bims-meluca 2022-07-10 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2022–07–10
six 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

Determination of essential biomarkers in lung cancer: a real-world data study in Spain with demographic, clinical, epidemiological and pathological characteristics.
Prognostic assessment of C‑reactive protein and neutrophil to lymphocyte ratio in patients with non-small cell lung cancer.
Metabolism-Related Gene Expression in Circulating Tumor Cells from Patients with Early Stage Non-Small Cell Lung Cancer.
The correlation between PD-L1 expression and metabolic parameters of 18FDG PET/CT and the prognostic value of PD-L1 in non-small cell lung cancer.
Knockdown of NUPR1 Enhances the Sensitivity of Non-small-cell Lung Cancer Cells to Metformin by AKT Inhibition.
Anti-Angiogenic Drugs Inhibit Interstitial Lung Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer.

BMC Cancer. 2022 Jul 05. 22(1): 732

Determination of essential biomarkers in lung cancer: a real-world data study in Spain with demographic, clinical, epidemiological and pathological characteristics.

Mariano Provencio, Manuel Cobo, Delvys Rodriguez-Abreu, Virginia Calvo, Enric Carcereny, Alexandra Cantero, Reyes Bernabé, Gretel Benitez, Rafael López Castro, Bartomeu Massutí, Edel Del Barco, Rosario García Campelo, Maria Guirado, Carlos Camps, Ana Laura Ortega, Jose Luis González Larriba, Alfredo Sánchez, Joaquín Casal, M Angeles Sala, Oscar Juan-Vidal, Joaquim Bosch-Barrera, Juana Oramas, Manuel Dómine, Jose Manuel Trigo, Remei Blanco, Julia Calzas, Idoia Morilla, Airam Padilla, Joao Pimentao, Pedro A Sousa, Maria Torrente.

   BACKGROUND: The survival of patients with lung cancer has substantially increased in the last decade by about 15%. This increase is, basically, due to targeted therapies available for advanced stages and the emergence of immunotherapy itself. This work aims to study the situation of biomarker testing in Spain.
PATIENTS AND METHODS: The Thoracic Tumours Registry (TTR) is an observational, prospective, registry-based study that included patients diagnosed with lung cancer and other thoracic tumours, from September 2016 to 2020. This TTR study was sponsored by the Spanish Lung Cancer Group (GECP) Foundation, an independent, scientific, multidisciplinary oncology society that coordinates more than 550 experts and 182 hospitals across the Spanish territory.
RESULTS: Nine thousand two hundred thirty-nine patients diagnosed with stage IV non-small cell lung cancer (NSCLC) between 2106 and 2020 were analysed. 7,467 (80.8%) were non-squamous and 1,772 (19.2%) were squamous. Tumour marker testing was performed in 85.0% of patients with non-squamous tumours vs 56.3% in those with squamous tumours (p-value < 0.001). The global testing of EGFR, ALK, and ROS1 was 78.9, 64.7, 35.6% respectively, in non-squamous histology. PDL1 was determined globally in the same period (46.9%), although if we focus on the last 3 years it exceeds 85%. There has been a significant increase in the last few years of all determinations and there are even close to 10% of molecular determinations that do not yet have targeted drug approval but will have it in the near future. 4,115 cases had a positive result (44.5%) for either EGFR, ALK, KRAS, BRAF, ROS1, or high PDL1.
CONCLUSIONS: Despite the lack of a national project and standard protocol in Spain that regulates the determination of biomarkers, the situation is similar to other European countries. Given the growing number of different determinations and their high positivity, national strategies are urgently needed to implement next-generation sequencing (NGS) in an integrated and cost-effective way in lung cancer.

Keywords:  Biomarkers; Metastatic lung cancer; Targeted therapies; Testing

DOI:  https://doi.org/10.1186/s12885-022-09830-8
Wien Klin Wochenschr. 2022 Jul 06.

Prognostic assessment of C‑reactive protein and neutrophil to lymphocyte ratio in patients with non-small cell lung cancer.

Tingting Zhao.

