bims-meluca 2020-12-13 papers

Lung Cancer. 2020 Nov 19. pii: S0169-5002(20)30686-3. [Epub ahead of print]151 8-15

Randomized phase II study of platinum-based chemotherapy plus controlled diet with or without metformin in patients with advanced non-small cell lung cancer.

Youngjoo Lee, Jungnam Joo, You Jin Lee, Eun Kyung Lee, Sohyun Park, Tae-Sung Kim, Soo-Hyun Lee, So Young Kim, Gyung-Ah Wie, Minjoung Park, Mi-Jung Kim, Jin Soo Lee, Ji-Youn Han.

OBJECTIVES: Accumulating evidence indicates anti-diabetic drug metformin has anti-cancer effect by controlling cancer metabolism. We evaluated whether addition of metformin to chemotherapy improved survival of lung cancer patients.
MATERIALS AND METHODS: This randomized phase II study enrolled 164 patients with chemo-native, EGFR-ALK wild-type, stage IIIB/IV non-small-cell lung cancer (NSCLC). Patients were randomized to receive chemotherapy either with metformin (1000 mg twice daily) or alone every 3 weeks for six cycles. The patients received gemcitabine (1000 mg/m2) on days 1 and 8 and carboplatin (5 area under the curve) on day 1. Exploratory studies included serum metabolic panels, positron-emission tomography (PET) imaging, and genetic mutation tests for metabolism-related genes.
RESULTS: Metformin group showed no significant difference in the risk of progression and death compared to control group (progression: hazard ratio [HR] = 1.01 [95% confidence interval (CI) = 0.72 - 1.42], P = 0.935; death: HR = 0.95 [95% CI = 0.67-1.34], P = 0.757). Squamous cell carcinoma (SqCC) had significantly higher fluorodeoxyglucose (FDG) uptake on baseline PET image than non-SqCC NSCLC (P = 0.004). In the SqCC with high FDG uptake, the addition of metformin significantly decreased the risk of progression and death (progression: HR = 0.31 [95% CI = 0.12-0.78], P = 0.013; death: HR = 0.42 [95% CI = 0.18-0.94], P = 0.035). The HDL-cholesterol level was significantly increased after the treatment in metformin group compared to control group (P = 0.011). The metformin group showed no survival benefit in the patients with hyperinsulinemia or patients whose insulin level was decreased after treatment.
CONCLUSIONS: Addition of metformin to chemotherapy provided no survival benefit in unselected NSCLC patients. However, it significantly improved the survival of the selected patients with SqCC showing high FDG uptake. It suggests metformin shows the synergistic anti-tumor effect in the tumor which are highly dependent on glucose metabolism.

Keywords: Cancer metabolism; Fluorodeoxyglucose uptake; Lung cancer; Metformin; Squamous cell carcinoma

DOI: https://doi.org/10.1016/j.lungcan.2020.11.011

Front Oncol. 2020 ;10 559543

HPV 16 E6/E7 Promote the Glucose Uptake of GLUT1 in Lung Cancer Through Downregulation of TXNIP Due to Inhibition of PTEN Phosphorylation.

Jia-Yi Tang, Dong-Yu Li, Ling He, Xue-Shan Qiu, En-Hua Wang, Guang-Ping Wu.

