bims-meluca 2022-09-18 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2022‒09‒18
nine papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab
L’Institut d’Investigació Biomèdica de Bellvitge

Chronic hyperglycemia is an adverse prognostic factor for locoregional recurrence-free survival in small cell lung cancer patients treated with radical radiotherapy.
Identification of lactate metabolism-related subtypes and development of a lactate-related prognostic indicator of lung adenocarcinoma.
Characterization of the Oncogenic Potential of Eukaryotic Initiation Factor 4A1 in Lung Adenocarcinoma via Cell Cycle Regulation and Immune Microenvironment Reprogramming.
Validation of Patras Immunotherapy Score model for prediction and prognosis of patients with advanced NSCLC treated with nivolumab or pembrolizumab: results from a European multicentre study.
A retrospective study for prognostic significance of type II diabetes mellitus and hemoglobin A1c levels in non-small cell lung cancer patients treated with pembrolizumab.
Arginine Deprivation in SCLC: Mechanisms and Perspectives for Therapy.
The Glasgow Prognostic Score Predicts Outcomes of Pembrolizumab or Atezolizumab Monotherapy in Patients with Pretreated Non-small Cell Lung Cancer.
Lactate Dehydrogenase and its clinical significance in pancreatic and thoracic cancers.
Development of a Clinical Prognostic Model for Metabolism-Related Genes in Squamous Lung Cancer and Correlation Analysis of Immune Microenvironment.

Thorac Cancer. 2022 Sep;13(18): 2633-2640

Chronic hyperglycemia is an adverse prognostic factor for locoregional recurrence-free survival in small cell lung cancer patients treated with radical radiotherapy.

Moonkyoo Kong, Yu Jin Lim.

  BACKGROUND: Plasma glucose levels might be associated with the severity of tumor hypoxia in patients with cancer. In our previous study, we found that chronic hyperglycemia significantly increased the risk of locoregional recurrence in patients with non-small cell lung cancer treated with radical radiotherapy (RT). Here, we evaluated the association between plasma glucose levels in terms of hemoglobin A1c (HbA1c) and locoregional recurrence-free survival in patients with limited-stage small cell lung cancer treated with radical RT.METHODS: We retrospectively analyzed the clinical data of 59 patients with small cell lung cancer. HbA1c levels were measured 1 week before the start of RT. Survival outcomes were analyzed according to HbA1c levels. Multivariable analysis was conducted to identify whether HbA1c level was a significant prognostic factor for survival.
RESULTS: The 1-, 2-, and 3-year locoregional recurrence-free survival rates were 90.9, 86.1, and 78.9%, respectively, in the low HbA1c group, and 45.1, 27.1, and 20.3%, respectively, in the high HbA1c group (p < 0.001). The 1-, 2-, and 3-year distant metastasis-free survival rates were 67.2, 57, and 57%, respectively, in the low HbA1c group, while it was 56.6, 24.9, and 24.9%, respectively, in the high HbA1c group (p = 0.024). HbA1c level remained a significant prognostic factor for locoregional recurrence-free survival in the multivariable analysis (p = 0.010).
CONCLUSIONS: Chronic hyperglycemia is a significant prognostic factor for locoregional recurrence-free survival in patients with limited-stage small cell lung cancer treated with radical RT. Routine monitoring of plasma glucose levels and aggressive glycemic control should be conducted to prevent locoregional recurrence.

Keywords:  hyperglycemia; locoregional recurrence; lung cancer; radiotherapy

DOI:  https://doi.org/10.1111/1759-7714.14601
Front Genet. 2022 ;13 949310

Identification of lactate metabolism-related subtypes and development of a lactate-related prognostic indicator of lung adenocarcinoma.

Xiaoyan Chang, Tong Lu, Ran Xu, Chenghao Wang, Jiaying Zhao, Linyou Zhang.

