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Huang HY, Chen CH, Cheng FJ, Wang BW, Tu CY, Chen YJ, He YH, Yao CH, Huang WC. Incense-burning smoke ingredient Auramine enhances lincRNA-p21 expression for chemosensitization in p53-mutated non-small cell lung cancer. JOURNAL OF HAZARDOUS MATERIALS 2024; 477:135105. [PMID: 39047551 DOI: 10.1016/j.jhazmat.2024.135105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 06/21/2024] [Accepted: 07/03/2024] [Indexed: 07/27/2024]
Abstract
Incense-burning smoke is a deleterious air pollutant that initiates cytotoxic effects by inducing apoptosis in lung epithelial cells and also acts as a risk factor for lung cancers. Auramine, an ingredient of incense smoke, has been implicated in tumor progression and cellular sensitivity in non-small cell lung cancer (NSCLC) towards anti-cancer agents through unclear mechanisms. Tumor protein p53 (TP53)-activated long intergenic non-coding RNA-p21 (lincRNA-p21) undertakes a pivotal role in regulating cell apoptosis and chemosensitivity. TP53 mutations prevalent in 50% of NSCLC, contribute to diminished therapeutic efficacy. However, the influence of auramine on chemotherapy-induced lincRNA-p21 expression and apoptosis in NSCLC with different TP53 genetic statuses remains unexplored. This study disclosed that both wild-type p53 (wtp53) and mutant p53 (mutp53) mediate lincRNA-p21 expression, albeit through distinct promoter enhancers, p53-response element (p53RE) and non-B DNA structure G-quadruplex (GQ), respectively. Intriguingly, auramine functions as an effective stabilizer of the GQ structure, augmenting mutp53-mediated lincRNA-p21 expression and enhancing apoptosis and cellular sensitivity to chemotherapy in mutp53-expressing NSCLC cells. These findings suggest a mechanism by which mutp53, in the presence of auramine, is endowed with tumor-suppressing function akin to wtp53, thereby aiding in combating chemoresistance in NSCLC cells harboring TP53 mutations.
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Affiliation(s)
- Hsuan-Yu Huang
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Chia-Hung Chen
- School of Medicine, China Medical University, Taichung 404, Taiwan; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; Department of Respiratory Therapy, China Medical University, Taichung 404, Taiwan
| | - Fang-Ju Cheng
- School of Medicine, China Medical University, Taichung 404, Taiwan; Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan
| | - Bo-Wei Wang
- Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan
| | - Chih-Yen Tu
- School of Medicine, China Medical University, Taichung 404, Taiwan; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; Department of Respiratory Therapy, China Medical University, Taichung 404, Taiwan
| | - Yun-Ju Chen
- School of Medicine for International Students, I-Shou University, Kaohsiung 824, Taiwan; Department of Medical Research, E-Da Hospital, Kaohsiung 824, Taiwan
| | - Yu-Hao He
- Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan; Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung 404, Taiwan.
| | - Chun-Hsu Yao
- Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung 404, Taiwan; Biomaterials Translational Research Center, China Medical University Hospital, Taichung 404, Taiwan; Department of Bioinformatics and Medical Engineering, Asia University, Taichung 413, Taiwan.
| | - Wei-Chien Huang
- Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan; Drug Development Center, China Medical University, Taichung 404, Taiwan; Department of Medical Research, China Medical University Hsinchu Hospital, Hsinchu 302, Taiwan; Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung 413, Taiwan.
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Xiong F, Shen Y, Liu T, Zhang Y, Jiang X. Osimerinib haematological toxicities in non-small cell lung cancer: a randomised controlled trials meta-analysis. BMJ Support Palliat Care 2024:spcare-2024-005113. [PMID: 39159992 DOI: 10.1136/spcare-2024-005113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 08/05/2024] [Indexed: 08/21/2024]
Abstract
OBJECTIVE Osimertinib plays a crucial role in patients with non-small cell lung cancer (NSCLC). However, the haematological toxicities caused by osimertinib in such a population have not been well characterised. This analysis was performed to determine the incidence of osimertinib-related haematological toxicity in patients with NSCLC. METHOD A literature search was conducted in PubMed, Embase, Cochrane Library and Web of Science. Eligible studies were included to describe the pooled incidences of anaemia, neutropenia and thrombocytopenia secondary to osimertinib in NSCLC patients. RESULTS 1288 patients from 10 studies were enrolled in this study. The overall incidences of osimertinib-related all-grade anaemia, neutropenia and thrombocytopenia in NSCLC patients were 21.1% (95% CI 10.9% to 33.3%), 14.6% (95% CI 5.9% to 26.1%) and 28.4% (95% CI 12.4% to 47.6%), respectively. In items of high-grade haematological toxicities, there were 0.5% (95% CI 0.1% to 1.1%) for anaemia, 2.0% (95% CI 0.3% to 4.6%) for neutropenia and 0.4% (95% CI 0% to 1.1%) for thrombocytopenia. CONCLUSIONS There is non-negligible haematological toxicity associated with osimertinib, and it should be taken seriously.
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Affiliation(s)
- Fangfang Xiong
- Department of Pharmacy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Yunzhu Shen
- Department of Pharmacy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Ting Liu
- Department of Pharmacy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Yin Zhang
- Department of Pharmacy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Xuehui Jiang
- Department of Pharmacy, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, China
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Pal Choudhuri S, Girard L, Lim JYS, Wise JF, Freitas B, Yang D, Wong E, Hamilton S, Chien VD, Kim YJ, Gilbreath C, Zhong J, Phat S, Myers DT, Christensen CL, Mazloom-Farsibaf H, Stanzione M, Wong KK, Hung YP, Farago AF, Meador CB, Dyson NJ, Lawrence MS, Wu S, Drapkin BJ. Acquired Cross-Resistance in Small Cell Lung Cancer due to Extrachromosomal DNA Amplification of MYC Paralogs. Cancer Discov 2024; 14:804-827. [PMID: 38386926 PMCID: PMC11061613 DOI: 10.1158/2159-8290.cd-23-0656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 12/15/2023] [Accepted: 02/20/2024] [Indexed: 02/24/2024]
Abstract
Small cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. This transformation is nearly inevitable in patients but has been difficult to capture in laboratory models. Here, we present a preclinical system that recapitulates acquired cross-resistance, developed from 51 patient-derived xenograft (PDX) models. Each model was tested in vivo against three clinical regimens: cisplatin plus etoposide, olaparib plus temozolomide, and topotecan. These drug-response profiles captured hallmark clinical features of SCLC, such as the emergence of treatment-refractory disease after early relapse. For one patient, serial PDX models revealed that cross-resistance was acquired through MYC amplification on extrachromosomal DNA (ecDNA). Genomic and transcriptional profiles of the full PDX panel revealed that MYC paralog amplifications on ecDNAs were recurrent in relapsed cross-resistant SCLC, and this was corroborated in tumor biopsies from relapsed patients. We conclude that ecDNAs with MYC paralogs are recurrent drivers of cross-resistance in SCLC. SIGNIFICANCE SCLC is initially chemosensitive, but acquired cross-resistance renders this disease refractory to further treatment and ultimately fatal. The genomic drivers of this transformation are unknown. We use a population of PDX models to discover that amplifications of MYC paralogs on ecDNA are recurrent drivers of acquired cross-resistance in SCLC. This article is featured in Selected Articles from This Issue, p. 695.
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Affiliation(s)
- Shreoshi Pal Choudhuri
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Luc Girard
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jun Yi Stanley Lim
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jillian F. Wise
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts
| | - Braeden Freitas
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Di Yang
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Edmond Wong
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts
| | - Seth Hamilton
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Victor D. Chien
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Yoon Jung Kim
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Collin Gilbreath
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jun Zhong
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts
| | - Sarah Phat
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts
| | - David T. Myers
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts
| | | | - Hanieh Mazloom-Farsibaf
- Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Marcello Stanzione
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts
| | - Kwok-Kin Wong
- Perlmutter Cancer Center, NYU Langone Health, New York, New York
| | - Yin P. Hung
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Anna F. Farago
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts
| | - Catherine B. Meador
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts
| | - Nicholas J. Dyson
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts
| | - Michael S. Lawrence
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts
| | - Sihan Wu
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Benjamin J. Drapkin
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
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Najafiyan B, Bokaii Hosseini Z, Esmaelian S, Firuzpour F, Rahimipour Anaraki S, Kalantari L, Hheidari A, Mesgari H, Nabi-Afjadi M. Unveiling the potential effects of resveratrol in lung cancer treatment: Mechanisms and nanoparticle-based drug delivery strategies. Biomed Pharmacother 2024; 172:116207. [PMID: 38295754 DOI: 10.1016/j.biopha.2024.116207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Revised: 01/17/2024] [Accepted: 01/22/2024] [Indexed: 03/03/2024] Open
Abstract
Lung cancer ranks among the most prevalent forms of cancer and remains a significant factor in cancer-related mortality across the world. It poses significant challenges to healthcare systems and society as a whole due to its high incidence, mortality rates, and late-stage diagnosis. Resveratrol (RV), a natural compound found in various plants, has shown potential as a nanomedicine for lung cancer treatment. RV has varied effects on cancer cells, including promoting apoptosis by increasing pro-apoptotic proteins (Bax and Bak) and decreasing anti-apoptotic proteins (Bcl-2). It also hinders cell proliferation by influencing important signaling pathways (MAPK, mTOR, PI3K/Akt, and Wnt/β-catenin) that govern cancer progression. In addition, RV acts as a potent antioxidant, diminishing oxidative stress and safeguarding cells against DNA damage. However, using RV alone in cancer treatment has drawbacks, such as low bioavailability, lack of targeting ability, and susceptibility to degradation. In contrast, nanoparticle-based delivery systems address these limitations and hold promise for improving treatment outcomes in lung cancer; nanoparticle formulations of RV offer advantages such as improved drug delivery, increased stability, controlled release, and targeted delivery to lung cancer cells. This article will provide an overview of lung cancer, explore the potential of RV as a therapeutic agent, discuss the benefits and challenges of nanoparticle-based drug delivery, and highlight the promise of RV nanoparticles for cancer treatment, including lung cancer. By optimizing these systems for clinical application, future studies aim to enhance overall treatment outcomes and improve the prognosis for lung cancer patients.
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Affiliation(s)
- Behnam Najafiyan
- Faculty of Pharmacy, Shiraz University of Medical Science, Shiraz, Iran
| | | | - Samar Esmaelian
- Faculty of Dentistry, Islamic Azad University, Tehran Branch, Tehran, Iran
| | - Faezeh Firuzpour
- Student of Research Committee, Babol University of Medical Sciences, Babol, Iran
| | | | - Leila Kalantari
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Ali Hheidari
- Department of Mechanical Engineering, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Hassan Mesgari
- Oral and Maxillofacial Surgery Department, Faculty of Dentistry, Islamic Azad University, Tehran Branch, Tehran, Iran.
| | - Mohsen Nabi-Afjadi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
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Gentili N, Balzi W, Foca F, Danesi V, Altini M, Delmonte A, Bronte G, Crinò L, De Luigi N, Mariotti M, Verlicchi A, Burgio MA, Roncadori A, Burke T, Massa I. Healthcare Costs and Resource Utilisation of Italian Metastatic Non-Small Cell Lung Cancer Patients. Cancers (Basel) 2024; 16:592. [PMID: 38339345 PMCID: PMC10854909 DOI: 10.3390/cancers16030592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 01/12/2024] [Accepted: 01/26/2024] [Indexed: 02/12/2024] Open
Abstract
This study evaluated the economic burden of metastatic non-small cell lung cancer patients before and after the availability of an immuno-oncology (IO) regimen as a first-line (1L) treatment. Patients from 2014 to 2020 were categorized according to mutational status into mutation-positive and negative/unknown groups, which were further divided into pre-1L IO and post-1L IO sub-groups depending on the availability of pembrolizumab monotherapy in 1L. Healthcare costs and HCRU for a 1L treatment and overall follow-up were reported as the mean total and per-month cost per patient by groups. Of 644 patients, 125were mutation-positive and 519 negative/unknown (229 and 290 in pre- and post-1L IO, respectively). The mean total per-patient cost in 1L was lower in pre- (EUR 7804) and post-1L IO (EUR 19,301) than the mutation-positive group (EUR 45,247), persisting throughout overall disease follow-up. However, this difference was less when analyzing monthly costs. Therapy costs were the primary driver in 1L, while hospitalization costs rose during follow-up. In both mutation-positive and post-IO 1L groups, the 1L costs represented a significant portion (70.1% and 66.3%, respectively) of the total costs in the overall follow-up. Pembrolizumab introduction increased expenses but improved survival. Higher hospitalisation and emergency room occupation rates during follow-up reflected worsening clinical conditions of the negative/unknown group than the mutation-positive population.
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Affiliation(s)
- Nicola Gentili
- Outcome Research, Healthcare Administration, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (N.G.); (V.D.); (A.R.); (I.M.)
| | - William Balzi
- Outcome Research, Healthcare Administration, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (N.G.); (V.D.); (A.R.); (I.M.)
| | - Flavia Foca
- Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy;
| | - Valentina Danesi
- Outcome Research, Healthcare Administration, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (N.G.); (V.D.); (A.R.); (I.M.)
| | - Mattia Altini
- Healthcare Administration, Azienda Unità Sanitaria Locale della Romagna, 48121 Ravenna, Italy;
| | - Angelo Delmonte
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (A.D.); (G.B.); (L.C.); (M.M.); (A.V.); (M.A.B.)
| | - Giuseppe Bronte
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (A.D.); (G.B.); (L.C.); (M.M.); (A.V.); (M.A.B.)
| | - Lucio Crinò
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (A.D.); (G.B.); (L.C.); (M.M.); (A.V.); (M.A.B.)
| | - Nicoletta De Luigi
- Ospedale di Stato della Repubblica di San Marino, 47893 San Marino City, San Marino;
| | - Marita Mariotti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (A.D.); (G.B.); (L.C.); (M.M.); (A.V.); (M.A.B.)
| | - Alberto Verlicchi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (A.D.); (G.B.); (L.C.); (M.M.); (A.V.); (M.A.B.)
| | - Marco Angelo Burgio
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (A.D.); (G.B.); (L.C.); (M.M.); (A.V.); (M.A.B.)
| | - Andrea Roncadori
- Outcome Research, Healthcare Administration, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (N.G.); (V.D.); (A.R.); (I.M.)
| | - Thomas Burke
- MSD Innovation & Development GmbH, 8004 Zurich, Switzerland
| | - Ilaria Massa
- Outcome Research, Healthcare Administration, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (N.G.); (V.D.); (A.R.); (I.M.)