High-risk human papillomavirus (HPV) infection play an important role in the development of lung cancer. Our previously study showed that E6 and E7 in HPV16 upregulated the expression of GLUT1 in lung cancer cells. However, whether they can promote the glucose uptake by GLUT1 and the underlying molecular mechanism has not been identified. It has been reported that thioredoxin interacting protein (TXNIP) regulates both the expression of GLUT1 and its glucose uptake. We speculate that high risk HPV16 infection may be closely related to TXNIP expression. Therefore, we associate HPV16 with TXNIP to explore the potential molecular mechanism of their regulation of GLUT1 expression and glucose uptake. Using double directional genetic manipulation in lung cancer cells, we showed that HPV16 E6/E7 proteins downregulated the expression of p-PTEN in lung cancer cells, the knockdown of PTEN further inhibited the expression of TXNIP, the inhibition of TXNIP further promoted the accumulation of HIF-1α by inhibiting the translocation of nuclear HIF-1α to the cytoplasm, and subsequently upregulated the expression of GLUT1 at the protein and mRNA levels. More interestingly, we found that the knockdown of TXNIP played a decisive role to promote the glucose uptake by GLUT1. Together, these findings suggested that the PTEN-TXNIP-HIF-1α axis might be related to the E6/E7-mediated expression of GLUT1 and its glucose uptake.

Keywords: glucose transporter 1; glucose uptake; human papillomavirus; lung cancer; thioredoxin interacting protein

DOI: https://doi.org/10.3389/fonc.2020.559543

J Thorac Oncol. 2020 Dec 08. pii: S1556-0864(20)31089-3. [Epub ahead of print]

Clinical implications of KEAP1-NFE2L2 mutations in non-small cell lung cancer.

Jessica A Hellyer, Sukhmani K Padda, Maximilian Diehn, Heather A Wakelee.

The KEAP1-NFE2L2 pathway is an important modulator of cell homeostasis. Mutations in this pathway are common in non-small cell lung cancer (NSCLC) and have been associated with enhanced tumor growth and aggressiveness. In addition, tumors with mutations in the KEAP1-NFE2L2 pathway have been shown in pre-clinical and clinical studies to convey refractoriness to cancer-directed therapy such as radiation, chemotherapy and targeted therapy. The role of immunotherapy in this patient population is less clear and there are conflicting studies on the efficacy of immune checkpoint inhibitors in KEAP1-NFE2L2 mutant NSCLC. Here we review the current clinical evidence on several classes of anti-cancer therapeutics in KEAP1 -NFE2L2 mutant tumors. We also provide an overview of the landscape of the current clinical trials in this patient population, highlighting work being done with mTORC1/2 and glutaminase inhibition.

Keywords: KEAP1-NFE2L2; chemotherapy; clinical trials; glutaminase; immunotherapy; mTORC1/2; targeted therapy

DOI: https://doi.org/10.1016/j.jtho.2020.11.015

Clin Lung Cancer. 2020 Oct 21. pii: S1525-7304(20)30310-7. [Epub ahead of print]

Nutritional Support in Lung Cancer Patients: The State of the Art.

Maria Cristina Mele, Emanuele Rinninella, Marco Cintoni, Gabriele Pulcini, Agnese Di Donato, Futura Grassi, Ilaria Trestini, Carmelo Pozzo, Giampaolo Tortora, Antonio Gasbarrini, Emilio Bria.

Lung cancer (LC) represents the most commonly diagnosed neoplasm worldwide for both sexes and is the leading cause of cancer mortality. Malnutrition is a comorbidity frequently found in neoplastic patients, but it remains often underestimated and thus undertreated. In this review, we aimed to investigate the incidence of malnutrition among LC patients according to different screening and assessment tools, to evaluate the impact of weight loss and body composition on survival, and to analyze the efficacy of different nutritional interventions in this setting. Although malnutrition, weight loss, and body composition changes can affect survival and other clinical outcomes in LC patients, the role of nutritional interventions is not yet strongly proven, and further studies are recommended. Nevertheless, screening, assessing, and eventually treating malnutrition in LC patients are strongly recommended, according to the most recent nutritional intervention guidelines for oncology patients.

Keywords: Body composition; CT scan; Clinical nutrition; Malnutrition; Muscle mass; Personalized nutrition

DOI: https://doi.org/10.1016/j.cllc.2020.10.008

Cancer Cell Int. 2020 Dec 09. 20(1): 590

Prediction of the VeriStrat test in first-line therapy of pemetrexed-based regimens for advanced lung adenocarcinoma patients.