  Background: Increasing evidence supports that lactate plays an important role in tumor proliferation, invasion and within the tumor microenvironment (TME). This is particularly relevant in lung adenocarcinoma (LUAD). Therefore, there is a current need to investigate lactate metabolism in LUAD patients and how lactate metabolism is affected by different therapies. Methods: Data from LUAD patients were collected from The Cancer Genome Atlas (TCGA) and patients were divided into two subtypes according to 12 lactate metabolism-related genes to explore the effect of lactate metabolism in LUAD. We established a lactate-related prognostic indicator (LRPI) based on different gene expression profiles. Subsequently, we investigated associations between this LRPI and patient survival, molecular characteristics and response to therapy. Some analyses were conducted using the Genomics of Drug Sensitivity in Cancer (GDSC) database. Results: The two LUAD subtypes exhibited different levels of lactate metabolism, in which patients that displayed high lactate metabolism also had a worse prognosis and a poorer immune environment. Indeed, LRPI was shown to accurately predict the prognosis of LUAD patients. Patients with a high LRPI showed a poor prognosis coupled with high sensitivity to chemotherapy using GDSC data. Meanwhile, these patients exhibited a high responsiveness to immunotherapy in TMB (Tumor mutation burden) and TIDE (Tumor Immune Dysfunction and Exclusion) analyses. Conclusion: We validated the effect of lactate metabolism on the prognosis of LUAD patients and established a promising biomarker. LRPI can predict LUAD patient survival, molecular characteristics and response to therapy, which can aid the individualized treatment of LUAD patients.

Keywords:  immune cell infiltration; immune checkpoint blockade therapy; immune-related genes; lung adenocarcinoma; prognosis biomarker

DOI:  https://doi.org/10.3389/fgene.2022.949310
Biology (Basel). 2022 Jun 28. pii: 975. [Epub ahead of print]11(7):

Characterization of the Oncogenic Potential of Eukaryotic Initiation Factor 4A1 in Lung Adenocarcinoma via Cell Cycle Regulation and Immune Microenvironment Reprogramming.

Kuan-Li Wu, Yung-Chi Huang, Yu-Yuan Wu, Chao-Yuan Chang, Yung-Yun Chang, Hung-Hsing Chiang, Lian-Xiu Liu, Ying-Ming Tsai, Jen-Yu Hung.

  Lung adenocarcinoma (LUAD) is a common type of lung cancer. Although the diagnosis and treatment of LUAD have significantly improved in recent decades, the survival for advanced LUAD is still poor. It is necessary to identify more targets for developing potential agents against LUAD. This study explored the dysregulation of translation initiation factors, specifically eukaryotic initiation factors 4A1 (EIF4A1) and EIF4A2, in developing LUAD, as well as their underlying mechanisms. We found that the expression of EIF4A1, but not EIF4A2, was higher in tumor tissue and associated with poor clinical outcomes in LUAD patients. Elevated expression of EIF4H with poor prognosis may potentiate the oncogenic role of EIF4A1. Functional enrichment analysis revealed that upregulation of EIF4A1 was related to cell cycle regulation and DNA repair. The oncogenic effect of EIF4A1 was further elucidated by Gene Set Variation Analysis (GSVA). The GSVA score of the gene set positively correlated with EIF4A1 was higher in tumors and significantly associated with worse survival. In the meantime, gene set enrichment analysis (GSEA) also indicated that elevated EIF4A1 expression in LUAD patients was associated with a decreased infiltration score for immune cells by reducing anticancer immune cell types and recruiting immunosuppressive cells. Consistent with the results, the GSVA score of genes whose expression was negatively correlated with EIF4A1 was lower in the tumor tissue of LUAD cases with worse clinical outcomes and was strongly associated with the disequilibrium of anti-cancer immunity by recruiting anticancer immune cells. Based on the results from the present study, we hypothesize that the dysregulation of EIF4A1 might be involved in the pathophysiology of LUAD development by promoting cancer growth and changing the tumor immune microenvironment. This can be used to develop potential diagnostic biomarkers or therapeutic targets for LUAD.

Keywords:  DNA repair; EIF4A1; LUAD; cell cycle; tumor immune microenvironment

DOI:  https://doi.org/10.3390/biology11070975
Ther Adv Med Oncol. 2022 ;14 17588359221122728

Validation of Patras Immunotherapy Score model for prediction and prognosis of patients with advanced NSCLC treated with nivolumab or pembrolizumab: results from a European multicentre study.

Foteinos-Ioannis Dimitrakopoulos, Giannis Mountzios, Petros Christopoulos, Thomas Papastergiou, Mariam Elshiaty, Lea Daniello, Elefterios Zervas, Sofia Agelaki, Epaminondas Samantas, Adamantia Nikolaidi, Ilias Athanasiadis, Sofia Baka, Konstantinos Syrigos, Athina Christopoulou, Evangelos Lianos, Konstantinos Samitas, Nikolaos Tsoukalas, Eleni-Isidora Perdikouri, George Oikonomopoulos, Anastasia Kottorou, Foteini Kalofonou, Thomas Makatsoris, Angelos Koutras, Vasileios Megalooikonomou, Haralabos Kalofonos.

