scholarly journals Lung Cancer Management with Silibinin: A Historical and Translational Perspective

2021 ◽  
Vol 14 (6) ◽  
pp. 559
Author(s):  
Sara Verdura ◽  
Elisabet Cuyàs ◽  
Verónica Ruiz-Torres ◽  
Vicente Micol ◽  
Jorge Joven ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Selective Vulnerability ◽  
Lung Tumors ◽  
Human Lung Cancer ◽  
Cancer Subtypes ◽  
Cancer Management ◽  
Primary Lung Tumors ◽  
Hexosamine Biosynthesis ◽  
Historical Developments

The flavonolignan silibinin, the major bioactive component of the silymarin extract of Silybum marianum (milk thistle) seeds, is gaining traction as a novel anti-cancer therapeutic. Here, we review the historical developments that have laid the groundwork for the evaluation of silibinin as a chemopreventive and therapeutic agent in human lung cancer, including translational insights into its mechanism of action to control the aggressive behavior of lung carcinoma subtypes prone to metastasis. First, we summarize the evidence from chemically induced primary lung tumors supporting a role for silibinin in lung cancer prevention. Second, we reassess the preclinical and clinical evidence on the effectiveness of silibinin against drug resistance and brain metastasis traits of lung carcinomas. Third, we revisit the transcription factor STAT3 as a central tumor-cell intrinsic and microenvironmental target of silibinin in primary lung tumors and brain metastasis. Finally, by unraveling the selective vulnerability of silibinin-treated tumor cells to drugs using CRISPR-based chemosensitivity screenings (e.g., the hexosamine biosynthesis pathway inhibitor azaserine), we illustrate how the therapeutic use of silibinin against targetable weaknesses might be capitalized in specific lung cancer subtypes (e.g., KRAS/STK11 co-mutant tumors). Forthcoming studies should take up the challenge of developing silibinin and/or next-generation silibinin derivatives as novel lung cancer-preventive and therapeutic biomolecules.

scholarly journals A Pathway-Based Strategy to Identify Biomarkers for Lung Cancer Diagnosis and Prognosis

2019 ◽  
Vol 15 ◽  
pp. 117693431983849 ◽  
Author(s):  
Mengying Sheng ◽  
Xueying Xie ◽  
Jun Wang ◽  
Wanjun Gu
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Cancer Diagnosis ◽  
Large Scale ◽  
Gene Signature ◽  
Multiple Sources ◽  
Cancer Subtypes ◽  
Cancer Management ◽  
Lung Cancer Diagnosis ◽  
Gene Expression Signatures

Current research has identified several potential biomarkers for lung cancer diagnosis or prognosis. However, most of these biomarkers are derived from a relatively small number of samples using algorithms at the gene level. Hence, gene expression signatures discovered in these studies have little overlaps. In this study, we proposed a new strategy to identify biomarkers from multiple datasets at the pathway level. We integrated the genome-wide expression data of lung cancer tissues from 13 published studies and applied our strategy to identify lung cancer diagnostic and prognostic biomarkers. We identified a 32-gene signature that differentiates lung adenocarcinomas from other lung cancer subtypes. We also discovered a 43-gene signature that can predict the outcome of human lung cancers. We tested their performance in several independent cohorts, which confirmed their robust prognostic and diagnostic power. Furthermore, we showed that the proposed gene expression signatures were independent of several traditional clinical indicators in lung cancer management. Our results suggest that the pathway-based strategy is useful to identify transcriptomic biomarkers from large-scale gene expression datasets that were collected from multiple sources.

scholarly journals Identification of Genetic Mutations in Human Lung Cancer by Targeted Sequencing

2015 ◽  
Vol 14 ◽  
pp. CIN.S22941 ◽  
Author(s):  
Hongxiang Feng ◽  
Xiaowei Wang ◽  
Zhenrong Zhang ◽  
Chuanning Tang ◽  
Hua Ye ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Human Lung ◽  
Chinese Patients ◽  
Human Lung Cancer ◽  
Genetic Mutations ◽  
Ion Torrent ◽  
Cancer Subtypes ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Frequent Mutations