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García-Fumero R, Fernández-López C, Calleja-Hernández MÁ, Expósito-Ruiz M, Espín J, Expósito-Hernández J. Clinical Outcomes of First-line Therapies for Advanced Non-Small Cell Lung Cancer: A Systematic Review of Trials Published Between 2010 and 2020. Am J Clin Oncol 2023; 46:433-438. [PMID: 37522643 DOI: 10.1097/coc.0000000000001031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/01/2023]
Abstract
OBJECTIVES To analyze the evolution of clinical outcomes derived from clinical trials on first-line therapies for advanced or metastatic non-small cell lung cancer (NSCLC) published between 2010 and 2020, focusing on how these outcomes impact survival rates and management of patients. METHODS A systematic review of phase III and pivotal phase II clinical trials was conducted by a structured search on Medline and Embase. A comprehensive set of variables was collected to assess their influence on survival rates. We also estimated the clinical benefit by applying the ESMO-MCBS v1.1 and extracted the authors' conclusions. RESULTS Sixty-six studies involving 34,951 patients were included. Best survival outcomes were found for nonsquamous non-small cell lung cancer (OS and progression-free survival medians: 19.4 and 10.2 mo) and for those expressing molecular targets (OS and progression-free survival medians: 23.8 and 11.0 mo). No significant influence on survival rates was observed for industry funding and disease stage (IIIB/IV vs. IV). ESMO-MCBS v1.1 was applied in 45 positive studies and resulted in a meaningful clinical benefit score in 37.8%. Quality of life (QoL) was reported in 57.6% of the original publications and showed statistical significance favoring the experimental arm in 33.3%. Positive authors' conclusions (75.7% of trials) were based on OS and/or QoL in 34% and on surrogate endpoints in 66%. CONCLUSIONS Extended survival times and a steady improvement in QoL have been observed. However, there were more than twice as many studies reporting positive authors' conclusions as studies meeting the ESMO threshold for meaningful clinical benefit.
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Affiliation(s)
| | | | | | | | - Jaime Espín
- Andalusian School of Public Health/Escuela Andaluza de Salud Pública (EASP), Granada
- CIBER of Epidemiology and Public Health (CIBERESP), Spain
- Instituto de Investigación Biosanitaria ibs
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7
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Choudhuri SP, Girard L, Lim JYS, Wise JF, Freitas B, Yang D, Wong E, Hamilton S, Chien VD, Gilbreath C, Zhong J, Phat S, Myers DT, Christensen CL, Stanzione M, Wong KK, Farago AF, Meador CB, Dyson NJ, Lawrence MS, Wu S, Drapkin BJ. Acquired Cross-resistance in Small Cell Lung Cancer due to Extrachromosomal DNA Amplification of MYC paralogs. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.23.546278. [PMID: 37425738 PMCID: PMC10327110 DOI: 10.1101/2023.06.23.546278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/11/2023]
Abstract
Small cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. This transformation is nearly inevitable in patients but has been difficult to capture in laboratory models. Here we present a pre-clinical system that recapitulates acquired cross-resistance in SCLC, developed from 51 patient-derived xenografts (PDXs). Each model was tested for in vivo sensitivity to three clinical regimens: cisplatin plus etoposide, olaparib plus temozolomide, and topotecan. These functional profiles captured hallmark clinical features, such as the emergence of treatment-refractory disease after early relapse. Serially derived PDX models from the same patient revealed that cross-resistance was acquired through a MYC amplification on extrachromosomal DNA (ecDNA). Genomic and transcriptional profiles of the full PDX panel revealed that this was not unique to one patient, as MYC paralog amplifications on ecDNAs were recurrent among cross-resistant models derived from patients after relapse. We conclude that ecDNAs with MYC paralogs are recurrent drivers of cross-resistance in SCLC. SIGNIFICANCE SCLC is initially chemosensitive, but acquired cross-resistance renders this disease refractory to further treatment and ultimately fatal. The genomic drivers of this transformation are unknown. We use a population of PDX models to discover that amplifications of MYC paralogs on ecDNA are recurrent drivers of acquired cross-resistance in SCLC.
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8
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Motafeghi F, Mortazavi P, Ghassemi-Barghi N, Zahedi M, Shokrzadeh M. Dexamethasone as an anti-cancer or hepatotoxic. Toxicol Mech Methods 2023; 33:161-171. [PMID: 35866224 DOI: 10.1080/15376516.2022.2105183] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The linkage between inflammation and oxidative stress in liver damage has been proven and is undeniable; dexamethasone with some antioxidants can reduce the toxicity of liver tissue. Due to the importance of cancer treatment, glucocorticoids' synergistic effect in inhibiting cancer cell growth is also investigated. Dexamethasone alone and combined with etoposide were tested at concentrations of 1, 5, and 10 μM to evaluate the potency of dexamethasone in inhibiting the growth of A549 cells using oxidative stress factors and DNA damage. Also, intraperitoneal injection of dexamethasone in rats was used to induce liver toxicity. Coenzyme Q10 at different concentrations (1, 10, and 50 mg/kg) was used as an antioxidant to assess the oxidative stress factors and measure Caspase-3 activity. The results showed that dexamethasone combined with etoposide could significantly inhibit the growth of cancer cells and induce apoptosis. Treatment of A549 cells using dexamethasone also inhibits cancer cells' growth by inducing oxidative stress and DNA damage. Dexamethasone also, by inducing oxidative stress and activation of caspase 3, ultimately causes hepatotoxicity. Treatment with different concentrations of CoQ10 showed improved mitochondrial function, antioxidant defense, and liver enzyme. The best effect of coenzyme Q10 on dexamethasone-induced hepatotoxicity is 50 mg/kg. As a result, dexamethasone (alone and combined with etoposide) has an anti-cancer effect by damaging DNA and inducing oxidative stress. Also, CoQ10 has antioxidant effects against dexamethasone-induced hepatotoxicity by improving mitochondrial function and reducing caspase-3 activity.
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Affiliation(s)
- Farzaneh Motafeghi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Parham Mortazavi
- Department of Pharmacology and Toxicology, Student Research Committee, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Nasrin Ghassemi-Barghi
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Zahedi
- Department of Medical Biotechnology, School of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran.,Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Shokrzadeh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
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9
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Liu D, Benzaquen J, Morris LGT, Ilié M, Hofman P. Mutations in KMT2C, BCOR and KDM5C Predict Response to Immune Checkpoint Blockade Therapy in Non-Small Cell Lung Cancer. Cancers (Basel) 2022; 14:cancers14112816. [PMID: 35681795 PMCID: PMC9179442 DOI: 10.3390/cancers14112816] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/24/2022] [Accepted: 06/01/2022] [Indexed: 12/22/2022] Open
Abstract
Simple Summary Efficient biomarkers are urgently needed to predict response to immune checkpoint blockade (ICB) therapy for non-small cell lung cancer (NSCLC), particularly NSCLC with low tumor mutational burden (TMB). Here, we show that mutations of three chromatin remodeling-related genes, including KMT2C, BCOR and KDM5C, are associated with the ICB response in NSCLC, including NSCLC with low TMB level. Furthermore, this association is further improved by a combined use of KMT2C/BCOR/KDM5C mutations with TMB or PD-L1 expression. These data suggest that KMT2C/BCOR/KDM5C mutation status has the potential to serve as a predictive biomarker for ICB therapy in NSCLC. Abstract Efficient predictive biomarkers are urgently needed to identify non-small cell lung cancer (NSCLC) patients who could benefit from immune checkpoint blockade (ICB) therapy. Since chromatin remodeling is required for DNA repair process, we asked whether mutations in chromatin remodeling genes could increase tumor mutational burden (TMB) and predict response to ICB therapy in NSCLC. Analysis of seven ICB-treated NSCLC cohorts revealed that mutations of three chromatin remodeling-related genes, including KMT2C, BCOR and KDM5C, were significantly associated with ICB response, and combined mutations of these three genes further enhance this association. NSCLC patients with KMT2C/BCOR/KDM5C mutations had comparable clinical outcomes to TMB-high patients in terms of objective response rate, durable clinical benefit and overall survival. Although KMT2C/BCOR/KDM5C mutations were positively correlated with TMB levels in NSCLC, the association of this mutation with better ICB response was independent of tumor TMB and programmed death-ligand 1 (PD-L1) level, and combination of KMT2C/BCOR/KDM5C mutations with TMB or PD-L1 further improve the prediction of ICB response in NSCLC patients. Cancer Genome Atlas (TCGA) pan-cancer analysis suggested that the association of KMT2C/BCOR/KDM5C mutations with ICB response observed here might not result from DNA repair defects. In conclusion, our data indicate that KMT2C/BCOR/KDM5C mutation has the potential to serve as a predictive biomarker, alone or combined with PD-L1 expression or TMB, for ICB therapy in NSCLC.
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Affiliation(s)
- Dingxie Liu
- Bluewater Biotech LLC, New Providence, NJ 07974, USA
- Correspondence: (D.L.); (P.H.)
| | - Jonathan Benzaquen
- Department of Pneumology, Pasteur Hospital, FHU OncoAge, 06000 Nice, France; (J.B.); (M.I.)
| | - Luc G. T. Morris
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
| | - Marius Ilié
- Department of Pneumology, Pasteur Hospital, FHU OncoAge, 06000 Nice, France; (J.B.); (M.I.)
| | - Paul Hofman
- Laboratory of Clinical and Experimental Pathology, CHU Nice, FHU OncoAge, University Côte d’Azur, 06100 Nice, France
- Team 4, IRCAN, UMR 7284/U10181, FHU OncoAge, University Côte d’Azur, 06107 Nice, France
- Hospital-Integrated Biobank (BB-0033-00025), CHU of Nice, FHU OncoAge, University Côte d’Azur, 06100 Nice, France
- Correspondence: (D.L.); (P.H.)
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Kumar N, Mandal CC. Cholesterol-Lowering Drugs on Akt Signaling for Prevention of Tumorigenesis. Front Genet 2021; 12:724149. [PMID: 34603386 PMCID: PMC8483559 DOI: 10.3389/fgene.2021.724149] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 08/23/2021] [Indexed: 12/12/2022] Open
Abstract
Cholesterol has been reported to be accumulated in cancer cells. The metabolic dysregulation of the cholesterol is associated with tumor development and progression. The cholesterol-lowering drugs have been found to be involved in the prevention and treatment of various cancers. Akt, a serine/threonine kinase, can modulate the role of several downstream proteins involved in cell proliferation, migration, invasion, metabolism, and apoptosis. Since its involvement in several signaling pathways, its dysregulation is commonly reported in several cancers. Thus, targeting Akt could be an effective approach for cancer prevention and therapy. Cholesterol-lowering drugs have been found to affect the expression of Akt, and its activation in the cancer cells and thus have shown anticancer activity in different type of cancers. These drugs act on various signaling pathways such as PTEN/Akt, PI3k/Akt, Akt/NF-κB, Akt/FOXO1, Akt/mTOR, etc., which will be discussed in this article. This review article will discuss the significance of cholesterol in cancer cells, cholesterol-lowering drugs, the role of Akt in cancer cells, and the effects of cholesterol-lowering drugs on Akt in the prevention of therapy resistance and metastasis.
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Affiliation(s)
- Navneet Kumar
- Department of Biochemistry, All India Institute of Medical Sciences, Bhopal, India
| | - Chandi C Mandal
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, India
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11
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Preliminary Report on Computed Tomography Radiomics Features as Biomarkers to Immunotherapy Selection in Lung Adenocarcinoma Patients. Cancers (Basel) 2021; 13:cancers13163992. [PMID: 34439148 PMCID: PMC8393664 DOI: 10.3390/cancers13163992] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/03/2021] [Accepted: 08/04/2021] [Indexed: 12/29/2022] Open
Abstract
PURPOSE To assess the efficacy of radiomics features obtained by computed tomography (CT) examination as biomarkers in order to select patients with lung adenocarcinoma who would benefit from immunotherapy. METHODS Seventy-four patients (median age 63 years, range 42-86 years) with histologically confirmed lung cancer who underwent immunotherapy as first- or second-line therapy and who had baseline CT studies were enrolled in this approved retrospective study. As a control group, we selected 50 patients (median age 66 years, range 36-86 years) from 2005 to 2013 with histologically confirmed lung adenocarcinoma who underwent chemotherapy alone or in combination with targeted therapy. A total of 573 radiomic metrics were extracted: 14 features based on Hounsfield unit values specific for lung CT images; 66 first-order profile features based on intensity values; 43 second-order profile features based on lesion shape; 393 third-order profile features; and 57 features with higher-order profiles. Univariate and multivariate statistical analysis with pattern recognition approaches and the least absolute shrinkage and selection operator (LASSO) method were used to assess the capability of extracted radiomics features to predict overall survival (OS) and progression free survival (PFS) time. RESULTS A total of 38 patients (median age 61; range 41-78 years) with confirmed lung adenocarcinoma and subjected to immunotherapy satisfied inclusion criteria, and 50 patients in a control group were included in the analysis The shift in the center of mass of the lesion due to image intensity was significant both to predict OS in patients subjected to immunotherapy and to predict PFS in patients subjected to immunotherapy and in patients in the control group. With univariate analysis, low diagnostic accuracy was reached to stratify patients based on OS and PFS time. Regarding multivariate analysis, considering the robust (two morphological features, three textural features and three higher-order statistical metrics) application of the LASSO approach and all patients, a support vector machine reached the best results for stratifying patients based on OS (area under curve (AUC) of 0.89 and accuracy of 81.6%). Alternatively, considering the robust predictors (six textural features and one higher-order statistical metric) and application of the LASSO approach including all patients, a decision tree reached the best results for stratifying patients based on PFS time (AUC of 0.96 and accuracy of 94.7%). CONCLUSIONS Specific radiomic features could be used to select patients with lung adenocarcinoma who would benefit from immunotherapy because a subset of imaging radiomic features useful to predict OS or PFS time were different between the control group and the immunotherapy group.