   OBJECTIVE: To investigate the prognostic assessment of inflammatory factor serum C‑reactive protein CRP and neutrophil to lymphocyte ratio NLR value in patients with non-small cell lung cancer NSCLC.
METHODS: A retrospective analysis was conducted for 475 patients with NSCLC who visited our hospital with complete follow-up data from January 2017 to 1 January 2019. The changes of serum CRP, NLR levels in patients with NSCLC of different stages, as well as the changes in the levels of the two indexes before and after chemotherapy in patients with advanced stage were compared using t tests with SPSS19.0 software. Serum CRP and NLR were divided into low and high groups with median intercept values and the relationship between inflammation score index and tumor progression-free survival time (PFS) was analyzed retrospectively. Clinical factors that may affect disease prognosis were included in the proportional hazards (COX) regression model for multifactorial prognostic analysis.
RESULTS: Pretreatment serum levels of NLR and CRP were significantly higher in non-operated patients relative to preoperative levels in surgical patients. Advanced patients had higher levels of both indexes than locally advanced patients. After chemotherapy, the levels of the two indexes reaching remission were significantly lower than those before chemotherapy. The levels of the two indexes in patients with stable disease after chemotherapy were not statistically significant compared with those before chemotherapy, and the levels of the two indexes in the group with progressive disease after chemotherapy were significantly higher than those before chemotherapy. The results of PFS survival analyses showed that PFS was prolonged in the low score CRP and the low score NLR group, compared with the high score group. Multifactorial prognostic analysis showed that smoking, CRP and NLR were risk factors for PFS prognosis in patients with NSCLC.
CONCLUSION: Serum CRP and NLR are effective predictors of poor prognosis in patients with NSCLC.

Keywords:  Clinical examination; C‑reactive protein; Neutrophil to lymphocyte ratio; Non-small cell lung cancer; Prognosis assessment; Survival analysis; Valid marker

DOI:  https://doi.org/10.1007/s00508-022-02049-4
Cancers (Basel). 2022 Jun 30. pii: 3237. [Epub ahead of print]14(13):

Metabolism-Related Gene Expression in Circulating Tumor Cells from Patients with Early Stage Non-Small Cell Lung Cancer.

A Zafeiriadou, I Kollias, T Londra, E Tsaroucha, V Georgoulias, A Kotsakis, E Lianidou, A Markou.

   PURPOSE: Metabolic reprogramming is now characterized as one of the core hallmarks of cancer, and it has already been shown that the altered genomic profile of metabolically rewired cancer cells can give valuable information. In this study, we quantified three Metabolism-Related Gene (MRG) transcripts in the circulating tumor cells (CTCs) of early stage NSCLC patients and evaluated their associations with epithelial and EMT markers.
EXPERIMENTAL DESIGN: We first developed and analytically validated highly sensitive RT-qPCR assays for the quantification of HK2, MCT1 and PHGDH transcripts, and further studied the expression of MRGs in CTCs that were isolated using a size-dependent microfluidic device (Parsortix, Angle) from the peripheral blood of: (a) 46 NSCLC patients at baseline, (b) 39/46 of these patients one month after surgery, (c) 10/46 patients at relapse and (d) 10 pairs of cancerous and adjacent non-cancerous FFPE tissues from the same NSCLC patients. Epithelial and EMT markers were also evaluated.
RESULTS: MCT1 and HK2 were differentially expressed between HD and NSCLC patients. An overexpression of MCT1 was detected in 15/46 (32.6%) and 3/10 (30%) patients at baseline and at progression disease (PD), respectively, whereas an overexpression of HK2 was detected in 30.4% and 0% of CTCs in the same group of samples. The expression levels of all tested MRGs decreased in CTCs one month after surgery, but a significant increase was noticed at the time of relapse for PHGDH and MCT1 only. The expression levels of HK2 and MCT1 were associated with the overexpression of mesenchymal markers (TWIST-1 and VIM).
CONCLUSION: An overexpression of MRGs was observed at a high frequency in the CTCs isolated from early NSCLC patients, thereby supporting the role of MRGs in metastatic processes. The glycolytic and mesenchymal subpopulation of CTCs was significantly predominant compared to CTCs that were glycolytic but not mesenchymal-like. Our data indicate that MRGs merit further evaluation through large and well-defined cohort studies.

Keywords:  EMT; Warburg effect; circulating tumor cells; epithelial markers; glycolysis; molecular characterization

DOI:  https://doi.org/10.3390/cancers14133237
Clin Imaging. 2022 Jul 02. pii: S0899-7071(22)00173-5. [Epub ahead of print]89 120-127

The correlation between PD-L1 expression and metabolic parameters of 18FDG PET/CT and the prognostic value of PD-L1 in non-small cell lung cancer.

Xin Xu, Jihui Li, Yi Yang, Shibiao Sang, Shengming Deng.

