bims-meluca 2022-03-13 papers

Ann Med. 2022 Dec;54(1): 790-802

Exhaled metabolic markers and relevant dysregulated pathways of lung cancer: a pilot study.

Yingchang Zou, Yanjie Hu, Zaile Jiang, Ying Chen, Yuan Zhou, Zhiyou Wang, Yu Wang, Guobao Jiang, Zhiguang Tan, Fangrong Hu.

INTRODUCTION: The clinical application of lung cancer detection based on breath test is still challenging due to lack of predictive molecular markers in exhaled breath. This study explored potential lung cancer biomarkers and their related pathways using a typical process for metabolomics investigation.
MATERIAL AND METHODS: Breath samples from 60 lung cancer patients and 176 healthy people were analyzed by GC-MS. The original data were GC-MS peak intensity removing background signal. Differential metabolites were selected after univariate statistical analysis and multivariate statistical analysis based on OPLS-DA and Spearman rank correlation analysis. A multivariate PLS-DA model was established based on differential metabolites for pattern recognition. Subsequently, pathway enrichment analysis was performed on differential metabolites.
RESULTS: The discriminant capability was assessed by ROC curve of whom the average AUC and average accuracy in 100-fold cross validations were 0.871 and 0.787, respectively. Eight potential biomarkers were involved in a total of 18 metabolic pathways. Among them, 11 metabolic pathways have p-value smaller than .1.
DISCUSSION: Some pathways among them are related to risk factors or therapies of lung cancer. However, more of them are dysregulated pathways of lung cancer reported in studies based on genome or transcriptome data.
CONCLUSION: We believe that it opens the possibility of using metabolomics methods to analyze data of exhaled breath and promotes involvement of knowledge dataset to cover more volatile metabolites.
CLINICAL SIGNIFICANCE: Although a series of related research reported diagnostic models with highly sensitive and specific prediction, the clinical application of lung cancer detection based on breath test is still challenging due to disease heterogeneity and lack of predictive molecular markers in exhaled breath. This study may promote the clinical application of this technique which is suitable for large-scale screening thanks to its low-cost and non-invasiveness. As a result, the mortality of lung cancer may be decreased in future.Key messagesIn the present study, 11 pathways involving 8 potential biomarkers were discovered to be dysregulated pathways of lung cancer.We found that it is possible to apply metabolomics methods in analysis of data from breath test, which is meaningful to discover convinced volatile markers with definite pathological and histological significance.

Keywords: Exhaled metabolic markers; lung cancer; metabolomics; pathway enrichment; volatile organic compounds

DOI: https://doi.org/10.1080/07853890.2022.2048064

J Chemother. 2022 Mar 09. 1-10

VEGF single nucleotide polymorphisms predict improved outcome in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy.

Huijie Qi, Wenxin Zhang, Yan Wang, Mengxi Ge, Tianxiao Wang, Liudi Zhang, Mingkang Zhong, Xiaojin Shi, Xiaohua Liang, Qiong Zhan, Qunyi Li.

We aimed to investigate the prognostic role of genetic variants of VEGF in advanced NSCLC patients treated with platinum-based chemotherapy. A total of 196 patients with advanced NSCLC treated with first-line platinum-based chemotherapy were enrolled. We evaluated the relationship between VEGF polymorphisms and efficacy outcomes and chemotherapy toxicity. We found that rs699947, rs833061 and rs1005230 were in full linkage disequilibrium. Patients with CC genotype of rs833061 had a significant longer PFS than TT genotype (CC vs TT, HR = 1.67, 95%CI = 1.01-2.76, P = 0.043). Patients harbouring CC genotype had longer PFS compared with CT genotype (P < 0.001). Moreover, CC genotypes conferred a significantly increased PFS compared to CT and TT genotype in dominant model (CC vs CT + TT, HR = 1.95, 95%CI = 1.23-3.10, P = 0.005). Patients carrying TT genotype of rs833061 had improved both ORR (HR = 0.54, 95%CI = 0.30-0.98, P = 0.041) and DCR (HR = 0.37, 95%CI = 0.20-0.66, P = 0.001) than non-TT patients. Furthermore, no association was found between any rs833061 alleles and adverse events (P = 0.425), but patients carrying rs1570360 AA genotype were more likely to experience grade 3-4 toxicities (P = 0.004) (GG vs AA, HR = 3.16, 95%CI = 1.26-7.94, P = 0.015). In conclusion, the variant homozygote CC of rs833061 exhibited a better prognosis based on association analysis. The present study provides reference for the future study of platinum-based chemotherapy response and toxicity.

Keywords: Gene polymorphism; NSCLC; VEGF; chemotherapy toxicity; clinical outcome

DOI: https://doi.org/10.1080/1120009X.2022.2045825

Mol Clin Oncol. 2022 Apr;16(4): 91

Cancer cachexia as a determinant of efficacy of first-line pembrolizumab in patients with advanced non-small cell lung cancer.

Hironori Fujii, Ayumu Araki, Hirotoshi Iihara, Daizo Kaito, Chiemi Hirose, Motohiko Kinomura, Mizuki Yamazaki, Junki Endo, Toshiya Inui, Komei Yanase, Yuka Sasaki, Takenobu Gomyo, Chizuru Sakai, Daisuke Kawae, Yu Kitamura, Masachika Fukui, Ryo Kobayashi, Yasushi Ohno, Akio Suzuki.

