bims-meluca 2020-05-03 papers

Future Oncol. 2020 May 01.

Analysis of differential metabolites in lung cancer patients based on metabolomics and bioinformatics.

Chenchen Zhao, Xianbin Kong, Shuang Han, Xiaojiang Li, Tong Wu, Jie Zhou, Yuzhu Guo, Zhichao Bu, Chuanxin Liu, Chenning Zhang, Yingjie Jia.

Aim: Based on metabonomics, the metabolic markers of lung cancer patients were analyzed, combined with bioinformatics to explore the underlying disease mechanism. Materials & methods: Based on case-control design, using UPLC-Q-TOF/MS, urine metabolites were detected in discovery and validation set. Multivariate statistical analysis were performed to identify potential markers for lung cancer. A network analysis was constructed to integrate lung cancer disease targets with the above metabolic markers, and its possible mechanism and biological significance were explained. Results: A total of 35 potential markers were identified, 11 of which overlapped. Five key markers have a good linear correlation with serum biochemical indicators. Conclusion: The occurrence and development of lung cancer are closely related to disturbance of D-Glutamine and D-glutamate metabolism, amino acid imbalance. This test was registered on China clinical trial registration center (www.chictr.org.cn/index.aspx), registration number was ChiCTR1900025543.

Keywords: ROC curve; UPLC-Q-TOF/HRMSE; bioinformatics; case–control design; clinical metabolomics; lung cancer; metabolic markers; qualitative analysis; spearman correlation; urine

DOI: https://doi.org/10.2217/fon-2019-0818

Lung Cancer Manag. 2020 Apr 24. 9(2): LMT31

Pretreatment nutritional status and response to checkpoint inhibitors in lung cancer.

Chung-Shien Lee, Craig E Devoe, Xinhua Zhu, Joanna Stein Fishbein, Nagashree Seetharamu.

Background: Checkpoint inhibitors are integral to non-small-cell lung cancer treatment. Existing data suggests that nutritional status may play a role in antitumor immunity.
Materials & methods: This retrospective study of 106 non-small-cell lung cancer patients who started checkpoint inhibitors between 2014 and 2017 at our institution assessed relationship of nutritional parameters to overall survival (OS) and progression-free survival.
Results: Mean age was 68.7 ± 9.2 years and 59.4% patients were male. On multivariate analysis for OS, hypoalbuminemia and significant weight loss were prognostic at p-values of 0.0005 and 0.0052, respectively. We noted a parabolic association between age and OS (p = 0.026, 0.0025).
Conclusion: In our study, some malnutrition parameters were associated with decreased OS. U-shape relationship between age and OS noted here warrants further evaluation.

Keywords: immunotherapy; malnutrition; non-small-cell lung cancer

DOI: https://doi.org/10.2217/lmt-2020-0008

Cancer Immunol Immunother. 2020 Apr 29.

Peripheral blood markers predictive of outcome and immune-related adverse events in advanced non-small cell lung cancer treated with PD-1 inhibitors.

Lihong Peng, Yong Wang, Fen Liu, Xiaotong Qiu, Xinwei Zhang, Chen Fang, Xiaoyin Qian, Yong Li.

BACKGROUND: Selected patients with advanced non-small cell lung cancer (NSCLC) benefit from immunotherapy, especially immune checkpoint inhibitors such as PD-1 (programmed cell death protein 1) inhibitor. Peripheral blood biomarkers would be most convenient to predict treatment outcome and immune-related adverse events (irAEs) in candidate patients. This study explored associations between inflammation-related peripheral blood markers and onset of irAEs and outcome in patients with advanced NSCLC receiving PD-1 inhibitors.
METHODS: A retrospective analysis was conducted of 102 patients with advanced NSCLC receiving PD-1 inhibitors from January 2017 to May 2019. Cox regression models were employed to assess the prognostic effect of low/high neutrophil/lymphocyte ratio (NLR), lactate dehydrogenase (LDH), and prognostic nutrition index (PNI) on overall survival (OS) and progression-free survival (PFS). Logistic regression models were used to analyze the correlation between peripheral blood markers and the onset of irAEs.
RESULT: NLR < 5, LDH < 240 U/L, or PNI ≥ 45 was favorably associated with significantly better outcomes compared with higher, higher, or lower values, respectively. The multivariate analysis determined that these parameters were independently associated with both better PFS (p = 0.049, 0.046, 0.014, respectively) and longer OS (p = 0.007, 0.031, < 0.001, respectively). Patients with three favorable factors among NLR, LDH, and PNI had better PFS and OS than did those with two, one, or none. PNI and NLR were associated with the onset of irAEs.
CONCLUSION: In patients with advanced NSCLC treated with PD-1 inhibitors, pretreatment NLR, LDH, and PNI may be useful predictive markers of clinical outcome and irAEs.