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12
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Pereira I, Gaspar C, Pina M, Azevedo I, Rodrigues A. Real-World T790M Mutation Frequency and Impact of Rebiopsy in Patients With EGFR-Mutated Advanced Non-Small Cell Lung Cancer. Cureus 2020; 12:e12128. [PMID: 33489541 PMCID: PMC7810175 DOI: 10.7759/cureus.12128] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Introduction The T790M resistance mutation is present in about one-half of epidermal growth factor receptor (EGFR)-positive advanced non-small cell lung cancer (NSCLC) patients at disease progression. We aimed to assess the prevalence of this mutation in a real-world setting and the clinical impact of repeated biopsies in its detection. Methods This was a single-center retrospective cohort study of patients with EGFR-positive advanced NSCLC diagnosed between 2016 and 2018, who experienced radiographic disease progression during first-line treatment with first- or second-generation EGFR-tyrosine kinase inhibitor (TKI). The frequency of T790M detection and the number of rebiopsies were determined. Results A total of 88 patients were included, with a median age of 65 years (range: 38-84 years). The majority of the participants were females (63 (72%)) and non-smokers (70 (81%)). Upon disease progression, 80 (91%) patients were tested for T790M mutation, and the resistance mutation was detected in 57 (71%) cases (58% in plasma samples and 42% in tissue/cytology samples). In 14 (25%) cases, T790M mutation was only detected after rebiopsy (57% by liquid biopsy), which increased the rate of mutation detection in 17%. Subsequent treatment with third-generation EGFR-TKI was possible in 42 (74%) of T790M-positive cases. Detection of T790M mutation was more likely in patients who were less than 65 years old, with EGFR exon 19 deletions and duration of first-line treatment of more than 12 months (p < 0.05). Conclusions The frequency of T790M mutation in this study was higher than previously reported, suggesting that repeated biopsies after a negative result are beneficial. This allowed a greater percentage of patients to receive sequential osimertinib in our clinical practice.
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Affiliation(s)
- Isabel Pereira
- Medical Oncology, Instituto Português de Oncologia do Porto Francisco Gentil, EPE, Porto, PRT
| | - Cátia Gaspar
- Medical Oncology, Instituto Português de Oncologia do Porto Francisco Gentil, EPE, Porto, PRT
| | - Marta Pina
- Medical Oncology, Instituto Português de Oncologia do Porto Francisco Gentil, EPE, Porto, PRT
| | - Isabel Azevedo
- Medical Oncology, Instituto Português de Oncologia do Porto Francisco Gentil, EPE, Porto, PRT
| | - Ana Rodrigues
- Medical Oncology, Instituto Português de Oncologia do Porto Francisco Gentil, EPE, Porto, PRT
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Xu H, Gao H, Li H, Li D, Yuan W, Zhang L, Cheng P, Su X, Li Z, Wang G, Zhang T. Downregulated Mucin 1 alleviates paclitaxel resistance in non‑small cell lung cancer cells. Mol Med Rep 2020; 22:2966-2972. [PMID: 32945387 DOI: 10.3892/mmr.2020.11349] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 01/14/2020] [Indexed: 11/06/2022] Open
Abstract
Multidrug resistance of non‑small cell lung cancer (NSCLC) is a common clinical problem, which is one of the main reasons leading to the failure of chemotherapy. Therefore, how to overcome or prevent drug resistance has become a hot and difficult issue in clinical research. The present study was designed to investigate the expression patterns, functions and underlying mechanisms of MUC1 in regulating paclitaxel‑resistant cell line A549/PR in NSCLC. RT‑qPCR and western blot was performed to determine the mRNA and protein level, respectively. CCK‑8 was conducted to determine the cell viability of A549/PR cells. Moreover, flow cytometry assay was applied to examine the apoptosis rate of A549/PR. Herein, the MUC1 was over‑expressed in clinic NSCLC tissues and A549/PR cells. Silence of MUC1 could obviously suppress the proliferation and promote apoptosis of A549/PR cells in treatment of paclitaxel through up‑regulating the expression of Bax and Caspase‑3, and down‑regulating the expression of Bcl‑2, suggesting that chemotherapy combined with the modulation of MUC1 might be characterized as a promising therapeutic approach to overcome paclitaxel‑resistance in NSCLC in the future.
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Affiliation(s)
- Hongyu Xu
- Department of Oncology, The General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P.R. China
| | - Hui Gao
- Department of Oncology, The General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P.R. China
| | - Hua Li
- Department of Oncology, The General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P.R. China
| | - Dong Li
- Department of Oncology, The General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P.R. China
| | - Weiwei Yuan
- Department of Oncology, The General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P.R. China
| | - Ling Zhang
- Department of Oncology, The General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P.R. China
| | - Peng Cheng
- Department of Oncology, The General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P.R. China
| | - Xiaomei Su
- Department of Oncology, The General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P.R. China
| | - Zhihui Li
- Department of Oncology, The General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P.R. China
| | - Guangjie Wang
- Department of Oncology, The General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P.R. China
| | - Tao Zhang
- Department of Oncology, The General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P.R. China
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Hałas-Wiśniewska M, Zielińska W, Izdebska M, Grzanka A. The Synergistic Effect of Piperlongumine and Sanguinarine on the Non-Small Lung Cancer. Molecules 2020; 25:E3045. [PMID: 32635287 PMCID: PMC7411589 DOI: 10.3390/molecules25133045] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 06/30/2020] [Accepted: 07/01/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Cancers are one of the leading causes of deaths nowadays. The development of new treatment schemes for oncological diseases is an interesting direction in experimental medicine. Therefore, the evaluation of the influence of two alkaloids-piperlongumine (PL), sanguinarine (SAN) and their combination-on the basic life processes of the A549 cell line was considered reasonable. METHODS The aim was achieved by analyzing the cytotoxic effects of PL and SAN and their combination in the ratio of 4:1 on the induction of cell death, changes in the distribution of cell cycle phases, reorganization of cytoskeleton and metastatic potential of A549 cells. The versatility of the applied concentration ratio was evaluated in terms of other cancer cell lines: MCF-7, H1299 and HepG2. RESULTS The results obtained from the MTT assay indicated that the interaction between the alkaloids depends on the concentration and type of cells. Additionally, the compounds and their combination did not exhibit a cytotoxic effect against normal cells. The combined effects of PL and SAN increased apoptosis and favored metastasis inhibition. CONCLUSION Selected alkaloids exhibit a cytotoxic effect on A549 cells. In turn, treatment with the combination of PL and SAN in a 4:1 ratio indicates a synergistic effect and is associated with an increase in the level of reactive oxygen species (ROS).
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Affiliation(s)
- Marta Hałas-Wiśniewska
- Department of Histology and Embryology, Faculty of Medicine, Nicolaus Copernicus University in Toruń, Collegium Medicum in Bydgoszcz, Karłowicza 24, 85-092 Bydgoszcz, Poland; (W.Z.); (M.I.); (A.G.)
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Cavaille F, Peretti M, Garcia ME, Giorgi R, Ausias N, Vanelle P, Barlesi F, Montana M. Real-world efficacy and safety of pembrolizumab in patients with non-small cell lung cancer: a retrospective observational study. TUMORI JOURNAL 2020; 107:32-38. [PMID: 32458769 DOI: 10.1177/0300891620926244] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Pembrolizumab, a humanized immunoglobulin monoclonal antibody directed against the programmed cell death 1 receptor, demonstrated robust efficacy and a manageable safety profile across multiple tumor types in clinical trials. AIM To investigate the efficacy and safety of first-line pembrolizumab for patients with non-small cell lung cancers (NSCLCs) in clinical practice. METHODS In this observational monocentric retrospective study, 38 patients with PD-L1 >50% were enrolled between November 2017 and November 2018. RESULTS The global median overall survival was 11.08 months (95% confidence interval [CI], 5.98-not reached) and the global median progression-free survival was 6 months (95% CI, 3-not reached). In the univariate analysis, clinical performance status score and the development of immune-related adverse events were the only 2 clinical factors significantly correlated with overall survival. CONCLUSION The results of the present study suggest that pembrolizumab seems less effective in the real-life population than in the pivotal clinical trials in patients with NSCLC but remains an effective treatment option for patients with NSCLC. Longer follow-up is needed.
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Affiliation(s)
| | | | - Marie Eve Garcia
- Oncologie Multidisciplinaire et Innovations Thérapeutiques, Aix Marseille Université, CNRS, INSERM, CRCM, AP-HM, Marseille, France
| | - Roch Giorgi
- APHM, INSERM, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, Hop Timone, BioSTIC, Biostatistique et Technologies de l'Information et de la Communication, Aix Marseille Université, Marseille, France
| | | | - Patrice Vanelle
- Oncologie Multidisciplinaire et Innovations Thérapeutiques, Aix Marseille Université, CNRS, INSERM, CRCM, AP-HM, Marseille, France.,Service Central de la Qualité et de l'Information Pharmaceutiques (SCQIP), APHM, Marseille, France
| | - Fabrice Barlesi
- Oncologie Multidisciplinaire et Innovations Thérapeutiques, Aix Marseille Université, CNRS, INSERM, CRCM, AP-HM, Marseille, France
| | - Marc Montana
- Oncopharma, AP-HM, Hôpital Nord, Marseille, France.,CNRS, Institut de Chimie Radicalaire ICR, UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Aix Marseille Université, Marseille, France
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Fernandes MT, Calado SM, Mendes-Silva L, Bragança J. CITED2 and the modulation of the hypoxic response in cancer. World J Clin Oncol 2020; 11:260-274. [PMID: 32728529 PMCID: PMC7360518 DOI: 10.5306/wjco.v11.i5.260] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 04/13/2020] [Accepted: 05/12/2020] [Indexed: 02/06/2023] Open
Abstract
CITED2 (CBP/p300-interacting transactivator with Glu/Asp-rich C-terminal domain, 2) is a ubiquitously expressed protein exhibiting a high affinity for the CH1 domain of the transcriptional co-activators CBP/p300, for which it competes with hypoxia-inducible factors (HIFs). CITED2 is particularly efficient in the inhibition of HIF-1α-dependent transcription in different contexts, ranging from organ development and metabolic homeostasis to tissue regeneration and immunity, being also potentially involved in various other physiological processes. In addition, CITED2 plays an important role in inhibiting HIF in some diseases, including kidney and heart diseases and type 2-diabetes. In the particular case of cancer, CITED2 either functions by promoting or suppressing cancer development depending on the context and type of tumors. For instance, CITED2 overexpression promotes breast and prostate cancers, as well as acute myeloid leukemia, while its expression is downregulated to sustain colorectal cancer and hepatocellular carcinoma. In addition, the role of CITED2 in the maintenance of cancer stem cells reveals its potential as a target in non-small cell lung carcinoma and acute myeloid leukemia, for example. But besides the wide body of evidence linking both CITED2 and HIF signaling to carcinogenesis, little data is available regarding CITED2 role as a negative regulator of HIF-1α specifically in cancer. Therefore, comprehensive studies exploring further the interactions of these two important mediators in cancer-specific models are sorely needed and this can potentially lead to the development of novel targeted therapies.
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Affiliation(s)
- Mónica T Fernandes
- School of Health, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Centre for Biomedical Research, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Algarve Biomedical Centre, Faro 8005-139, Portugal
| | - Sofia M Calado
- Centre for Biomedical Research, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Algarve Biomedical Centre, Faro 8005-139, Portugal
| | - Leonardo Mendes-Silva
- Centre for Biomedical Research, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Algarve Biomedical Centre, Faro 8005-139, Portugal
- Department of Biomedical Sciences and Medicine, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
| | - José Bragança
- Centre for Biomedical Research, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Algarve Biomedical Centre, Faro 8005-139, Portugal
- Department of Biomedical Sciences and Medicine, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
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Wang C, Zhang S, Liu J, Tian Y, Ma B, Xu S, Fu Y, Luo Y. Secreted Pyruvate Kinase M2 Promotes Lung Cancer Metastasis through Activating the Integrin Beta1/FAK Signaling Pathway. Cell Rep 2020; 30:1780-1797.e6. [PMID: 32049010 DOI: 10.1016/j.celrep.2020.01.037] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 12/01/2019] [Accepted: 01/10/2020] [Indexed: 12/31/2022] Open
Abstract
Cancer cell-derived secretomes have been documented to play critical roles in cancer progression. Intriguingly, alternative extracellular roles of intracellular proteins are involved in various steps of tumor progression, which can offer strategies to fight cancer. Herein, we identify lung cancer progression-associated secretome signatures using mass spectrometry analysis. Among them, PKM2 is verified to be highly expressed and secreted in lung cancer cells and clinical samples. Functional analyses demonstrates that secreted PKM2 facilitates tumor metastasis. Furthermore, mass spectrometry analysis and functional validation identify integrin β1 as a receptor of secreted PKM2. Mechanistically, secreted PKM2 directly bound to integrin β1 and subsequently activated the FAK/SRC/ERK axis to promote tumor metastasis. Collectively, our findings suggest that PKM2 is a potential serum biomarker for diagnosing lung cancer and that targeting the secreted PKM2-integrin β1 axis can inhibit lung cancer development, which provides evidence of a potential therapeutic strategy in lung cancer.