  Background: Recently, the Patras Immunotherapy Score (PIOS) has been developed to estimate the survival benefit of patients with advanced non-small-cell lung cancer (aNSCLC) treated with nivolumab or pembrolizumab. The aim of this study was to validate the clinical value of PIOS in an external cohort of aNSCLC patients.Methods: PIOS is a baseline formula produced by the combination of performance status, body mass index, age and line of treatment. In this multicentre study, 626 patients with confirmed NSCLC pathology, who had been treated with nivolumab or pembrolizumab, as well as 444 patients with aNSCLC, who had been managed with chemotherapy alone, were retrospectively enrolled. Predictive and prognostic values of PIOS were finally evaluated.
Results: Patients treated with immunotherapy and higher PIOS score had an improved progression-free survival not only in univariate [hazard ratio (HR) = 0.621, p = 0.001], but also in multivariable analysis (HR = 0.651, p = 0.003). In addition, improved overall survival with increasing PIOS score was also observed (HR = 0.608, p < 0.001) with this association remaining statistically significant after adjusting for programmed-cell death ligand 1 (PD-L1) expression (HR = 0.620, p < 0.001). In addition, patients with disease progression (PD) had lower scores compared to those with stable disease (SD), partial response (PR) or complete response (CR) in a two-tier model (p < 0.001) as well as in a four-tier model (PD, SD, PR and CR; p < 0.001). Prognostic significance of PIOS score also persisted using a binary logistic regression analysis, adjusted for disease stage and PD-L1 status (p = 0.002, odds ratio: 0.578). Contrarily, PIOS had no prognostic significance in the chemotherapy group; however, upon combined analysis of the two cohorts, PIOS was found to have a significant interaction with the type of treatment (HR = 0.066 with p < 0.001), confirming its predictive value for immunotherapy.
Conclusions: This study provides further validation of PIOS in aNSCLC patients treated with anti-PD-1 monotherapy.

Keywords:  NSCLC; PIOS; Patras Immunotherapy Score; biomarker; nivolumab; pembrolizumab

DOI:  https://doi.org/10.1177/17588359221122728
Transl Lung Cancer Res. 2022 Aug;11(8): 1619-1630

A retrospective study for prognostic significance of type II diabetes mellitus and hemoglobin A1c levels in non-small cell lung cancer patients treated with pembrolizumab.

Yinchen Shen, Jiaqi Li, Huiping Qiang, Yuqiong Lei, Qing Chang, Runbo Zhong, Giulia Maria Stella, Francesco Gelsomino, Yeon Wook Kim, Afaf Abed, Jialin Qian, Tianqing Chu.

  Background: Diabetes mellitus (DM) is common and recognized as a risk factor for developing non-small cell lung cancer (NSCLC) while the prognostic evaluation is still controversial. As immunotherapy is widely used in clinical practice, its efficacy and survival should be investigated in patients with DM.Methods: We retrospectively recruited 266 locally advanced and metastatic NSCLC patients who received pembrolizumab alone or in combination with chemotherapy. Patients' clinicopathological data, including age, history of DM, hemoglobin A1c (HbA1c), genetic tumor profiling, and survival data were collected. Associations between clinical characteristics and survival were evaluated by univariate and multivariate analyses.
Results: In this cohort, 15.04% (40/266) of the patients had a history of DM. Fifty-nine (22.2%) patients had a HbA1c level ≥6.5%. A total of 169 (63.5%) patients received 1st-line therapy, and 97 (36.5%) received 2nd- or subsequent-line therapy. Patients with high (≥6.5%) HbA1c and lower (<35 g/L) albumin levels at baseline had worse survivals, and epidermal growth factor receptor (EGFR) mutants significantly associated with worse outcomes at normal HbA1c (<6.5%) levels (all P<0.05). Among the 1st-line therapy patients, a higher HbA1c level (≥6.5%) at baseline indicated a worse overall survival (OS) (2-year survival rate: 31.25% vs. 27.03%, P=0.045), tumor protein p53 (TP53) alternations and high programmed death-ligand 1 (PD-L1) expression (≥50%) were significantly associated with better outcomes (P<0.05). For 2nd- or subsequent-line patients, EGFR mutants and non-squamous carcinomas (non-SCs) indicated worse survivals, and the normal peripheral blood markers of the carcinoembryonic antigen (CEA), C-reactive protein (CRP), albumin levels were favorable prognostic factors for survivals. In non-SCs, Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, high PD-L1 expression, and normal alkaline phosphatase (ALP) levels favored better progression-free survival (PFS), while EGFR mutants indicated poor PFS (P<0.05).
Conclusions: Among patients treated with 1st-line immunotherapy, a higher HbA1c level (≥6.5%) indicated dismal OS, while history of DM, baseline blood glucose levels, and glucose changes during the treatment process were not significantly associated with any of the outcomes.