Lung cancer remains the most prevalent malignancy and the primary cause of cancer-related deaths worldwide. Unique mutations patterns can be found in lung cancer subtypes, in individual cancers, or within a single tumor, and drugs that target these genetic mutations and signal transduction pathways are often beneficial to patients. In this study, we used the Ion Torrent AmpliSeq Cancer Panel to sequence 737 loci from 45 cancer-related genes and oncogenes to identify genetic mutations in 48 formalin-fixed, paraffin-embedded (FFPE) human lung cancer samples from Chinese patients. We found frequent mutations in EGFR, KRAS, PIK3CA, and TP53 genes. Moreover, we observed that a portion of the lung cancer samples harbored two or more mutations in these key genes. This study demonstrates the feasibility of using the Ion Torrent sequencing to efficiently identify genetic mutations in individual tumors for targeted lung cancer therapy.

scholarly journals Common and Contrasting Genomic Profiles among the Major Human Lung Cancer Subtypes

2005 ◽  
Vol 70 (0) ◽  
pp. 11-24 ◽  
Author(s):  
G. TONON ◽  
C. BRENNAN ◽  
A. PROTOPOPOV ◽  
G. MAULIK ◽  
B. FENG ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Human Lung ◽  
Human Lung Cancer ◽  
Cancer Subtypes

Functional profile and clinical significance of major tumor infiltrating lymphocyte subsets in lung cancer-associated brain metastases.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2066-2066
Author(s):  
Benjamin Y. Lu ◽  
Richa Gupta ◽  
Tyler Stewart ◽  
Harriet M. Kluger ◽  
Lucia Jilaveanu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Granzyme B ◽  
Lung Tumors ◽  
Small Cell ◽  
T Cell Subsets ◽  
Functional Profile ◽  
Ki 67 ◽  
Primary Lung Tumors

2066 Background: Despite the biological and clinical implications, the immune composition and functional characteristics of adaptive immune cells in brain metastases (BrM) are poorly understood. Using multiplexed quantitative immunofluorescence (QIF), this study evaluates the level and functional profile of major T-cell subsets in primary lung tumors, BrM, and extracranial metastases (ECM) from lung cancers. Methods: A tissue microarray was constructed from formalin-fixed, paraffin-embedded tumor samples of 94 lung cancer patients treated at Yale Cancer Center between 2002-2013. Multiplexed QIF was used to evaluate the cases with a panel containing phenotype markers for major T-cell subsets (CD3, CD4, CD8 and FOXP3), and cell-localized activation and proliferation (granzyme-B and Ki-67). Signal for each marker was measured in marker-selected tissue compartments using the Automated Quantitative Analysis (AQUA) platform. Associations between markers and major clinicopathologic variables were studied. Results: In total, 40 primary lung tumors, 63 BrM, and 15 ECM were analyzed, including paired samples from 22 patients. Lung cancer histology included adenocarcinoma 62.5%, squamous cell carcinoma 11.5%, small cell 9.4%, and other non-small cell 16.7%. BrM had both significantly lower levels of CD3+ T-cells ( p< 0.0001) and T-cell granzyme B ( p= 0.0188) compared with primary lung tumors. No significant differences were observed in T-cell Ki-67 levels across tissues. FOXP3 measured in CD4+ T-cells were significantly lower in BrM compared with primary malignancies ( p= 0.0002) and ECM ( p= 0.0404). Among patients with BrM, higher levels of CD3+ T-cells in BrM were associated with longer overall survival. Conclusions: Lung cancer-associated BrM have lower T-cell infiltration, cytolytic function, and regulatory T-cells than primary lesions. These results indicate lower adaptive anti-tumor responses in BrM and suggest the presence of a tolerogenic microenvironment in the brain. Overcoming this could be used to design optimal treatment strategies.

scholarly journals The novel rexinoid MSU-42011 is effective for the treatment of preclinical Kras-driven lung cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jessica A. Moerland ◽  
Di Zhang ◽  
Lyndsey A. Reich ◽  
Sarah Carapellucci ◽  
Beth Lockwood ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Regulatory Element ◽  
Single Agent ◽  
Lung Tumors ◽  
Human Lung Cancer ◽  
Driver Mutations ◽  
Proliferating Cells ◽  
Activation Markers