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Affiliation(s)
- Caihong Wang
- Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084, China; The National Engineering Laboratory for Anti-Tumor Protein Therapeutics, Tsinghua University, Beijing 100084, China; Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing 100084, China
| | - Shaosen Zhang
- Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084, China; The National Engineering Laboratory for Anti-Tumor Protein Therapeutics, Tsinghua University, Beijing 100084, China; Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing 100084, China
| | - Jie Liu
- Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084, China; The National Engineering Laboratory for Anti-Tumor Protein Therapeutics, Tsinghua University, Beijing 100084, China; Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing 100084, China
| | - Yang Tian
- Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084, China; The National Engineering Laboratory for Anti-Tumor Protein Therapeutics, Tsinghua University, Beijing 100084, China; Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing 100084, China
| | - Boyuan Ma
- Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084, China; The National Engineering Laboratory for Anti-Tumor Protein Therapeutics, Tsinghua University, Beijing 100084, China; Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing 100084, China
| | - Siran Xu
- Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084, China; The National Engineering Laboratory for Anti-Tumor Protein Therapeutics, Tsinghua University, Beijing 100084, China; Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing 100084, China
| | - Yan Fu
- Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084, China; The National Engineering Laboratory for Anti-Tumor Protein Therapeutics, Tsinghua University, Beijing 100084, China; Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing 100084, China
| | - Yongzhang Luo
- Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084, China; The National Engineering Laboratory for Anti-Tumor Protein Therapeutics, Tsinghua University, Beijing 100084, China; Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing 100084, China.
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Topham M, Kim M, Iravani A. Cyclooxygenase-2 contributes to mutant epidermal growth factor receptor lung tumorigenesis by promoting an immunosuppressive environment. CANCER TRANSLATIONAL MEDICINE 2020. [DOI: 10.4103/ctm.ctm_7_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Abstract
Thoracic tumors are a leading cause of cancer-related morbidity and mortality. In recent years, developments in oncologic treatments for these tumors have ushered in an era of targeted therapy, and, in many cases, these novel treatments have replaced conventional strategies to become standard therapeutic options, particularly in those with lung cancer. Targeted medical therapies for lung cancer now include angiogenesis inhibitors, tyrosine kinase inhibitors, and immunotherapeutic agents. Several novel ablative therapies have also gained widespread acceptance as alternatives to conventional surgical options in appropriately selected patients. Tumors treated with targeted medical therapies can respond to treatment differently when compared with conventional therapies. For example, pseudoprogression is a well-described phenomenon in patients receiving checkpoint inhibitor immunotherapy in which an initial increase in tumor burden is followed by a decrease in tumor burden and sometimes partial or complete response, while the frequent cavitating responses seen when antiangiogenic agents are used can be difficult to quantify using existing response assessment criteria. In some cases, novel response assessment criteria are needed to adequately capture response. In addition, numerous treatment-related side effects have been described, which are important to recognize, both to ensure appropriate treatment and to avoid misclassification as worsening tumor. Imaging plays a vital role in the assessment of patients receiving targeted medical therapy, and it is essential that thoracic radiologists are familiar with the rationale underpinning these treatments and the expected posttherapy findings.
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Telomere-associated genes and telomeric lncRNAs are biomarker candidates in lung squamous cell carcinoma (LUSC). Exp Mol Pathol 2019; 112:104354. [PMID: 31837325 DOI: 10.1016/j.yexmp.2019.104354] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Revised: 11/28/2019] [Accepted: 12/06/2019] [Indexed: 12/13/2022]
Abstract
In the past decade, research efforts were made to identify molecular biomarkers useful as therapeutic targets in Non-Small Cell Lung Cancer (NSCLC), the most frequent type of lung carcinoma. NSCLC presents different histological subtypes being the most prevalent LUSC (Lung Squamous Cell Cancer) and LUAD (Lung Adenocarcinoma), and only a subset of LUAD patients' present tumors expressing known targetable genetic alterations. Telomeres and its components, including telomerase, the enzyme that replenishes telomeres, have been considered potential cancer biomarkers due to their crucial role in cell proliferation and genome stability. Our study aims to quantify expression changes affecting telomere-associated genes and ncRNAs associated with telomere regulation and maintenance in NSCLC. We first assessed the transcriptome (RNA-Seq) data of NSCLC patients from The Cancer Genome Atlas (TCGA) and then we tested the expression of telomere-associated genes and telomeric ncRNAs (TERC, telomerase RNA component, and TERRA, telomere repeat-containing RNA) in Brazilian NCSLC patient samples by quantitative RT-PCR, using matched normal adjacent tissue samples as the control. We also estimated the mean size of terminal restriction fragments (TRF) of some Brazilian NSCLC patients using telomeric Southern blot. The TCGA analysis identified alterations in the expression profile of TERT and telomere damage repair genes, mainly in the LUSC subtype. The study of Brazilian NSCLC samples by RT-qPCR showed that LUSC and LUAD express high amounts of TERT and that although the mean TRF size of tumor samples was shorter compared to normal cells, telomeres in NSCLC are probably maintained by telomerase. Also, the expression analysis of Brazilian NSCLC samples identified statistically significant alterations in the expression of genes involved with telomere damage repair, as well as in TERC and TERRA, mainly in the LUSC subtype. We, therefore, concluded that telomere maintenance genes are significantly deregulated in NSCLC, representing potential biomarkers in the LUSC subtype.
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Park H, Sholl LM, Hatabu H, Awad MM, Nishino M. Imaging of Precision Therapy for Lung Cancer: Current State of the Art. Radiology 2019; 293:15-29. [PMID: 31385753 DOI: 10.1148/radiol.2019190173] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Advances in characterization of molecular and genomic abnormalities specific to lung cancer have made precision therapy the current standard of care for lung cancer treatment. This article will provide a cutting-edge review of imaging of lung cancer in the current era of precision medicine. The focus of the article includes (a) an update on the recent advances in precision therapy for non-small cell lung cancer and their implications on imaging; (b) molecular and genomic biomarkers and pitfalls of image interpretations for lung cancer precision therapy; and (c) review of the current approaches and future directions of precision imaging for lung cancer, emphasizing emerging observations in longitudinal tumor kinetics, radiomics, and molecular and functional imaging. The article is designed to help radiologists to remain up to date in the rapidly evolving world of lung cancer therapy and serve as key members of multidisciplinary teams caring for these patients.
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Affiliation(s)
- Hyesun Park
- From the Departments of Imaging (H.P., M.N.) and Medical Oncology (M.M.A.), Dana-Farber Cancer Institute, and Departments of Radiology (H.P., H.H., M.N.), Pathology (L.M.S.), and Medicine (M.M.A.), Brigham and Women's Hospital, 450 Brookline Ave, Boston, MA 02215
| | - Lynette M Sholl
- From the Departments of Imaging (H.P., M.N.) and Medical Oncology (M.M.A.), Dana-Farber Cancer Institute, and Departments of Radiology (H.P., H.H., M.N.), Pathology (L.M.S.), and Medicine (M.M.A.), Brigham and Women's Hospital, 450 Brookline Ave, Boston, MA 02215
| | - Hiroto Hatabu
- From the Departments of Imaging (H.P., M.N.) and Medical Oncology (M.M.A.), Dana-Farber Cancer Institute, and Departments of Radiology (H.P., H.H., M.N.), Pathology (L.M.S.), and Medicine (M.M.A.), Brigham and Women's Hospital, 450 Brookline Ave, Boston, MA 02215
| | - Mark M Awad
- From the Departments of Imaging (H.P., M.N.) and Medical Oncology (M.M.A.), Dana-Farber Cancer Institute, and Departments of Radiology (H.P., H.H., M.N.), Pathology (L.M.S.), and Medicine (M.M.A.), Brigham and Women's Hospital, 450 Brookline Ave, Boston, MA 02215
| | - Mizuki Nishino
- From the Departments of Imaging (H.P., M.N.) and Medical Oncology (M.M.A.), Dana-Farber Cancer Institute, and Departments of Radiology (H.P., H.H., M.N.), Pathology (L.M.S.), and Medicine (M.M.A.), Brigham and Women's Hospital, 450 Brookline Ave, Boston, MA 02215
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A Radiologist's Guide to the Changing Treatment Paradigm of Advanced Non-Small Cell Lung Cancer: The ASCO 2018 Molecular Testing Guidelines and Targeted Therapies. AJR Am J Roentgenol 2019; 213:1047-1058. [PMID: 31361530 DOI: 10.2214/ajr.19.21135] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
OBJECTIVE. The purpose of this article is to provide an imaging-based guide of the modern genomic classifications and targeted therapies for advanced non-small cell lung cancer (NSCLC) with an emphasis on the relevance of the 2018 American Society of Clinical Oncology molecular testing guidelines for radiologists. CONCLUSION. Knowledge of the radiologic relevance of lung cancer driver mutations and modern targeted agents is essential for imaging interpretation of advanced NSCLC in the modern age of precision medicine.
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Trinidad López C, De La Fuente Aguado J, Oca Pernas R, Delgado Sánchez-Gracián C, Santos Armentia E, Vaamonde Liste A, Prada González R, Souto Bayarri M. Evaluation of response to conventional chemotherapy and radiotherapy by perfusion computed tomography in non-small cell lung cancer (NSCLC). Eur Radiol Exp 2019; 3:23. [PMID: 31197486 PMCID: PMC6565789 DOI: 10.1186/s41747-019-0101-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 05/02/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND To evaluate changes in perfusion computed tomography (PCT) parameters induced by treatment with conventional chemotherapy (CCT) alone or with CCT and radiation therapy (RT) in patients with non-small cell lung cancer (NSCLC) and to determine whether these changes correlate with response as defined by the response evaluation criteria in solid tumours version 1.1 (RECIST-1.1). METHODS Fifty-three patients with a histological diagnosis of NSCLC prospectively underwent PCT of the whole tumour, before/after CCT or before/after CCT and RT. Blood flow (BF), blood volume (BV), permeability (PMB), and mean transit time (MTT) were compared before and after treatment and with the response as defined by RECIST-1.1. The relationship between changes in the perfusion parameters and in tumour size was also evaluated. RESULTS PCT parameters decreased after treatment, significantly for BV (p = 0.002) and MTT (p = 0.027). The 30 patients with partial response had a significant decrease of 21% for BV (p = 0.006) and 17% for MTT (p = 0.031). A non-significant decrease in all perfusion parameters was found in patients with stable disease (p > 0.137). In patients with progressive disease, MTT decreased by 10% (p = 0.465) and the other parameters did not significantly vary (p > 0.809). No significant correlation was found between changes in size and PCT parameters (p > 0.145). CONCLUSIONS Treatment of NSCLC with platinum derivatives, with or without RT, induces changes in PCT parameters. Partial response is associated with a significant decrease in BV and MTT, attributable to the effect of the treatment on tumour vascularisation.
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Affiliation(s)
- Carmen Trinidad López
- Department of Radiology, POVISA Hospital, 5 Salamanca st, 36208, Vigo, Pontevedra, Spain.
| | | | - Roque Oca Pernas
- Department of Radiology, Osatek, Urduliz Hospital, Vizcaya, Spain
| | | | - Eloisa Santos Armentia
- Department of Radiology, POVISA Hospital, 5 Salamanca st, 36208, Vigo, Pontevedra, Spain
| | - Antonio Vaamonde Liste
- Department of Statistics and Operational Research, Faculty of Economic and Business Sciences, Vigo University Spain, Vigo, Spain
| | - Raquel Prada González
- Department of Radiology, POVISA Hospital, 5 Salamanca st, 36208, Vigo, Pontevedra, Spain
| | - Miguel Souto Bayarri
- Department of Radiology, Complexo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain
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Rutkowski J, Saad ED, Burzykowski T, Buyse M, Jassem J. Chronological Trends in Progression-Free, Overall, and Post-Progression Survival in First-Line Therapy for Advanced NSCLC. J Thorac Oncol 2019; 14:1619-1627. [PMID: 31163279 DOI: 10.1016/j.jtho.2019.05.030] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 05/14/2019] [Accepted: 05/16/2019] [Indexed: 11/18/2022]
Abstract
BACKGROUND There is a debate about the merits of progression-free survival (PFS) versus overall survival (OS) as primary endpoints in NSCLC. It has been postulated that post-progression therapy may influence OS in both arms. To investigate this issue, we analyzed chronological trends in PFS and OS in advanced NSCLC using restricted mean survival times (RMSTs). METHODS We digitized survival curves from first-line phase III trials published between 1998 and 2015 in 13 leading journals to compute RMSTs for PFS and OS at three truncation landmarks (5, 12, and 18 months). RESULTS Among the 161 trials identified, RMSTs could be computed for both endpoints in 102, 97, and 82 trials for the 5-, 12-, and 18-month truncation landmarks, respectively. Post-progression survival in the control arm, quantified as mean OS minus mean PFS truncated at 18 months, was on average 3.3 months between 1998 and 2003, 4.4 months between 2004 and 2009, and 5.4 months between 2010 and 2015. This increase was due to increasing RMST for OS over time, with no increase in RMST for PFS. The average within-trial difference in RMSTs between experimental and control arm was close to 0 for OS and less than 1 month for PFS. CONCLUSIONS There is a progressive increase in post-progression survival in NSCLC trials, likely from salvage therapy. These results question both PFS and OS as sensitive endpoints in first-line trials, but suggest that the outlook for patients is improving regardless of within-trial gains.