Keywords:  Diabetes mellitus (DM); hemoglobin A1c (HbA1c); immunotherapy; non-small cell lung cancer (NSCLC)

DOI:  https://doi.org/10.21037/tlcr-22-493
Lung Cancer (Auckl). 2022 ;13 53-66

Arginine Deprivation in SCLC: Mechanisms and Perspectives for Therapy.

Joséphine Carpentier, Iuliia Pavlyk, Uma Mukherjee, Peter E Hall, Peter W Szlosarek.

  Arginine deprivation has gained increasing traction as a novel and safe antimetabolite strategy for the treatment of several hard-to-treat cancers characterised by a critical dependency on arginine. Small cell lung cancer (SCLC) displays marked arginine auxotrophy due to inactivation of the rate-limiting enzyme argininosuccinate synthetase 1 (ASS1), and as a consequence may be targeted with pegylated arginine deiminase or ADI-PEG20 (pegargiminase) and human recombinant pegylated arginases (rhArgPEG, BCT-100 and pegzilarginase). Although preclinical studies reveal that ASS1-deficient SCLC cell lines are highly sensitive to arginine-degrading enzymes, there is a clear disconnect with the clinic with minimal activity seen to date that may be due in part to patient selection. Recent studies have explored resistance mechanisms to arginine depletion focusing on tumor adaptation, such as ASS1 re-expression and autophagy, stromal cell inputs including macrophage infiltration, and tumor heterogeneity. Here, we explore how arginine deprivation may be combined strategically with novel agents to improve SCLC management by modulating resistance and increasing the efficacy of existing agents. Moreover, recent work has identified an intriguing role for targeting arginine in combination with PD-1/PD-L1 immune checkpoint inhibitors and clinical trials are in progress. Thus, future studies of arginine-depleting agents with chemoimmunotherapy, the current standard of care for SCLC, may lead to enhanced disease control and much needed improvements in long-term survival for patients.

Keywords:  ASS1; SCLC; arginine; arginine deprivation; argininosuccinate synthase 1; immunotherapy; small cell lung cancer; tumor microenvironment

DOI:  https://doi.org/10.2147/LCTT.S335117
Oncology. 2022 Sep 14.

The Glasgow Prognostic Score Predicts Outcomes of Pembrolizumab or Atezolizumab Monotherapy in Patients with Pretreated Non-small Cell Lung Cancer.

Masashi Kasajima, Satoshi Igawa, Hiroya Manaka, Kaori Yamada, Yuki Akazawa, Hideaki Manabe, Yuri Yagami, Hiroki Yamamoto, Hiroki Ito, Nobuki Kaizuka, Yoshiro Nakahara, Takashi Sato, Hisashi Mitsufuji, Masanori Yokoba, Masaru Kubota, Jiichiro Sasaki, Katsuhiko Naoki.

INTRODUCTION: Predictors of the effectiveness of immune checkpoint inhibitor (ICI) monotherapy in previously treated patients with non-small cell lung cancer (NSCLC) remain ill-defined. We investigated whether the Glasgow prognostic score (GPS) could serve as such predictors.METHODS: Eighty patients treated with pembrolizumab or atezolizumab monotherapy as second- or subsequent-line therapy for NSCLC were retrospectively reviewed, and the associations between GPS, BMI, and each of progression-free survival (PFS) and overall survival (OS) were assessed.
RESULTS: The median follow-up period was 11.1 months. Patients with a BMI ≥20.4 kg/m2 had significantly longer PFS and OS (3.7 and 22.2 month, respectively) than did those with a BMI <20.4 kg/m2 (2.2 and 11.5 months, respectively). Patients with a GPS of 0 had a significantly longer PFS (6.6 months) than did those with a GPS of 1 (2.2 months, P=0.002) and 2 (1.8 months, P=0.029). Patients with a GPS of 0 also had a significantly longer OS (22.2 month) than did those with a GPS of 1 (9.2 months, P=0.002) and 2 (4.7 months, P=0.002). Notably, the GPS, BMI, and clinical stage were independent predictors of PFS, while the GPS and performance status were independent predictors of OS. The response rate of patients with a GPS of 0 was significantly higher than that of patients with a GPS of 1-2 (26.2% vs. 7.9%, P=0.03).
CONCLUSION: The GPS is an independent predictor of PFS and OS in patients with NSCLC who received second- or subsequent-line pembrolizumab or atezolizumab monotherapy.

