = 0.012; LDL-2 triglyceride: FC = 1.4, p = 0.009; LDL-6 triglyceride: FC = 1.5, p < 0.001; LDL-4 cholesterol: FC = 0.5, p = 0.007; HDL-3 free cholesterol: FC = 0.7, p = 0.002; HDL-4 cholesterol FC = 0.8, p < 0.001; HDL-4 apolipoprotein-A1: FC = 0.8, p = 0.005; HDL-4 apolipoprotein-A2: FC ≥ 0.7, p ≤ 0.001), amino acids (glutamic acid: FC = 1.7, p < 0.001; glutamine: FC = 0.9, p = 0.007, leucine: FC = 0.8, p < 0.001; isoleucine: FC = 0.8, p = 0.016; valine: FC = 0.9, p = 0.032; lysine: FC = 0.8, p = 0.004; methionine: FC = 0.8, p < 0.001; tyrosine: FC = 0.7, p = 0.002; creatine: FC = 0.9, p = 0.030), and ketone body metabolism (3-hydroxybutyric acid FC = 2.5, p < 0.001; acetone FC = 1.6, p < 0.001), among other, were found deranged in SCLC.
Conclusions: This study provides novel insight into the metabolic disturbances in pre-treatment SCLC patients, expanding our molecular understanding of this malignant disease.

Keywords:  Diagnostic signatures; Metabolomics; Pathways; Serum metabolites; Small-cell lung cancer

DOI:  https://doi.org/10.1016/j.metop.2021.100127
Thorac Cancer. 2021 Sep 28.

Inflammation-nutritional markers of peripheral blood could predict survival in advanced non-small-cell lung cancer patients treated with PD-1 inhibitors.

Dan Pu, Qian Xu, Lai-Yan Zhou, Yu-Wen Zhou, Ji-Yan Liu, Xue-Lei Ma.

   BACKGROUND: Inflammation-nutritional markers of peripheral blood are easily assessed and can predict survival. The aim of this study was to investigate the association between inflammation-nutritional parameters and survival of anti-programmed death-1 (PD-1) therapy in non-small-cell lung cancer (NSCLC) patients.
METHODS: We performed a retrospective study from March 2017 to April 2020 in advanced NSCLC patients treated with PD-1 inhibitors. Univariable and multivariable analyses were conducted to evaluate the relationship between peripheral blood parameters (absolute lymphocyte count [ALC], absolute neutrophil count [ANC], absolute monocyte count [AMC], absolute eosinocyte count [AEC], lactic dehydrogenase [LDH], plasma-albumin [ALB], neutrophil/lymphocyte ratio [NLR], and platelet/lymphocyte ratio [PLR]) measured before therapy initiation and prognosis.
RESULTS: Among 184 evaluable patients, 134 (72.8%) were male and the median age was 58 years (range 33-87) with 31 (16.8%) ≥70 years. An elevated ANC (≥7500/ul), NLR (≥5), and PLR (≥200) was significantly associated with worse objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), while increased ALC (≥1000/ul) and ALB (≥3.5 g/dl) could significantly improve survival in terms of ORR, PFS, and OS. In multivariate analyses, higher AEC (≥150/ul) and AMC (≥650/ul) could significantly decrease the risk of death (hazard ratio [HR] 0.363, 95% confidence interval [CI] 0.141-0.931, p = 0.035; HR 0.370, 95% CI 0.203-0.675, p = 0.001). A higher NLR and PLR, and lower ALB were independent predictors of poor prognosis for OS (HR 1.964, 95% CI 1.027-3.755, p = 0.041; HR 4.255, 95% CI 2.364-7.658, p = 0.000; HR 1.962, 95% CI 1.213-3.174, p = 0.006, respectively).
CONCLUSION: Our research illustrated that pretreatment AEC, AMC, ALB, NLR, and PLR are independent predictors for survival in advanced NSCLC patients treated with PD-1 inhibitors.

Keywords:  PD-1 inhibitors; inflammation-nutritional markers; lung cancer; predictive parameters; survival

DOI:  https://doi.org/10.1111/1759-7714.14152