Pembrolizumab, either as a type of monotherapy or in combination with cytotoxic anticancer agents, is effective in the treatment of advanced non-small cell lung cancer (NSCLC). However, the development of cancer cachexia may adversely affect anticancer drug therapy. The present study investigated the effect of cancer cachexia on clinical outcomes in patients with advanced NSCLC who received first-line pembrolizumab. The data of patients with advanced NSCLC receiving first-line monotherapy or combination therapy with pembrolizumab were retrospectively analyzed. The primary endpoint was time to treatment failure (TTF), and the secondary endpoints were overall survival (OS) and incidence of adverse events (AEs). Clinical outcome was compared between patients with and without cancer cachexia. A total of 53 patients were analyzed. Among all patients, median TTF and OS were significantly shorter in patients with cancer cachexia than in those without [TTF: 5.8 vs. 10 months; hazard ratio (HR): 2.13; 95% confidence interval (CI): 1.07-4.24; P=0.016; OS: 12.1 months vs. not reached; HR: 5.85; 95% CI: 2.0-17.1; P=0.001]. In addition, TTF in the pembrolizumab monotherapy group was significantly shorter in patients with cancer cachexia than in those without, but no significant difference was detected in patients receiving pembrolizumab combination therapy. The incidence of AEs did not significantly differ between patients with and without cancer cachexia, except with regard to hypothyroidism. In conclusion, although cancer cachexia is prognostic of a poor outcome in patients with advanced NSCLC who receive first-line pembrolizumab, cancer cachexia might not affect therapeutic efficacy in combination therapy with pembrolizumab and cytotoxic anticancer agents.

Keywords: advanced non-small cell lung cancer; cancer cachexia; overall survival; pembrolizumab; time to treatment failure

DOI: https://doi.org/10.3892/mco.2022.2524

Anticancer Drugs. 2022 Mar 08.

Inhibiting nonhomologous end-joining repair would promote the antitumor activity of gemcitabine in nonsmall cell lung cancer cell lines.

Nannan Guo, Shaojun Li, Bo Liu, Ping Chen, Jingbo Li, Yunlong Zhao, Yingnan Zhao, Jian Tang, Wen Zhang.

Nonsmall cell lung cancer (NSCLC) is a major type of lung cancer. In current study, we aim to evaluate whether the combination of Ku70/80 heterodimer protein inhibitor STL127705 and gemcitabine would be more favorable approach for the treatment of NSCLC compared with monotreatment with gemcitabine. Clongenic survival assay was used to determine the survival and sensitivity to irradiation. H1299 was stained with fluorescein isothiocyanate-Annexin V, and cell apoptosis was measured by flow cytometry. H1299 cells were transfected with nonhomologous end-joining (NHEJ) repair reporter, and stable cell line was selected by puromycin. NHEJ activity was determined based on the intensity of green fluorescent protein. DNA double-strand breaks (DSBs) were determined by the fluorescence intensity of γH2AX using flow cytometry. The mRNA expressions of Ku70 and Ku80 were determined using quantitative real-time PCR. Combination of STL127705 enhanced sensitivity of NSCLC cell lines to irradiation when compared with treatment with gemcitabine alone. However, small cell lung cancer cell line was not affected. H1299 cells treated with STL127705 in combination with gemcitabine showed a significantly increased apoptosis compared with H1299 cells treated with gemcitabine alone. Moreover, STL127705 treatment dramatically reduced NHEJ activity in H1299 cells when compared with gemcitabine single treatment. Increased DSBs were consistently observed in H1299 when treated with the combination of STL127705 and gemcitabine. However, the mRNA levels of Ku70 and Ku80 were upregulated by the combination treatment. It demonstrated that STL127705 enhanced antitumor activity of gemcitabine. Mechanistically, treatment with STL127705 enhanced DNA damage via inhibiting NHEJ pathway, blocking DNA-PK, and forming Ku70/80 heterodimer, eventually leading to tumor cells apoptosis.

DOI: https://doi.org/10.1097/CAD.0000000000001290

Biomed Chromatogr. 2022 Mar 10. e5367

Metabolomics analysis reveals Oct4 overexpression drives metabolic reprogramming and enhanced glycolysis and pentose phosphate pathway in lung adenocarcinoma cells.

Yabin Tang, Liang Zhu, Hongzhuan Chen, Shuang Meng.

Poor prognosis in the underlying mechanisms involved in lung adenocarcinoma and its treatment leads to low survival rates in patients. Emerging evidence indicates that cancer is primarily a metabolic disease and metabolic reprogramming is a well-established hallmark and driving force of cancer. Oct4, acting as an oncogene, is a major regulator of cell pluripotency. It can reprogram the differentiated cells into cancer stem cells (CSCs) and plays an oncogenic role when pathologically hijacked. However, data that Oct4, the genetic reprogramming factor, could induce metabolic reprogramming has been very limited and the direct evidence in metabolic level whether Oct4 reprograms metabolome is lacking. In the present study, integrated untargeted and targeted metabolomics analyses were utilized to investigate metabolic changes induced by Oct4 overexpression in lung adenocarcinoma cells. The results suggested that elevated expression levels of Oct4 drives metabolic reprogramming. Oct4 overexpression redirects glucose catabolism to glycolysis pathway and to the oxidative pentose phosphate pathway (PPP). This study identifies unique pathways that are candidate therapeutic targets for the treatment of lung adenocarcinoma. This study also aims to improve our understanding of the cancer-promoting activity of Oct4 and help identify novel diagnostic and therapeutic strategies for cancer treatment.

Keywords: Oct4; lung adenocarcinoma; metabolic reprogramming; metabolomics

DOI: https://doi.org/10.1002/bmc.5367