AbstractEffective drugs are needed for lung cancer, as this disease remains the leading cause of cancer-related deaths. Rexinoids are promising drug candidates for cancer therapy because of their ability to modulate genes involved in inflammation, cell proliferation or differentiation, and apoptosis through activation of the retinoid X receptor (RXR). The only currently FDA-approved rexinoid, bexarotene, is ineffective as a single agent for treating epithelial cancers and induces hypertriglyceridemia. Here, we used a previously validated screening paradigm to evaluate 23 novel rexinoids for biomarkers related to efficacy and safety. These biomarkers include suppression of inducible nitric oxide synthase (iNOS) and induction of sterol regulatory element-binding protein (SREBP). Because of its potent iNOS suppression, low SREBP induction, and activation of RXR, MSU-42011 was selected as our lead compound. We next used MSU-42011 to treat established tumors in a clinically relevant Kras-driven mouse model of lung cancer. KRAS is one of the most common driver mutations in human lung cancer and correlates with aggressive disease progression and poor patient prognosis. Ultrasound imaging was used to detect and monitor tumor development and growth over time in the lungs of the A/J mice. MSU-42011 markedly decreased the tumor number, size, and histopathology of lung tumors compared to the control and bexarotene groups. Histological sections of lung tumors in mice treated with MSU-42011 exhibited reduced cell density and fewer actively proliferating cells compared to the control and bexarotene-treated tumors. Although bexarotene significantly (p < 0.01) elevated plasma triglycerides and cholesterol, treatment with MSU-42011 did not increase these biomarkers, demonstrating a more favorable toxicity profile in vivo. The combination of MSU-42011 and carboplatin and paclitaxel reduced macrophages in the lung and increased activation markers of CD8+T cells compared to the control groups. Our results validate our screening paradigm for in vitro testing of novel rexinoids and demonstrate the potential for MSU-42011 to be developed for the treatment of KRAS-driven lung cancer.

scholarly journals MALDI Profiling of Human Lung Cancer Subtypes

PLoS ONE ◽  
2009 ◽  
Vol 4 (11) ◽  
pp. e7731 ◽  
Author(s):  
Angelo Gámez-Pozo ◽  
Iker Sánchez-Navarro ◽  
Manuel Nistal ◽  
Enrique Calvo ◽  
Rosario Madero ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Human Lung ◽  
Human Lung Cancer ◽  
Cancer Subtypes

Comparison of immune microenvironment between primary lung tumors and paired brain metastatic tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2020-2020
Author(s):  
Likun Chen ◽  
Lihong Wu ◽  
Meichen Li ◽  
Huan Chen ◽  
Lijia Wu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cell ◽  
Brain Metastases ◽  
Poor Prognosis ◽  
Cd8 T Cell ◽  
Lung Tumors ◽  
Immune Gene ◽  
Immune Microenvironment ◽  
Primary Lung Tumors ◽  
Tumor Immune Microenvironment

2020 Background: Lung cancer is one of the most common causes of brain metastases (BMs) and is always associated with poor prognosis. To evaluate the characteristics of the tumor immune microenvironment in brain metastases of non-small-cell lung cancer (NSCLC), we investigated the immunophenotype of primary NSCLC and paired brain metastases. Methods: Forty-three Chinese patients with NSCLC who had BMs at presentation or during the course of their disease were admitted to the Sun Yat-Sen University Cancer Center (Guangzhou, China) from 2000 to 2019. RNA sequencing (RNA-seq) of eighty-six formalin-fixed, paraffin embedded (FFPE) samples from primary lung tumors and paired brain metastases of 43 patients was conducted to comprehensively analyze the tumor immune microenvironment. Results: Our data revealed that brain metastases compared with primary lung tumors exhibited reduced tumor infiltrating lymphocytes (TILs) (all 28 immune cell subtypes P < 0.05), lower fraction of activated CD8 T cell and effector memory CD8 T cell in total TILs (P = 0.028, P < 0.001, respectively); higher fraction of macrophage and neutrophil in total TILs (P < 0.001, P < 0.01, respectively). Comparing with the primary lung tumors, the scores of some immune related signatures, including MHC non-class signature, IFN gamma signature and T-cell-inflamed gene-expression profile (GEP) signature, were significantly lower in brain metastases (P = 0.004, P = 0.009, P = 0.004, respectively), while the score of MHC class-II signature was higher in brain metastases (P = 0.045). We found the distributions of tumor microenvironment immune types (TMIT) in brain metastases and primary lung tumors were different. Brain metastases contained significantly lower proportion of TMIT I (high PD-L1/ high CD8A) (23%) than primary lung tumors (47%) (P < 0.05). Besides, we found three immune inhibitory checkpoint molecules, namely C10orf54 (VISTA), CTLA4 and CD274 (PD-L1) were downregulated in brain metastases than in primary lung tumors (P < 0.001, P < 0.001, P = 0.034, respectively). Moreover, there was poor correlation of PD-L1 expression between paired brain metastases and primary lung tumors (R = 0.28, P = 0.068). Unsupervised hierarchic cluster analysis revealed the primary lung tumors had two distinct patterns of immune gene signatures, namely Cluster A and Cluster B, and the tumors in Cluster B were immune rich, but associated with poor prognosis (log-rank P = 0.021). Conclusions: Our work illustrates the immune landscape of brain metastases from NSCLC, and suggests that the tumor immune microenvironment in brain metastases compared with primary lung tumors is further immunosuppressed, that may help guide immunotherapeutic strategies for NSCLC brain metastases.