   OBJECTIVES: In the present study, we aimed to investigate the relationship between metabolic parameters of 18F-fluorodeoxyglucose positron emission computed tomography (18F-FDG PET/CT) and the expression of programmed death ligand-1 (PD-L1), as well as the prognostic value of PD-L1, in patients with surgically resected non-small-cell lung cancer (NSCLC).
MATERIALS AND METHODS: A total of 169 NSCLC patients who received preoperative 18F-FDG PET were retrospectively enrolled in the present study. The correlation between PD-L1 and patient characteristics was evaluated. Based on the expression of PD-L1 and metabolic parameters, patients were classified into low-, medium-, or high-risk groups.
RESULTS: The maximum standardized uptake value (SUVmax) and total lesion glycolysis (TLG) were significantly higher in NSCLC patients with high PD-L1 expression compared with the low expression group (P < 0.001 for all). Multivariate analysis revealed that pleural invasion (P < 0.001) and SUVmax (P < 0.001) were independent predictors of PD-L1 expression. Survival analysis showed that tumor stage (P = 0.004) and pleural invasion (P = 0.007) were independent prognostic indicators of progression-free survival (PFS). Tumor stage (P = 0.001), TLG (P = 0.039), and PD-L1 expression (P = 0.001) were independent prognostic indicators of overall survival (OS). Patients of the high-risk group with high PD-L1 expression and high TLG had a poor prognosis compared with the low-risk group (P < 0.05) and medium-risk group (P < 0.05).
CONCLUSIONS: In NSCLC patients, the SUVmax of 18F-FDG PET/CT was a predictor of PD-L1 expression. The expression of PD-L1 and TLG were independent prognostic factors of OS. The risk stratification standard based on the PD-L1 expression and TLG provided valuable insights into the development of personalized treatment and follow-up.
REGISTRATION NUMBER: ChiCTR2100051554.

Keywords:  (18)F-fluorodeoxyglucose; Non-small-cell lung cancer; Positron emission computed tomography; Prognosis; Programmed death ligand-1

DOI:  https://doi.org/10.1016/j.clinimag.2022.06.016
Anticancer Res. 2022 Jul;42(7): 3475-3481

Knockdown of NUPR1 Enhances the Sensitivity of Non-small-cell Lung Cancer Cells to Metformin by AKT Inhibition.

Yu Jin Kim, Sung-Eun Hong, Se-Kyeong Jang, Ki Soo Park, Chun-Ho Kim, In-Chul Park, Hyeon-Ok Jin.

   BACKGROUND/AIM: Metformin is a widely used drug for type 2 diabetes mellitus and has recently attracted broad attention for its therapeutic effects on many cancers. This study aimed to investigate the molecular mechanism of metformin's anticancer activity.
MATERIALS AND METHODS: Cell viability was measured by MTT assay. Gene and protein expression levels were determined by reverse transcription-polymerase chain reaction and western blot analyses, respectively.
RESULTS: Metformin and phenformin markedly induced NUPR1 expression in a dose- and time-dependent manner in H1299 non-small-cell lung cancer (NSCLC) cells. The silencing of NUPR1 in H1299 NSCLC cells enhanced cell sensitivity to metformin or ionizing radiation. Our previous report showed that metformin induces AKT serine/threonine kinase (AKT) activation in an activating transcription factor 4 (ATF4)-dependent manner and that the inhibition of AKT promotes cell sensitivity to metformin in H1299 NSCLC cells. Interestingly, ATF4-induced AKT activation in H1299 NSCLC cells treated with metformin was suppressed by the knockdown of NUPR1.
CONCLUSION: Targeting NUPR1 could enhance the sensitivity of H1299 NSCLC cells to metformin by AKT inhibition.

Keywords:  AKT; ATF4; Metformin; NUPR1; non-small-cell lung cancer

DOI:  https://doi.org/10.21873/anticanres.15834
Front Oncol. 2022 ;12 873709

Anti-Angiogenic Drugs Inhibit Interstitial Lung Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer.

Yanning Wang, Xiaoling Gong, Yuxuan Hu, Qing Yi, Qianning Zhang, Liyun Miao, Yujie Zhou.

   Background: Interstitial lung disease (ILD) is the most serious complication of chemotherapy in lung cancer patients with pre-existing ILD. The effect of anti-angiogenic drugs in lung cancer patients with ILD remains unclear. We examined the effect of anti-angiogenic drugs on reducing the risk of ILD progression in non-small cell lung cancer (NSCLC) patients receiving chemotherapy.
Methods: We analyzed the risk of ILD progression in 52 patients with advanced NSCLC with ILD who received first-line chemotherapy with (anti-angiogenic group, n = 22) and without (non-anti-angiogenic group, n = 30) anti-angiogenic drugs between August 2014 and January 2021.
Results: The incidences of chemotherapy-related ILD progression were significantly lower in the anti-angiogenic than in the non-anti-angiogenic groups (0% vs. 20.0%, p = 0.033). However, there were no differences in other events as the competing risk factors of ILD progression between the two groups. The overall-cumulative incidence of ILD progression during the first-line and subsequent chemotherapy was 30.8% (16 of the 52). The median progression-free survival had no significant difference between the anti-angiogenic and the non-anti-angiogenic groups (10.3 vs. 8.1 months, p = 0.386).
Conclusions: The addition of anti-angiogenic drugs to chemotherapy regimens may reduce the risk of chemotherapy-related ILD progression in patients with NSCLC-ILD.

Keywords:  acute exacerbation; anti-angiogenic; chemotherapy; interstitial lung disease; non-small cell lung cancer

DOI:  https://doi.org/10.3389/fonc.2022.873709