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Affiliation(s)
| | - Everardo D Saad
- Dendrix Research, Sao Paulo, Brazil; International Drug Development Institute, Louvain-la-Neuve, Belgium
| | - Tomasz Burzykowski
- International Drug Development Institute, Louvain-la-Neuve, Belgium; Interuniversity Institute for Biostatistics and statistical Bioinformatics (I-BioStat), Hasselt University, Diepenbeek, Belgium
| | - Marc Buyse
- Interuniversity Institute for Biostatistics and statistical Bioinformatics (I-BioStat), Hasselt University, Diepenbeek, Belgium; International Drug Development Institute, San Francisco, California
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25
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Song YH, Zhang CQ, Chen FF, Lin XY. Upregulation of Neural Precursor Cell Expressed Developmentally Downregulated 4-1 is Associated with Poor Prognosis and Chemoresistance in Lung Adenocarcinoma. Chin Med J (Engl) 2019; 131:16-24. [PMID: 29271375 PMCID: PMC5754953 DOI: 10.4103/0366-6999.221262] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND The E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated 4-1 (NEDD4-1) negatively regulates phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein levels through polyubiquitination and proteolysis, but its significance in lung cancer is still unclear. This study investigated the expression and the role of NEDD4-1 in tumor development and chemosensitivity of lung adenocarcinoma (ADC). METHODS We retrospectively investigated the expression and significance of NEDD4-1, PTEN, and p-Akt proteins in 135 paired ADC and adjacent noncancerous tissue specimens using immunohistochemistry. Furthermore, we evaluated the relationship between NEDD4-1 expression and clinicopathologic characteristics and prognosis. The effects of small interfering RNA against NEDD4-1 on proliferation and chemosensitivity were examined in A549 cells in vitro using 3- (4,5-dimethylthiazol-2-yl) -5-(3-carboxymethoxyphenyl) -2-(4-sulfophenyl)- 2H-tetrazolium method. The ability of migration and invasion of A549 cells was tested by transwell assay. Moreover, reverse-transcription quantitative polymerase chain reaction and Western blotting analyses were used to determine the expression of NEDD4-1, PTEN, phosphoinositide 3-kinase (PI3K)/Akt activity, and its downstream target proteins. RESULTS NEDD4-1 protein was significantly upregulated in lung ADC tissues, whereas it was weak or negative in normal lung epithelial cells. The expression of NEDD4-1 in ADC (78.5%, 106/135) was significantly much higher than that in adjacent normal lung tissue (13.3%, 29/135, P < 0.01), and it was associated with lymph node metastasis, tumor-node-metastasis (TNM) stage, and chemotherapy resistance. PTEN expression was downregulated in lung ADC (60.7% vs. 100.0% in noncancerous specimens, P = 0.007), and was negatively correlated with lymph node metastasis, histological variants, clinical stage, chemoresistance. In addition, expression of p-Akt in ADC tissues (71.1% 96/135) was much higher than that in adjacent lung epithelial cells (6.7%, 9/135, P < 0.01). Kaplan-Meier and multivariate analysis demonstrated that expressions of NEDD4-1 and PTEN were both independent risk factors for survival in patients with lung ADC. NEDD4-1 knockdown in vivo decreased proliferation, migration, and invasion and improved chemosensitivity to cisplatin and paclitaxel in A549 cells. NEDD4-1 knockdown also significantly enhanced PTEN expression and inhibited p-Akt activity and downstream target proteins. CONCLUSIONS NEDD4-1 upregulation may contribute to the progression of lung ADC. NEDD4-1 may regulate the proliferation, invasion, migration, and chemoresistance of lung ADC cells through the PI3K/Akt pathway, suggesting that it may be regarded as a therapeutic target for the treatment of lung ADC.
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Affiliation(s)
- Ying-Hua Song
- Department of Respiratory Medicine, Shandong Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, China
| | - Cai-Qing Zhang
- Department of Respiratory Medicine, Shandong Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, China
| | - Fang-Fang Chen
- Department of Respiratory Medicine, Shandong Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, China
| | - Xiao-Yan Lin
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China
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Boysen G, Jamshidi-Parsian A, Davis MA, Siegel ER, Simecka CM, Kore RA, Dings RPM, Griffin RJ. Glutaminase inhibitor CB-839 increases radiation sensitivity of lung tumor cells and human lung tumor xenografts in mice. Int J Radiat Biol 2019; 95:436-442. [PMID: 30557074 DOI: 10.1080/09553002.2018.1558299] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
PURPOSE The purpose of this study was to translate our in vitro therapy approach to an in vivo model. Increased glutamine uptake is known to drive cancer cell proliferation, making tumor cells glutamine-dependent. Studying lymph-node aspirates containing malignant lung tumor cells showed a strong correlation between glutamine consumption and glutathione (GSH) excretion. Subsequent experiments with A549 and H460 lung tumor cell lines provided additional evidence for glutamine's role in driving synthesis and excretion of GSH. Using stable-isotope-labeled glutamine as a tracer metabolite, we demonstrated that the glutamate group in GSH is directly derived from glutamine, linking glutamine utilization intimately to GSH syntheses. MATERIALS AND METHODS To understand the possible mechanistic link between glutamine consumption and GSH excretion, we studied GSH metabolism in more detail. Inhibition of glutaminase (GLS) with BPTES, a GLS-specific inhibitor, effectively abolished GSH synthesis and excretion. Since our previous work, several novel GLS inhibitors became available and we report herein effects of CB-839 in A427, H460 and A549 lung tumor cells and human lungtumor xenografts in mice. RESULTS Inhibition of GLS markedly reduced cell viability, producing ED50 values for inhibition of colony formation of 9, 27 and 217 nM in A427, A549 and H460, respectively. Inhibition of GLS is accompanied by ∼30% increased response to radiation, suggesting an important role of glutamine-derived GSH in protecting tumor cells against radiation-induced injury. In subsequent mouse xenografts, short-term CB-839 treatments reduced serum GSH by >50% and increased response to radiotherapy of H460-derived tumor xenografts by 30%. CONCLUSION The results support the proposed mechanistic link between GLS activity and GSH synthesis and suggest that GLS inhibitors are effective radiosensitizers.
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Affiliation(s)
- Gunnar Boysen
- a Department of Environment and Occupational Health , University of Arkansas for Medical Sciences , Little Rock , AR , USA.,b The Winthrop P. Rockefeller Cancer Institute , University of Arkansas for Medical Sciences , Little Rock , AR , USA
| | - Azemat Jamshidi-Parsian
- c Department of Radiation Oncology , University of Arkansas for Medical Sciences , Little Rock , AR , USA
| | - Mary A Davis
- a Department of Environment and Occupational Health , University of Arkansas for Medical Sciences , Little Rock , AR , USA
| | - Eric R Siegel
- b The Winthrop P. Rockefeller Cancer Institute , University of Arkansas for Medical Sciences , Little Rock , AR , USA.,d Department of Biostatistics , University of Arkansas for Medical Sciences , Little Rock , AR , USA
| | - Christine M Simecka
- e Division of Laboratory Animal Science , University of Arkansas for Medical Sciences , Little Rock , AR , USA
| | - Rajshekhar A Kore
- b The Winthrop P. Rockefeller Cancer Institute , University of Arkansas for Medical Sciences , Little Rock , AR , USA.,c Department of Radiation Oncology , University of Arkansas for Medical Sciences , Little Rock , AR , USA
| | - Ruud P M Dings
- b The Winthrop P. Rockefeller Cancer Institute , University of Arkansas for Medical Sciences , Little Rock , AR , USA.,c Department of Radiation Oncology , University of Arkansas for Medical Sciences , Little Rock , AR , USA
| | - Robert J Griffin
- b The Winthrop P. Rockefeller Cancer Institute , University of Arkansas for Medical Sciences , Little Rock , AR , USA.,c Department of Radiation Oncology , University of Arkansas for Medical Sciences , Little Rock , AR , USA
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Montana M, Garcia ME, Ausias N, Jeanpierre M, Meiffren M, Giorgi R, Vanelle P, Barlesi F. Efficacy and safety of nivolumab in patients with non-small cell lung cancer: a retrospective study in clinical practice. J Chemother 2018; 31:90-94. [DOI: 10.1080/1120009x.2018.1551753] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
- Marc Montana
- Oncopharma, AP-HM, Marseille, France
- UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Aix Marseille Univ, CNRS, Institut de Chimie Radicalaire ICR, Marseille, France
| | - Marie-Eve Garcia
- Oncologie multidisciplinaire et innovations thérapeutiques, AP-HM, Marseille, France
| | | | | | | | - Roch Giorgi
- Hôpital de la Timone, Service Biostatistique et Technologies de l'Information et de la Communication, APHM, Marseille, France
- INSERM, IRD, SESSTIM, Aix Marseille Univ, Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, Marseille, France
| | - Patrice Vanelle
- UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Aix Marseille Univ, CNRS, Institut de Chimie Radicalaire ICR, Marseille, France
- Service Central de la Qualité et de l’Information Pharmaceutiques (SCQIP), APHM, Marseille, France
| | - Fabrice Barlesi
- Oncologie multidisciplinaire et innovations thérapeutiques, AP-HM, Marseille, France
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28
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Gill RR, Murphy DJ, Kravets S, Sholl LM, Janne PA, Johnson BE. Success of genomic profiling of non-small cell lung cancer biopsies obtained by trans-thoracic percutaneous needle biopsy. J Surg Oncol 2018; 118:1170-1177. [PMID: 30261097 DOI: 10.1002/jso.25241] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 08/24/2018] [Indexed: 01/05/2023]
Abstract
PURPOSE Genomic profiling for personalized targeted therapy has become standard of care. We report the success of genomic profiling of non-small cell lung cancer (NSCLC) obtained by trans-thoracic needle biopsy (TTNB) in a single center experience. MATERIALS AND METHODS Patients with NSCLC who underwent TTNB for genomic were identified. Pathology specimens were evaluated for tumor adequacy and then analyzed for selected exons of epidermal growth factor receptor, KRAS, BRAF, PIK3CA, and ERBB2. ALK rearrangements were detected with fluorescence in situ hybridization and/or immunohistochemistry. Technical success was recorded and the factors affecting successful profiling were evaluated. Complications (pneumothorax, hemorrhage, and admission) were recorded. Comparison of yield and complications were done between the two groups (core biopsy and fine needle aspiration only group). Utility of PET-CT to guide the needle track for optimized yield was assessed in a subset of patients. RESULTS Between December 6, 2009, and December 30, 2016, 765 patients with NSCLC underwent TTNB. Five-hundred and seventy-seven of 765 (75%) of all TTNB were profiled, for genomic analysis. Five-hundred and eight of 577 (88%) were successfully profiled. The number of samples obtained ranged from 1 to 10 (1 to 2 cm, 18 to 20 G). Lesions biopsied ranged in size from 0.6 to 16 cm. No statistically significant difference was observed in the incidence of pneumothorax between two groups (P = 0.26). PET guidance was not found to be statistically significant ( P = 0.79) in the overall yield. CONCLUSION Computed tomographic guided TTNB is a safe and efficacious technique for genomic profiling, enables the acquisition of sufficient tissue for genetic mutation analyses allowing for personalized therapy with an acceptable complication rate.
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Affiliation(s)
- Ritu R Gill
- Department of Radiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - David John Murphy
- Department of Radiology, Guy's & St Thomas, NHS Foundation Trust & King's College, London, UK
| | - Sasha Kravets
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Lynnette Mary Sholl
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Pasi Antero Janne
- Department of Medical Oncology, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Bruce Evan Johnson
- Department of Medical Oncology, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
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Trinidad López C, Souto Bayarri M, Oca Pernas R, Delgado Sánchez-Gracián C, González Vázquez M, Vaamonde Liste A, Tardáguila De La Fuente G, De La Fuente Aguado J. Characteristics of computed tomography perfusion parameters in non-small-cell-lung-cancer and its relationship to histology, size, stage an treatment response. Clin Imaging 2018; 50:5-12. [DOI: 10.1016/j.clinimag.2017.12.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 10/27/2017] [Accepted: 12/01/2017] [Indexed: 11/29/2022]
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30
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Cao X, Zhou Y, Sun H, Xu M, Bi X, Zhao Z, Shen B, Wan F, Hong Z, Lan L, Luo L, Guo Z, Yin Z. EGFR-TKI-induced HSP70 degradation and BER suppression facilitate the occurrence of the EGFR T790 M resistant mutation in lung cancer cells. Cancer Lett 2018. [PMID: 29524558 DOI: 10.1016/j.canlet.2018.03.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Non-small cell lung cancer (NSCLC) patients harboring EGFR-activating mutations initially respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs) and have shown favorable outcomes. However, acquired drug resistance to EGFR-TKIs develops in almost all patients mainly due to the EGFR T790 M mutation. Here, we show that treatment with low-dose EGFR-TKI results in the emergence of the EGFR T790 M mutation and in the reduction of HSP70 protein levels in HCC827 cells. Erlotinib treatment inhibits HSP70 phosphorylation at tyrosine 41 and increases HSP70 ubiquitination, resulting in HSP70 degradation. We show that EGFR-TKI treatment causes increased DNA damage and enhanced gene mutation rates, which are secondary to the EGFR-TKI-induced reduction of HSP70 protein. Importantly, HSP70 overexpression delays the occurrence of Erlotinib-induced EGFR T790 M mutation. We further demonstrate that HSP70 interacts with multiple enzymes in the base excision repair (BER) pathway and promotes not only the efficiency but also the fidelity of BER. Collectively, our findings show that EGFR-TKI treatment facilitates gene mutation and the emergence of EGFR T790 M secondary mutation by the attenuation of BER via induction of HSP70 protein degradation.
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Affiliation(s)
- Xiang Cao
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, 210046, Jiangsu, PR China
| | - Yi Zhou
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, 210046, Jiangsu, PR China
| | - Hongfang Sun
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, 210046, Jiangsu, PR China
| | - Miao Xu
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, 210046, Jiangsu, PR China
| | - Xiaowen Bi
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, 210046, Jiangsu, PR China
| | - Zhihui Zhao
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, 210046, Jiangsu, PR China
| | - Binghui Shen
- Department of Radiation Biology, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, 91010, USA
| | - Fengyi Wan
- Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Zhuan Hong
- Jiangsu Cancer Hospital, Nanjing, 210009, Jiangsu, PR China
| | - Lei Lan
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, 210046, Jiangsu, PR China.
| | - Lan Luo
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, Jiangsu, PR China.
| | - Zhigang Guo
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, 210046, Jiangsu, PR China.
| | - Zhimin Yin
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, 210046, Jiangsu, PR China.