scholarly journals Correlation between Imaging Features and Pathological Stages of Primary Lung Tumors Based on Nanocontrast Agents

2021 ◽  
Vol 2021 ◽  
pp. 1-5
Author(s):  
Jin Li ◽  
Qian Xu ◽  
Cunhua Mao ◽  
Yuliang Liu
Keyword(s):  
Lung Cancer ◽  
Contrast Agents ◽  
Adverse Reactions ◽  
Lung Tumors ◽  
Ct Imaging ◽  
Ct Scans ◽  
Imaging Features ◽  
Display Time ◽  
Imaging Characteristics ◽  
Primary Lung Tumors

As one of the conventional methods of lung cancer detection, computed tomography (CT) usually requires the use of contrast agents to enhance the imaging effect. Conventional iodine contrast agents have poor signal-to-noise ratio and are prone to adverse reactions. It is necessary to find more effective and safe contrast agents for CT scans. The gold nanoparticles with secondary electron effect and photoelectric absorption effect can prolong the display time of the patient’s blood circulation after being injected into the patient’s body, which makes the nanocontrast agent a research hotspot in the field of CT imaging. In this study, ultrasmall gold nanoclusters with a diameter of about 5 nm were used as the contrast agent in CT scans. It was found that CT scans based on nanocontrast agents can obtain high-quality lung cancer imaging images, and the patient has no obvious adverse reactions. When observing the CT image, it was found that the stage of lung cancer patients can be clearly distinguished through the CT scan image. When analyzing the consistency of CT imaging and pathological classification, the Kappa value was 0.810, indicating that the two have a high degree of consistency. Therefore, this study believes that the imaging characteristics of primary lung tumors based on nanocontrast agents are highly correlated with their pathological types.

Eradication of experimental brain metastases of human non-small cell lung cancer by macitentan, a dual antagonist of the endothelin A and B receptor, combined with paclitaxel.

2012 ◽  
Vol 30 (30_suppl) ◽  
pp. 92-92
Author(s):  
Masaki Hanibuchi ◽  
Sun-Jin Kim ◽  
Kenji Otsuka ◽  
Sho Tabata ◽  
Takuya Kuramoto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Biological Effects ◽  
Small Cell ◽  
Human Lung Cancer ◽  
Small Cell Lung ◽  
Endothelin A

92 Background: Treatment of patients with lung cancer brain metastases remains a major challenge because of the limited availability of standard therapy. Thus, the development of successful treatment options for these patients is mandatory. Recently, the endothelin axis was reported to be involved in cancer progression through its pleiotropic biological effects on cell survival, proliferation, invasion, and metastasis. Methods: In this study, we evaluated both the in vitro and in vivoeffects of macitentan, an orally bioavailable, dual endothelin A receptor and endothelin B receptor antagonist, as monotherapy, and in combination with paclitaxel. Results: In human non-small cell lung cancer PC-14 cells, macitentan treatment inhibited cell proliferation, corresponding with inhibition of Akt and p42/44 mitogen-activated protein kinase phosphorylation, and increased apoptosis. The combination of macitentan and paclitaxel resulted in the potentiation of all of these effects, suggesting that macitentan could enhance sensitivity to paclitaxel. Moreover, macitentan completely abrogated astrocyte-mediated protection of tumor cells against paclitaxel. In an experimental brain metastasis model of human lung cancer, the combination of macitentan and paclitaxel significantly inhibited the growth of brain metastasis and produced a striking survival prolongation of tumor-bearing mice. Conclusions: The endothelin A and B receptor blockade by macitentan could be a promising therapeutic strategy for brain metastases of non-small cell lung cancer.

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