DOI: https://doi.org/10.1159/000526964
Semin Cancer Biol. 2022 Sep 09. pii: S1044-579X(22)00198-5. [Epub ahead of print]

Lactate Dehydrogenase and its clinical significance in pancreatic and thoracic cancers.

Annalisa Comandatore, Marika Franczak, Ryszard T Smolenski, Luca Morelli, Godefridus J Peters, Elisa Giovannetti.

  The energy metabolism of tumor cells is considered one of the hallmarks of cancer because it is different from normal cells and mainly consists of aerobic glycolysis, fatty acid oxidation, and glutaminolysis. It is about one hundred years ago since Warburg observed that cancer cells prefer aerobic glycolysis even in normoxic conditions, favoring their high proliferation rate. A pivotal enzyme driving this phenomenon is lactate dehydrogenase (LDH), and this review describes prognostic and therapeutic opportunities associated with this enzyme, focussing on tumors with limited therapeutic strategies and life expectancy (i.e., pancreatic and thoracic cancers). Expression levels of LDH-A in pancreatic cancer tissues correlate with clinicopathological features: LDH-A is overexpressed during pancreatic carcinogenesis and showed significantly higher expression in more aggressive tumors. Similarly, LDH levels are a marker of negative prognosis in patients with both adenocarcinoma or squamous cell lung carcinoma, as well as in malignant pleural mesothelioma. Additionally, serum LDH levels may play a key role in the clinical management of these diseases because they are associated with tissue damage induced by tumor burden. Lastly, we discuss the promising results of strategies targeting LDH as a treatment strategy, reporting recent preclinical and translational studies supporting the use of LDH-inhibitors in combinations with current/novel chemotherapeutics that can synergistically target the oxygenated cells present in the tumor.

Keywords:  Pancreatic cancer Lung cancer; Tumor metabolism; glycolysis; lactate dehydrogenase

DOI:  https://doi.org/10.1016/j.semcancer.2022.09.001
Biomed Res Int. 2022 ;2022 6962056

Development of a Clinical Prognostic Model for Metabolism-Related Genes in Squamous Lung Cancer and Correlation Analysis of Immune Microenvironment.

Zifan Zhuang, Chundi Gao.

Background: The incidence of squamous lung cancer (LUSC) has substantially increased. Systematic studies of metabolic genomic patterns are fundamental for the treatment and prediction of LUSC. Because cancer metabolism and immune cell metabolism have been studied in depth, metabolism and the state and function of immune cells have become key factors in tumor development. This also indicates that metabolic genes and the tumor immune microenvironment (TME) are crucial in tumor treatment. This study is aimed at dissecting the connection between TME and LUSC digestion-related qualities.Methods: The information used in this study was obtained from The Cancer Genome Atlas dataset. Metabolism-related genes in patients with LUSC were screened, and relevant clinical data were collated. Next, genes associated with prognosis were screened using univariate COX regression and LASSO regression analyses. Finally, a timer database study was conducted to analyze the molecular mechanisms of immune cell infiltration of LUSC prognosis-related metabolic genes at the immune cell level.
Results: Nine metabolism-related genes were identified: ADCY7, ALDH3B1, CHIA, CYP2C18, ENTPD6, GGCT, HPRT1, PLA2G1B, and PTGIS. A clinical prediction model for LUSC based on metabolism-related genes was constructed. In addition, 22 subpopulations of tumor-infiltrating immune cells (TIIC) in the TME were analyzed using the CIBERSORT algorithm. Finally, we used the TIMER database to analyze the immune infiltration of LUSC and the relationship between metabolism-related genes and immune cells.
Conclusion: Our study identified metabolic genes associated with the prognosis of LUSC, which are important markers for its diagnosis, clinically relevant assessments, and prognosis. The relationship between metabolic genes with prognostic impact and immune infiltration was also analyzed, and a metabolic gene-based clinical prediction model was identified, providing a new perspective for LUSC treatment.

DOI: https://doi.org/10.1155/2022/6962056