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31
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Kang HJ, Park JH, Yoo HS, Park YM, Cho CK, Kang IC. Effects of HAD-B1 on the proliferation of A549 cisplatin-resistant lung cancer cells. Mol Med Rep 2018; 17:6745-6751. [PMID: 29512755 DOI: 10.3892/mmr.2018.8702] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 09/26/2017] [Indexed: 11/06/2022] Open
Abstract
The present study investigated the toxicity of HangAmDan-B1 (HAD-B1) on A549-Cisplatin resistant (A549CR) cells. HAD‑B1 inhibited the growth of A549CR cells in a concentration‑dependent manner; HAD‑B1 was more effective at inhibiting A549CR cell viability compared with vehicle‑treated cells. The reduction in viability may be due to S‑phase cell cycle arrest and the induction of apoptosis in HAD‑B1‑treated cells. Cell cycle protein profile analysis of HAD‑B1‑treated A549CR cells using an InnoPharmaScreen (IPS) ProteoChip‑based antibody microarray chip indicated downregulation of signal transducer and activator of transcription 3. The activities of caspase‑3, ‑8 and ‑9 were significantly increased in HAD‑B1‑treated cells when compared with the vehicle‑treated control group. Furthermore, the HAD‑B1‑treated group exhibited similarly increased caspase levels when compared with the Afatinib‑treated group. Taken together, these observations suggest that HAD‑B1 may be a promising candidate for further research into the therapeutic management of cisplatin-resistant lung cancer.
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Affiliation(s)
- Hwa Jeong Kang
- Department of Biological Science, College of Life & Health Sciences and BioChip Research Center, Hoseo University, Asan‑si, Chungcheongnam‑do 336‑795, Republic of Korea
| | - Ji-Hye Park
- East‑West Cancer Center, Dunsan Korean Medical Hospital of Daejeon University, Daejeon 302‑869, Republic of Korea
| | - Hwa-Seung Yoo
- East‑West Cancer Center, Dunsan Korean Medical Hospital of Daejeon University, Daejeon 302‑869, Republic of Korea
| | - Yu Mi Park
- Department of Biological Science, College of Life & Health Sciences and BioChip Research Center, Hoseo University, Asan‑si, Chungcheongnam‑do 336‑795, Republic of Korea
| | - Chong-Kwan Cho
- East‑West Cancer Center, Dunsan Korean Medical Hospital of Daejeon University, Daejeon 302‑869, Republic of Korea
| | - In-Cheol Kang
- Department of Biological Science, College of Life & Health Sciences and BioChip Research Center, Hoseo University, Asan‑si, Chungcheongnam‑do 336‑795, Republic of Korea
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Wang HY, Chang YL, Cheng CC, Chao MW, Lin SI, Pan SL, Hsu CC, Liu TW, Cheng HC, Tseng CP, Liu SJ, Tsai HJ, Chang HY, Hsu JTA. Glucocorticoids may compromise the effect of gefitinib in non-small cell lung cancer. Oncotarget 2018; 7:85917-85928. [PMID: 27835586 PMCID: PMC5349885 DOI: 10.18632/oncotarget.13185] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 10/29/2016] [Indexed: 11/25/2022] Open
Abstract
The epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitors (TKIs) have shown remarkable benefits in non-small cell lung cancer (NSCLC) patients with drug-sensitive mutations in the EGFR gene. Responsive patients are usually continuously prescribed with TKIs until disease progression. Glucocorticoids (GCs) are potent homeostasis maintaining drugs and are frequently used in cancer patients to alleviate discomforts caused by anti-cancer therapies. Several previous studies reported that concomitant use of GCs may compromise the efficacy of chemo-therapeutics in patients with solid tumors. Little is known in the concomitant use of target therapy with GCs in treating NSCLC. In this study, we hypothesized that concomitant use of GCs in EGFR-TKI therapy may be detrimental and addressed this issue using cell cultures and xenograft studies followed by a retrospective population study based on data from the Taiwan national health insurance system. In cell cultures and xenograft studies, GCs were shown to unequally compromise the anti-cancer efficacy of TKIs in both PC9 and NCI-H1975 NSCLC cells models. In the retrospective population study, patients with similar disease status that were co-medicated with GCs had a significantly higher risk of disease progression.
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Affiliation(s)
- Hsian-Yu Wang
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, Taiwan.,Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu City, Taiwan
| | - Yu-Ling Chang
- Institute of Population Health Sciences, National Health Research Institutes, Miaoli County, Taiwan
| | - Chun-Chun Cheng
- The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei City, Taiwan
| | - Min-Wu Chao
- The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei City, Taiwan
| | - Su-I Lin
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei City, Taiwan.,National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan
| | - Shiow-Lin Pan
- The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei City, Taiwan
| | - Chih-Cheng Hsu
- Institute of Population Health Sciences, National Health Research Institutes, Miaoli County, Taiwan
| | - Tsang-Wu Liu
- Institute of Cancer Research, National Health Research Institutes, Miaoli County, Taiwan
| | - Han-Chin Cheng
- Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu City, Taiwan.,Miaoli General Hospital, Ministry of Health and Welfare, Miaoli County, Taiwan
| | - Ching-Ping Tseng
- Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu City, Taiwan
| | - Shih-Jen Liu
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan.,Graduate Institute of Immunology, China Medical University, Taichung City, Taiwan
| | - Hui-Ju Tsai
- Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Miaoli County, Taiwan.,Department of Public Health, China Medical University, Taichung, Taiwan, Taichung City, Taiwan.,Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Hsing-Yi Chang
- Institute of Population Health Sciences, National Health Research Institutes, Miaoli County, Taiwan.,Institute of Public Health, National Yang-Ming University, Taipei City, Taiwan
| | - John T-A Hsu
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, Taiwan.,Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu City, Taiwan
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Ma Y, Xu P, Mi Y, Wang W, Pan X, Wu X, He Q, Liu H, Tang W, An H. Plasma MiRNA alterations between NSCLC patients harboring Del19 and L858R EGFR mutations. Oncotarget 2018; 7:54965-54972. [PMID: 27463019 PMCID: PMC5342394 DOI: 10.18632/oncotarget.10829] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Accepted: 07/10/2016] [Indexed: 01/06/2023] Open
Abstract
Based on recognition of driver mutations, treatment paradigm for non-small-cell lung cancer (NSCLC) patients has been shifted. However, recently exon 19 deletion mutation (del19) of epidermal growth factor receptor (EGFR) clearly shows better clinical benefit over single-point substitution mutation L858R in exon 21 (L858R). The aim of this study was to investigate the difference by analyzing the expression of plasma microRNAs (miRNAs) of NSCLC patients with EGFR mutation del19 or L858R. MiRNA microarray of plasma from patients' blood identified 79 mapped, network-eligible miRNAs (fold > 5), of which 76 were up regulated and 3 were down regulated. Genetic network was performed with Ingenuity Pathway Analysis (IPA). Among analysis, MYC, Argonaute2 (AGO2), Y-box binding protein 1 (YBX1), cyclin E1 (CCNE1) were involved in organismal abnormalities and cancer. Our findings provide information on the epigenetic signature of the two major sensitive mutations among NSCLC and add to the understanding of mechanisms underlying the different outcomes.
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Affiliation(s)
- Yihan Ma
- Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, 361003, Fujian, China
| | - Peiqi Xu
- Reproduction Center, The Second Affiliated Hospital of Kunming Medical University 650101, Yunnan, China
| | - Yanjun Mi
- Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, 361003, Fujian, China
| | - Wenyi Wang
- Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, 361003, Fujian, China
| | - Xiaoyan Pan
- Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, 361003, Fujian, China
| | - Xiaoting Wu
- Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, 361003, Fujian, China
| | - Qi He
- Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, 361003, Fujian, China
| | - Hongming Liu
- Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, 361003, Fujian, China
| | - Weiwei Tang
- Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, 361003, Fujian, China
| | - Hanxiang An
- Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, 361003, Fujian, China
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Hung MS, Fang YH, Lin YC, Lung JH, Hsieh MJ, Tsai YH. Survival-associated factors of first-line EGFR-tyrosine kinase inhibitor responders and non-responders in lung adenocarcinoma patients with common EGFR mutations. Mol Clin Oncol 2018; 8:421-428. [PMID: 29456848 PMCID: PMC5795572 DOI: 10.3892/mco.2018.1550] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Accepted: 11/28/2017] [Indexed: 12/20/2022] Open
Abstract
The aim of the present retrospective cohort study was to elucidate the clinical presentation of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) responders and non-responders in lung adenocarcinoma patients with common EGFR mutations. The cohort included 131 lung adenocarcinoma patients with common exon 19 or exon 21 EGFR mutations, who were receiving first-line EGFR-TKI therapy. The patient characteristics, treatment regimen and outcomes were recorded and analyzed. Of the 131 patients, 104 (79.3%) responded to treatment, while 27 (20.7%) did not. A significantly longer median progression-free survival (PFS) [14.3, 95% confidence interval (CI): 12.2-18.4 vs. 5.7, 95% CI: 2.7-9.9 months; P<0.001] and overall survival (OS) (42.2, 95% CI: 28.1-58.1 vs. 11.5, 95% CI: 8.3-19.7 months; P<0.001) were observed in responders compared with non-responders. In responders, bone [hazard ratio (HR)=1.87, 95% CI: 1.11-3.20, P=0.021] and pleural (HR=2.40, 95% CI: 1.37-4.22, P=0.002) metastasis were independent factors of PFS. Exon 19 mutations (HR=0.38, 95% CI: 0.19-0.76, P=0.006), Eastern Cooperative Oncology Group performance status score ≥2 (HR=3.53, 95% CI: 1.42-8.75, P=0.007) and bone metastasis (HR=2.01, 95% CI: 1.05-3.85, P=0.034), were independent factors of OS. In non-responders, smoking (HR=3.97, 95% CI: 1.13-13.91, P=0.031) was an independent factor of PFS. Different survival-associated factors were observed between EGFR-TKI responders and non-responders. The development of new treatment strategies should be advocated in EGFR-TKI non-responders.
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Affiliation(s)
- Ming-Szu Hung
- Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Chiayi 61363, Taiwan, R.O.C.,Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan, R.O.C.,Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi Campus, Chiayi 61363, Taiwan, R.O.C
| | - Yu-Hung Fang
- Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Chiayi 61363, Taiwan, R.O.C
| | - Yu-Ching Lin
- Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Chiayi 61363, Taiwan, R.O.C.,Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan, R.O.C.,Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi Campus, Chiayi 61363, Taiwan, R.O.C
| | - Jr-Hau Lung
- Department of Medical Research and Development, Chang Gung Memorial Hospital, Chiayi Branch, Chiayi 61363, Taiwan, R.O.C
| | - Meng-Jer Hsieh
- Division of Pulmonary Infection and Critical Care, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Chiayi 61363, Taiwan, R.O.C.,Department of Respiratory Care, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan, R.O.C
| | - Ying-Huang Tsai
- Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Chiayi 61363, Taiwan, R.O.C.,Department of Respiratory Care, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan, R.O.C
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Tamiya M, Tamiya A, Shiroyama T, Takeoka S, Naito Y, Omachi N, Kimura Y, Morishita N, Suzuki H, Okamoto N, Okishio K, Kawaguchi T, Atagi S, Hirashima T. Phase1 study of cisplatin plus pemetrexed with erlotinib and bevacizumab for chemotherapy-naïve advanced non-squamous non-small cell lung cancer with EGFR mutations. Invest New Drugs 2017; 36:608-614. [PMID: 29101518 DOI: 10.1007/s10637-017-0527-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Accepted: 10/22/2017] [Indexed: 12/23/2022]
Abstract
Background Cisplatin and pemetrexed are very effective against advanced non-squamous non-small cell lung cancer (NSCLC) without EGFR mutations. Erlotinib plus bevacizumab are highly effective against advanced NSCLCs with activating EGFR mutations. We performed this phase I 'Quartet Trial' to determine the safety and efficacy of all 4 agents as a first-line treatment for non-squamous NSCLC patients harboring activating EGFR mutations. Patients and Methods Patients received escalating quartet-agent doses every 3 weeks for 4 cycles. We examined the dose-limiting toxicity (DLT) to determine the maximum tolerated dose (MTD) and recommended dose (RD). Results Ten patients (3 men and 7 women) with a median age of 69 years were enrolled. Four and 6 patients had exon 19 and 21 mutations, respectively; 8 received maintenance therapy without unexpected or cumulative toxicities. One of 6 patients experienced grade 3 vagal reflex at 60 mg/m2 cisplatin plus 500 mg/m2 pemetrexed with 150 mg erlotinib and 15 mg/kg bevacizumab, which was designated the RD. Four patients experienced no DLT with 75 mg/m2 cisplatin plus 500 mg/m2 pemetrexed with 150 mg erlotinib and 15 mg/kg bevacizumab (designated the MTD); however, 3 underwent dose reduction due to severe toxicities (grade 3 gastrointestinal hemorrhage, skin rash, nausea, and febrile neutropenia) during induction chemotherapy. The most frequent DLT-phase adverse events were nausea, anorexia, and fatigue. The overall response rate was 100%. Furthermore, the progression-free and overall survival rates were 17.9 and 32.0 months, respectively. Conclusions This quartet chemotherapy regimen was tolerable and effective in our patient population (UMIN000012536).