Keywords: Immune-related adverse events; Immunotherapy; Lactate dehydrogenase; Lung cancer; Neutrophil-to-lymphocyte ratio; Prognostic nutrition index

DOI: https://doi.org/10.1007/s00262-020-02585-w

Cell Rep. 2020 Apr 28. pii: S2211-1247(20)30517-9. [Epub ahead of print]31(4): 107568

Inhibition of Tumor VEGFR2 Induces Serine 897 EphA2-Dependent Tumor Cell Invasion and Metastasis in NSCLC.

Anti-angiogenic treatment targeting vascular endothelial growth factor (VEGF)-VEGFR2 signaling has shown limited efficacy in lung cancer patients. Here, we demonstrate that inhibition of VEGFR2 in tumor cells, expressed in ∼20% of non-squamous non-small cell lung cancer (NSCLC) patients, leads to a pro-invasive phenotype. Drug-induced inhibition of tumor VEGFR2 interferes with the formation of the EphA2/VEGFR2 heterocomplex, thereby allowing RSK to interact with Serine 897 of EphA2. Inhibition of RSK decreases phosphorylation of Serine 897 EphA2. Selective genetic modeling of Serine 897 of EphA2 or inhibition of EphA2 abrogates the formation of metastases in vivo upon VEGFR2 inhibition. In summary, these findings demonstrate that VEGFR2-targeted therapy conditions VEGFR2-positive NSCLC to Serine 897 EphA2-dependent aggressive tumor growth and metastasis. These data shed light on the molecular mechanisms explaining the limited efficacy of VEGFR2-targeted anti-angiogenic treatment in lung cancer patients.

Keywords: NSCLC; RSK; S897 EphA2; VEGFR2 inhibition; tumor cell invasion

DOI: https://doi.org/10.1016/j.celrep.2020.107568

Radiat Res. 2020 Apr 30.

Effects of Hypoxia and Radiation-Induced Exosomes on Migration of Lung Cancer Cells and Angiogenesis of Umbilical Vein Endothelial Cells.

Fang Mo, Yanwu Xu, Junling Zhang, Lin Zhu, Chen Wang, Xiaofei Chu, Yan Pan, Yang Bai, Chunlin Shao, Jianghong Zhang.

Numerous studies have shown that exosomes play important roles in tumor biology development. However, the function of exosomal protein in cancer progression under different oxygen condition after irradiation is poorly understood. In this study, non-small cell lung cancer (NSCLC) A549 cells were γ-ray irradiated under normoxic or hypoxic conditions, then the exosomes released from the irradiated cells were collected and co-cultured with nonirradiated A549 cells or human umbilical vein endothelial cells (HUVECs). It was found that the exosomes significantly promoted the proliferation, migration and invasion of A549 cells as well as the proliferation and angiogenesis of HUVECs. Moreover, the exosomes released from hypoxic cells and/or irradiated cells had more powerful driving force in tumor progression compared to that generated from normoxia cells. Meanwhile, the proteins contained in the exosomes derived from A549 cells under different conditions were detected using tandem mass tag (TMT), and their expression profiles were analyzed. It was found that the exosome-derived protein of angiopoietin-like 4 (ANGPTL4) contributed to the migration of A549 cells as well as the angiogenesis of HUVECs, suggesting its potential as an effective diagnostic biomarker of metastasis and even a therapeutic target of lung cancer.

DOI: https://doi.org/10.1667/RR15555.1

Lung Cancer Manag. 2020 Feb 25. 9(2): LMT26

Status of correlation between BMI and response to immunocheck-point inhibitor in advanced non-small-cell lung cancer.

Alain Gelibter, Mario Occhipinti, Simona Pisegna, Alessio Cortellini, Enrico Cortesi, Paolo Marchetti.

Keywords: BMI; NSCLC; PD-1; cancer; immune checkpoint inhibitors; immune system; immunotherapy; obesity; prognostic clinical marker

DOI: https://doi.org/10.2217/lmt-2019-0016