BACKGROUND: Although advanced non-squamous non-small cell lung cancer (NSCLC) patients have significantly better survival outcomes after pemetrexed based treatment, a subset of patients still show intrinsic resistance and progress rapidly. Therefore we aimed to use a blood-based protein signature (VeriStrat, VS) to analyze whether VS could identify the subset of patients who had poor efficacy on pemetrexed therapy.
METHODS: This study retrospectively analysed 72 advanced lung adenocarcinoma patients who received first-line pemetrexed/platinum or combined with bevacizumab treatment.
RESULTS: Plasma samples from these patients were analysed using VS and classified into the Good (VS-G) or Poor (VS-P) group. The relationship between efficacy and VS status was further investigated. Of the 72 patients included in this study, 35 (48.6%) were treated with pemetrexed plus platinum and 37 (51.4%) were treated with pemetrexed/platinum combined with bevacizumab. Among all patients, 60 (83.3%) and 12 (16.7%) patients were classified as VS-G and VS-P, respectively. VS-G patients had significantly better median progression-free survival (PFS) (Unreached vs. 4.2 months; P < 0.001) than VS-P patients. In addition, the partial response (PR) rate was higher in the VS-G group than that in the VS-P group (46.7% vs. 25.0%, P = 0.212). Subgroup analysis showed that PFS was also significantly longer in the VS-G group than that in the VS-P group regardless of whether patients received chemotherapy alone or chemotherapy plus bevacizumab.
CONCLUSIONS: Our study indicated that VS might be considered as a novel and valid method to predict the efficacy of pemetrexed-based therapy and identify a subset of advanced lung adenocarcinoma patients who had intrinsic resistance to pemetrexed based regimens. However, larger sample studies are still needed to further confirm this result.

Keywords: Lung adenocarcinoma; Pemetrexed; Prognosis; Treatment; VeriStrat

DOI: https://doi.org/10.1186/s12935-020-01662-5

Diabetol Metab Syndr. 2020 Oct 28. 12(1): 95

Metabolic syndrome and the incidence of lung cancer: a meta-analysis of cohort studies.

Li Qiao, Deliang Ma, Hui Lv, Ding Shi, Min Fei, Yu Chen, Fei Xie, Zhuoyan Wang, Ying Wang, Wanhua Liang, Peiying Hu.

BACKGROUND: Metabolic syndrome (MetS) has been related to the pathogenesis of variety categories of cancers. This meta-analysis aimed to determine the association between MetS and the incidence of lung cancer.
METHODS: Relevant cohort studies were identified by search of PubMed, Embase, and Cochrane's Library databases. Cochrane's Q test and I2 statistic were used to analyze the heterogeneity. Random-effect model which incorporates the potential heterogeneity was used for the meta-analysis.
RESULTS: Five cohort studies with 188,970 participants were included. A total of 1,295 lung cancer cases occurred during follow-up. Meta-analyses showed that neither MetS defined by the revised NCEP-ATP III criteria (hazard ratio [HR]: 0.94, 95% confidence interval [CI]: 0.84 to 1.05, p = 0.25; I2 = 0) nor the IDF criteria (HR: 0.82, 95% CI: 0.61 to 1.11, p = 0.20; I2 = 0) was associated with an affected risk of lung cancer. Subgroup analyses showed consistent results in women and in men, in studies performed in Asian and non-Asian countries, and in prospective and retrospective cohorts (p all > 0.05). Meta-analysis limited to studies with the adjustment of smoking status also showed similar results (HR: 0.91, 95% CI: 0.80 to 1.05, p = 0.21; I2 = 0). No publication bias was detected based on the Egger regression test (p = 0.32).
CONCLUSIONS: Current evidence from cohort studies does not support that MetS is an independent risk factor for the incidence of lung cancer.

Keywords: Cohort study; Lung cancer; Meta-analysis; Metabolic syndrome

DOI: https://doi.org/10.1186/s13098-020-00598-0