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Affiliation(s)
- Motohiro Tamiya
- Department of Thoracic Oncology, Osaka International Cancer Institute, 3-1-69 Otemachi Chuo-ku, Osaka, 541-8567, Japan.
| | - Akihiro Tamiya
- Department of Internal Medicine, Kinki-chuo Chest Medical Center, Sakai, Japan
| | - Takayuki Shiroyama
- Department of Thoracic Malignancy, Osaka Prefectural Hospital Organization Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino, Japan
| | - Sawa Takeoka
- Department of Thoracic Malignancy, Osaka Prefectural Hospital Organization Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino, Japan
| | - Yujiro Naito
- Department of Internal Medicine, Kinki-chuo Chest Medical Center, Sakai, Japan
| | - Naoki Omachi
- Department of Internal Medicine, Kinki-chuo Chest Medical Center, Sakai, Japan
| | - Yohei Kimura
- Department of Internal Medicine, Kinki-chuo Chest Medical Center, Sakai, Japan
| | - Naoko Morishita
- Department of Thoracic Malignancy, Osaka Prefectural Hospital Organization Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino, Japan
| | - Hidekazu Suzuki
- Department of Thoracic Malignancy, Osaka Prefectural Hospital Organization Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino, Japan
| | - Norio Okamoto
- Department of Thoracic Malignancy, Osaka Prefectural Hospital Organization Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino, Japan
| | - Kyoichi Okishio
- Department of Clinical Research Center, Kinki-chuo Chest Medical Center, Sakai, Japan
| | - Tomoya Kawaguchi
- Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Shinji Atagi
- Department of Clinical Research Center, Kinki-chuo Chest Medical Center, Sakai, Japan
| | - Tomonori Hirashima
- Department of Internal Medicine, Kinki-chuo Chest Medical Center, Sakai, Japan
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36
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Capelle H, Tummino C, Greillier L, Gouitaa M, Birnbaum J, Ausias N, Barlesi F, Montana M. Retrospective study of hypersensitivity reactions to chemotherapeutic agents in a thoracic oncology service. J Clin Pharm Ther 2017; 43:320-326. [PMID: 29092096 DOI: 10.1111/jcpt.12645] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 10/10/2017] [Indexed: 11/27/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE With the increasing use of cancer chemotherapy agents, hypersensitivity reactions are commonly encountered. The allergic clinical symptoms are variable and unpredictable. The aim of this study was to identify the characteristics of hypersensitivity reactions and to assess the value of skin tests for platinum salts and pemetrexed in the treatment of patients with non-small cell lung cancers or malignant pleural mesothelioma. METHODS A single-centre retrospective study was performed for 2 years. Patients treated with the drugs of interest for an advanced or metastatic non-small cell lung cancers or malignant pleural mesothelioma and who experienced hypersensitivity reactions symptoms were eligible for this study. Clinical symptoms of hypersensitivity reactions, population characteristics and administered chemotherapy regimens were identified. RESULTS The hypersensitivity reactions frequency was rare (1.2%) and concerned 17 patients in our study. Typical clinical features of immediate hypersensitivity reactions associated with treatment were observed for nine patients (anaphylactic reactions for three cases, angioedema and hypotension associated with asthenia and heat in one case, respectively, and other cutaneous symptoms in the remaining four cases). Skin tests were positive in three patients, but only for platinum salts. The outcome after reintroduction of a negatively tested platinum salt allowed us to calculate a negative predictive value for platinum salt skin tests of 100%. For pemetrexed, skin tests were negative for all patients. WHAT IS NEW AND CONCLUSION Skin tests could be used to diagnose hypersensitivity reactions with platinum salts or to evaluate the possibility of cross-reactions between two platinum salts. A negative skin test may predict with reasonable reliability the absence of future hypersensitivity reactions in case of reintroduction of drug infusion. Because the IgE-mediated mechanism has never been demonstrated for pemetrexed, skin tests are not valid and have no diagnostic value for this molecule. Because hypersensitivity reactions are potentially fatal adverse events, we recommend that patients who experience a hypersensitivity reactions onset should be monitored closely and clinicians must be aware of hypersensitivity reaction signs.
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Affiliation(s)
- H Capelle
- Aix Marseille Univ, AP-HM, Oncopharma, Hôpital Nord, Marseille, France
| | - C Tummino
- Aix Marseille Univ, AP-HM, Service de Pneumologie, Hôpital Nord, Marseille, France
| | - L Greillier
- Aix Marseille Univ, AP-HM, Oncologie Multidisciplinaire et Innovations Thérapeutiques, Marseille, France
| | - M Gouitaa
- Aix Marseille Univ, AP-HM, Service de Pneumologie, Hôpital Nord, Marseille, France
| | - J Birnbaum
- Aix Marseille Univ, AP-HM, Dermatologie, Vénéréologie et Cancérologie Cutanée, Marseille, France
| | - N Ausias
- Aix Marseille Univ, AP-HM, Oncopharma, Hôpital Nord, Marseille, France
| | - F Barlesi
- Aix Marseille Univ, AP-HM, Oncologie Multidisciplinaire et Innovations Thérapeutiques, Marseille, France
| | - M Montana
- Aix Marseille Univ, AP-HM, Oncopharma, Hôpital Nord, Marseille, France.,Aix Marseille Univ, AP-HM, Service de Pneumologie, Hôpital Nord, Marseille, France.,Aix Marseille Univ, AP-HM, Oncologie Multidisciplinaire et Innovations Thérapeutiques, Marseille, France.,Aix Marseille Univ, AP-HM, Dermatologie, Vénéréologie et Cancérologie Cutanée, Marseille, France.,Aix Marseille Univ, CNRS, ICR, Marseille, France
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Ma Y, Pan X, Xu P, Mi Y, Wang W, Wu X, He Q, Liu X, Tang W, An HX. Plasma microRNA alterations between EGFR-activating mutational NSCLC patients with and without primary resistance to TKI. Oncotarget 2017; 8:88529-88536. [PMID: 29179454 PMCID: PMC5687624 DOI: 10.18632/oncotarget.19874] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 07/18/2017] [Indexed: 12/29/2022] Open
Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have obtained excellent therapeutic effects against non-small cell lung cancer (NSCLC) harboring activating EGFR mutations. However, some patients have exhibited primary resistance which becomes a major obstacle in effective treatment of NSCLC. The mechanisms of EGFR-TKIs resistance involved are still poorly understood. Many studies suggest that miRNAs play an important role in regulating drug sensitivity of EGFR-TKIs. The aim of the present study was to examine differentially expressed miRNAs in plasma between EGFR-TKIs sensitive and EGFR-TKIs primary resistance patients. MiRNA microarray of plasma from patients' blood identified 16 differentially expressed miRNAs of which 15 (hsv2-miR-H19, hsa-miR-744-5p, hsa-miR-3196, hsa-miR-3153, hsa-miR-4791, hsa-miR-4803, hsa-miR-4796-3p, hsa-miR-372-5p, hsa-miR-138-2-3p, hsa-miR-16-1-3p, hsa-miR-1469, hsa-miR-585-3p, ebv-miR-BART14-5p, hsa-miR-769-3p, hsa-miR-548aq-5p) were down regulated while only hsa-miR-503-3p was up regulated in primary resistant patients' plasma. Volcano plot and hierarchical clustering were performed to examine the accuracy of the miRNAs. Then validation with quantitative real-time PCR was performed and the result was in accordance with the array data. Functional analysis of these differentially expressed miRNAs with Ingenuity Pathway Analysis (IPA) revealed a common signaling network including MYC, CCND1, IGF1 and RELA. In conclusion, our finding may play important role in understanding the mechanisms underlying the problem and should be further evaluated as potential biomarkers in primary resistance of NSCLC.
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Affiliation(s)
- Yihan Ma
- Xiamen Cancer Hospital the First Affiliated Hospital of Xiamen University, 361003 Fujian, China
| | - Xiaoyan Pan
- Xiamen Cancer Hospital the First Affiliated Hospital of Xiamen University, 361003 Fujian, China.,Department of Medical Oncology, Linyi Cancer Hospital, 276000 Shandong, China
| | - Peiqi Xu
- Reproduction Center, The Second Affiliated Hospital of Kunming Medical University, 650101 Yunnan, China
| | - Yanjun Mi
- Xiamen Cancer Hospital the First Affiliated Hospital of Xiamen University, 361003 Fujian, China
| | - Wenyi Wang
- Xiamen Cancer Hospital the First Affiliated Hospital of Xiamen University, 361003 Fujian, China
| | - Xiaoting Wu
- Xiamen Cancer Hospital the First Affiliated Hospital of Xiamen University, 361003 Fujian, China
| | - Qi He
- Xiamen Cancer Hospital the First Affiliated Hospital of Xiamen University, 361003 Fujian, China
| | - Xinli Liu
- Xiamen Cancer Hospital the First Affiliated Hospital of Xiamen University, 361003 Fujian, China
| | - Weiwei Tang
- Xiamen Cancer Hospital the First Affiliated Hospital of Xiamen University, 361003 Fujian, China
| | - Han-Xiang An
- Xiamen Cancer Hospital the First Affiliated Hospital of Xiamen University, 361003 Fujian, China
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Huang G, Tong Y, He Q, Wang J, Chen Z. Aucklandia lappa DC. extract enhances gefitinib efficacy in gefitinib-resistance secondary epidermal growth factor receptor mutations. JOURNAL OF ETHNOPHARMACOLOGY 2017; 206:353-362. [PMID: 28619365 DOI: 10.1016/j.jep.2017.06.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Revised: 06/06/2017] [Accepted: 06/10/2017] [Indexed: 06/07/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Aucklandia lappa DC. is a widely used medicinal plant in China, India and Pakistan for a long time. Previously, a number of different pharmacological experiments in vitro and in vivo have convincingly demonstrated the abilities of it to exhibit anticancer activities. Reynoutria japonica Houtt. has also been widely used as traditional Chinese medicinal plant. Previous studies have demonstrated that it is bioactive to exhibit anticancer activities. AIM OF THE STUDY This study aims to investigate whether the extracts of Aucklandia lappa DC. and Reynoutria japonica Houtt. are capable of treating drug-resistant non-small cell lung cancer (NSCLC), providing support for novel usage beyond traditional uses. MATERIALS AND METHODS Extracts combined with gefitinib have been tested taking the vulval development of transgenic C. elegans (jgIs25) as an effective and simple in vivo model system, evaluating their efficacy against acquired NSCLC. Synchronous larval 1 (L1) larvae were treated with extracts plus gefitinib and cultured to obtain mainly L4 larvae. The multivulva (Muv) phenotype was recorded at the adult stage. RESULTS Our data showed that Aucklandia lappa DC. extract could significantly enhance the efficacy of gefitinib, suppressing the Muv phenotype of jgIs25. Meanwhile, it could also down-regulate the mRNA and protein expression of EGFR in jgIs25. Collectively, our results verified that the capability of Aucklandia lappa DC. to inhibit Muv phenotype may be based on the EGFR signaling pathway inhibition. CONCLUSION We demonstrated that the co-administration of Aucklandia lappa DC. with gefitinib may provide an effective strategy for the therapy of EGFR inhibitor resistant NSCLCs.
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Affiliation(s)
- Guan Huang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Yanli Tong
- Department of Pharmacy, Guangdong Second Provincial General Hospital, Guangzhou 510317, China.
| | - Qidi He
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Jie Wang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Zuanguang Chen
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
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Shang B, Jia Y, Chen G, Wang Z. Ku80 correlates with neoadjuvant chemotherapy resistance in human lung adenocarcinoma, but reduces cisplatin/pemetrexed-induced apoptosis in A549 cells. Respir Res 2017; 18:56. [PMID: 28399858 PMCID: PMC5387337 DOI: 10.1186/s12931-017-0545-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 04/06/2017] [Indexed: 12/12/2022] Open
Abstract
Background Ku80 is a DNA repair protein which involves in cell apoptosis and chemoresistance. However, it is unclear whether Ku80 correlates with the efficiency of neoadjuvant chemotherapy in human lung adenocarcinoma, and modulates cisplatin/pemetrexed-induced lung cancer cell apoptosis in vitro. Methods We recruited 110 patients with stage IIIA lung adenocarcinoma, who received 2 cycles of neoadjuvant chemotherapy, and their lungs were reevaluated by CT scan. Immunohistochemistry and qRT-PCR was performed to detect the expression level of Ku80. A549 cells were transfected by lentiviral vector containing shRNA and full length cDNA to knockdown or upregulate Ku80 gene expression. CCK8 assay, flow cytometry and Western blot were employed to determine the viability and apoptosis of A549 cells treated with cisplatin combined with pemetrexed. Results Ku80 expression was detected in 76 patients (69%). There were 38 patients who responded to chemotherapy, where Ku80 was positively expressed in 7 cases (18.4%). Immunohistochemical score of Ku80 protein in the response group (2.079 ± 1.617) to chemotherapy was lower than that in the nonresponse group (5.597 ± 2.114, P < 0.05). Tissue samples from the nonresponse group exhibited higher Ku80 mRNA levels compared to the response group. Ku80 knockdown by shRNA augmented cisplatin/pemetrexed-induced decline in viability, whereas Ku80 overexpression attenuated viability reduction induced by these drugs compared to control A549 cells. Both flow cytometry and Western blot analysis displayed that the apoptotic rate of Ku80 shRNA-transfected A549 cells was significantly increased compared to control cells treated with cisplatin/pemetrexed, which was lowered by Ku80 overexpression. Conclusion Ku80 could predict the probability of resistance to neoadjuvant chemotherapy in lung adenocarcinoma, and reduced cisplatin and pemetrexed-induced apoptosis in A549 cells.
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Affiliation(s)
- Bin Shang
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu Road, Jinan, Shandong, 250021, China
| | - Yang Jia
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu Road, Jinan, Shandong, 250021, China
| | - Gang Chen
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu Road, Jinan, Shandong, 250021, China.
| | - Zhou Wang
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu Road, Jinan, Shandong, 250021, China.
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40
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Fahrmann JF, Grapov DD, Wanichthanarak K, DeFelice BC, Salemi MR, Rom WN, Gandara DR, Phinney BS, Fiehn O, Pass H, Miyamoto S. Integrated Metabolomics and Proteomics Highlight Altered Nicotinamide- and Polyamine Pathways in Lung Adenocarcinoma. Carcinogenesis 2017; 38:271-280. [PMID: 28049629 PMCID: PMC5862279 DOI: 10.1093/carcin/bgw205] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 12/02/2016] [Accepted: 12/20/2016] [Indexed: 01/11/2023] Open
Abstract
Lung cancer is the leading cause of cancer mortality in the United States with non-small cell lung cancer (NSCLC) adenocarcinoma being the most common histological type. Early perturbations in cellular metabolism are a hallmark of cancer, but the extent of these changes in early stage lung adenocarcinoma remains largely unknown. In the current study, an integrated metabolomics and proteomics approach was utilized to characterize the biochemical and molecular alterations between malignant and matched control tissue from 27 subjects diagnosed with early stage lung adenocarcinoma. Differential analysis identified 71 metabolites and 1102 proteins that delineated tumor from control tissue. Integrated results indicated four major metabolic changes in early stage adenocarcinoma: (1) increased glycosylation and glutaminolysis; (2) elevated Nrf2 activation; (3) increase in nicotinic and nicotinamide salvaging pathways; and (4) elevated polyamine biosynthesis linked to differential regulation of the SAM/nicotinamide methyl-donor pathway. Genomic data from publicly available databases were included to strengthen proteomic findings. Our findings provide insight into the biochemical and molecular biological reprogramming that may accompanies early stage lung tumorigenesis and highlight potential therapeutic targets.
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Affiliation(s)
- Johannes F Fahrmann
- University of California, Davis, West Coast Metabolomics Center, Davis, California
| | | | | | - Brian C DeFelice
- University of California, Davis, West Coast Metabolomics Center, Davis, California
| | | | - William N Rom
- Division of Pulmonary, Critical Care, and Sleep, NYU School of Medicine, New York, NY, USA
| | - David R Gandara
- Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, University of California, Davis Medical Center, Sacramento, California
| | | | - Oliver Fiehn
- University of California, Davis, West Coast Metabolomics Center, Davis, California
- Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi-Arabia
| | - Harvey Pass
- Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Langone Medical Center, New York University, New York, NY, USA
| | - Suzanne Miyamoto
- Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, University of California, Davis Medical Center, Sacramento, California
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Zhang YK, Zhang XY, Zhang GN, Wang YJ, Xu H, Zhang D, Shukla S, Liu L, Yang DH, Ambudkar SV, Chen ZS. Selective reversal of BCRP-mediated MDR by VEGFR-2 inhibitor ZM323881. Biochem Pharmacol 2017; 132:29-37. [PMID: 28242251 DOI: 10.1016/j.bcp.2017.02.019] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 02/22/2017] [Indexed: 10/20/2022]
Abstract
The expression of breast cancer resistant protein (BCRP) in lung cancer is correlated with development of multidrug resistance (MDR) and therefore leads to lower response to chemotherapy. ZM323881, a previously developed selective VEGFR-2 inhibitor, was found to have inhibitory effects on BCRP-mediated MDR in this investigation. ZM323881 significantly decreased the cytotoxic doses of mitoxantrone and SN-38 in BCRP-overexpressing NCI-H460/MX20 cells. Mechanistic studies revealed that ZM323881 effected by inhibiting BCRP-mediated drug efflux, leading to intracellular accumulation of BCRP substrates. No significant alteration in the expression levels and localization pattern of BCRP was observed when BCRP-overexpressing cells were exposed to ZM323881. Stimulated bell-shaped ATPase activities were observed. Molecular docking suggested that ZM323881 binds to the modulator site of BCRP and the binding pose is stable validated by 100ns molecular dynamic simulation. Overall, our results indicated that ZM323881 reversed BCRP-related MDR by inhibiting its efflux function. These findings might be useful in developing combination chemotherapy for MDR cancer treatment.
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Affiliation(s)
- Yun-Kai Zhang
- College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Xiao-Yu Zhang
- College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Guan-Nan Zhang
- College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Yi-Jun Wang
- College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Huizhong Xu
- College of Liberal Arts and Sciences, St. John's University, Queens, NY 11439, USA
| | - Dongmei Zhang
- College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Suneet Shukla
- Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Lili Liu
- Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou 510300, China
| | - Dong-Hua Yang
- College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Suresh V Ambudkar
- Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Zhe-Sheng Chen
- College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
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Hu X, Liu L, Chen D, Wang Y, Zhang J, Shao L. Co-expression of the recombined alcohol dehydrogenase and glucose dehydrogenase and cross-linked enzyme aggregates stabilization. BIORESOURCE TECHNOLOGY 2017; 224:531-535. [PMID: 27838320 DOI: 10.1016/j.biortech.2016.10.076] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Revised: 10/22/2016] [Accepted: 10/24/2016] [Indexed: 06/06/2023]
Abstract
As the key chiral precursor of Crizotinib (S)-1-(2,6-dichloro-3-fluorophenyl) phenethyl alcohol can be prepared from 1-(2,6-dichloro-3-fluorophenyl) acetophenone by the reductive coupling reactions of alcohol dehydrogenase (ADH) and glucose dehydrogenases (GDH). In this work the heterologous expression plasmids harbouring the encoding genes of ADH and GDH were constructed respectively and co-expressed in the same E. coli strain. After optimization, a co-cross-linked enzyme aggregates (co-CLEAs) of both ADH and GDH were prepared from crude enzyme extracts by cross-linking with the mass ratio of Tween 80, glutaraldehyde and total protein (0.6:1:2) which rendered immobilized biocatalysts that retained 81.90% (ADH) and 40.29% (GDH) activity retention. The ADH/GDH co-CLEAs show increased thermal stability and pH stability compared to both enzymes. The ADH/GDH co-CLEAs also show 80% (ADH) and 87% (GDH) residual activity after seven cycles of repeated use. These results make the ADH/GDH co-CLEAs a potential biocatalyst for the industrial preparation of (S)-1-(2,6-dichloro-3-fluorophenyl) phenethyl alcohol.
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Affiliation(s)
- Xiaozhi Hu
- State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, 285 Gebaini Rd., Shanghai 200040, China; School of Engineering, China Pharmaceutical University, Nanjing 210009, China
| | - Liqin Liu
- State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, 285 Gebaini Rd., Shanghai 200040, China
| | - Daijie Chen
- State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, 285 Gebaini Rd., Shanghai 200040, China
| | - Yongzhong Wang
- School of Life Sciences, Collaborative Innovation Center of Modern Bio-manufacture, Anhui University, Hefei 230039, China
| | - Junliang Zhang
- State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, 285 Gebaini Rd., Shanghai 200040, China
| | - Lei Shao
- State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, 285 Gebaini Rd., Shanghai 200040, China.
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Jia M, Zhu M, Zhou F, Wang M, Sun M, Yang Y, Wang X, Wang J, Jin L, Xiang J, Zhang Y, Chang J, Wei Q. Genetic variants of JNK and p38α pathways and risk of non-small cell lung cancer in an Eastern Chinese population. Int J Cancer 2016; 140:807-817. [DOI: 10.1002/ijc.30508] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 10/19/2016] [Indexed: 12/12/2022]
Affiliation(s)
- Ming Jia
- Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center; Shanghai China
- Department of Oncology; Shanghai Medical College, Fudan University; Shanghai China
| | - Meiling Zhu
- Department of Oncology; Xinhua Hospital affiliated to Shanghai Jiaotong University, School of Medicine; Shanghai China
| | - Fei Zhou
- Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center; Shanghai China
- Department of Oncology; Shanghai Medical College, Fudan University; Shanghai China
| | - Mengyun Wang
- Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center; Shanghai China
- Department of Oncology; Shanghai Medical College, Fudan University; Shanghai China
| | - Menghong Sun
- Department of Oncology; Shanghai Medical College, Fudan University; Shanghai China
- Department of Pathology; Fudan University Shanghai Cancer Center; Xuhui, Shanghai China
| | - Yajun Yang
- Ministry of Education Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering, School of Life Sciences; Fudan University; Shanghai China
- Fudan-Taizhou Institute of Health Sciences; Taizhou Jiangsu China
| | - Xiaofeng Wang
- Ministry of Education Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering, School of Life Sciences; Fudan University; Shanghai China
- Fudan-Taizhou Institute of Health Sciences; Taizhou Jiangsu China
| | - Jiucun Wang
- Ministry of Education Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering, School of Life Sciences; Fudan University; Shanghai China
- Fudan-Taizhou Institute of Health Sciences; Taizhou Jiangsu China
| | - Li Jin
- Ministry of Education Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering, School of Life Sciences; Fudan University; Shanghai China
- Fudan-Taizhou Institute of Health Sciences; Taizhou Jiangsu China
| | - Jiaqing Xiang
- Department of Oncology; Shanghai Medical College, Fudan University; Shanghai China
- Department of Thoracic Surgery; Fudan University Shanghai Cancer Center; Xuhui, Shanghai China
| | - Yawei Zhang
- Department of Oncology; Shanghai Medical College, Fudan University; Shanghai China
- Department of Thoracic Surgery; Fudan University Shanghai Cancer Center; Xuhui, Shanghai China
| | - Jianhua Chang
- Department of Oncology; Shanghai Medical College, Fudan University; Shanghai China
- Department of Medical Oncology; Fudan University Shanghai Cancer Center; Xuhui, Shanghai China
| | - Qingyi Wei
- Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center; Shanghai China
- Department of Oncology; Shanghai Medical College, Fudan University; Shanghai China
- Duke Cancer Institute, Duke University Medical Center, and Department of Medicine; Duke University School of Medicine; Durham NC
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Fahrmann JF, Grapov D, Phinney BS, Stroble C, DeFelice BC, Rom W, Gandara DR, Zhang Y, Fiehn O, Pass H, Miyamoto S. Proteomic profiling of lung adenocarcinoma indicates heightened DNA repair, antioxidant mechanisms and identifies LASP1 as a potential negative predictor of survival. Clin Proteomics 2016; 13:31. [PMID: 27799870 PMCID: PMC5084393 DOI: 10.1186/s12014-016-9132-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Accepted: 10/12/2016] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Lung cancer is the leading cause of cancer mortality in the United States. Non-small cell lung cancer accounts for 85% of all lung cancers for which adenocarcinoma is the most common histological type. Management of lung cancer is hindered by high false-positive rates due to difficulty resolving between benign and malignant tumors. Better molecular analysis comparing malignant and non-malignant tissues will provide important evidence of the underlying biology contributing to tumorigenesis. METHODS We utilized a proteomics approach to analyze 38 malignant and non-malignant paired tissue samples obtained from current or former smokers with early stage (Stage IA/IB) lung adenocarcinoma. Statistical mixed effects modeling and orthogonal partial least squares discriminant analysis were used to identify key cancer-associated perturbations in the adenocarcinoma proteome. Identified proteins were subsequently assessed against clinicopathological variables. RESULTS Top cancer-associated protein alterations were characterized by: (1) elevations in APEX1, HYOU1 and PDIA4, indicative of increased DNA repair machinery and heightened anti-oxidant defense mechanisms; (2) increased LRPPRC, STOML2, COPG1 and EPRS, suggesting altered tumor metabolism and inflammation; (3) reductions in SPTB, SPTA1 and ANK1 implying dysregulation of membrane integrity; and (4) decreased SLCA41 suggesting altered pH regulation. Increased protein levels of HYOU1, EPRS and LASP1 in NSCLC adenocarcinoma was independently validated by tissue microarray immunohistochemistry. Immunohistochemistry for HYOU1 and EPRS indicated AUCs of 0.952 and 0.841, respectively, for classifying tissue as malignant. Increased LASP1 correlated with poor overall survival (HR 3.66 per unit increase; CI 1.37-9.78; p = 0.01). CONCLUSION These results reveal distinct proteomic changes associated with early stage lung adenocarcinoma that may be useful prognostic indicators and therapeutic targets.
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Affiliation(s)
- Johannes F Fahrmann
- University of California, Davis Genome Center, Davis, CA USA.,Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX USA
| | | | - Brett S Phinney
- Genome Center Proteomics Core Facility, University of California, Davis, Davis, CA USA
| | - Carol Stroble
- Division of Hematology and Oncology, Department of Internal Medicine, University of California, Davis Medical Center, 4501 X Street, Suite 3016, Sacramento, CA 95817 USA
| | | | - William Rom
- Division of Pulmonary, Critical Care, and Sleep, NYU School of Medicine, New York, NY USA
| | - David R Gandara
- Division of Hematology and Oncology, Department of Internal Medicine, University of California, Davis Medical Center, 4501 X Street, Suite 3016, Sacramento, CA 95817 USA
| | - Yanhong Zhang
- Department of Pathology and Laboratory Medicine, University of California, Davis Medical Center, Sacramento, CA USA
| | - Oliver Fiehn
- University of California, Davis Genome Center, Davis, CA USA.,Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, 21589 Saudi Arabia
| | - Harvey Pass
- Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Langone Medical Center, New York University, New York City, NY USA
| | - Suzanne Miyamoto
- Division of Hematology and Oncology, Department of Internal Medicine, University of California, Davis Medical Center, 4501 X Street, Suite 3016, Sacramento, CA 95817 USA
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Kasana BA, Dar WR, Aziz SA, Lone AR, Sofi NU, Dar IA, Latief M, Arshad F, Hussain M, Hussain M. Epidermal growth factor receptor mutation in adenocarcinoma lung in a North Indian population: Prevalence and relation with different clinical variables. Indian J Med Paediatr Oncol 2016; 37:189-95. [PMID: 27688613 PMCID: PMC5027792 DOI: 10.4103/0971-5851.190356] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Introduction: Lung cancer is one of the most common causes of cancer deaths worldwide. Adenocarcinoma is taking over squamous cell lung cancer as the predominant histological subtype. Several cytotoxic drugs are available for the treatment of lung cancer, but side effects limit their use. Recently, targeted therapies for cancers have come into clinical practice. Aims and Objectives: To determine the prevalence of epidermal growth factor receptor (EGFR) mutation in adenocarcinoma lung in a North Indian population and its relation with different clinical variables. Materials and Methods: A total of 57 patients who met inclusion criteria were recruited into the study. Relevant history, clinical examination and investigations were done. EGFR mutation was done in all patients. Results: A total of twenty patients tested positive for EGFR mutation. EGFR was more frequently detected in female patients (53.8%), while as only 19.4% of the male patients expressed EGFR mutation, which was statistically very significant (P = 0.007). EGFR mutation was more frequently detected in nonsmokers (52%) as compared to smokers (21.9%) which also was statistically significant (P value of 0.018). EGFR mutation was more common in Stage III and IV adenocarcinomas (48%) as compared to Stage I and II (21.4%) which was statistically significant (P value 0.034). Conclusion: EGFR mutation should be routinely done in all patients of adenocarcinoma lung particularly non-smoker females with Stage III and IV disease.
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Affiliation(s)
- Basharat Ahmad Kasana
- Department of Medicine, Oncology Division, Sher-i-Kashmir Institute of Medical Science, Soura, Jammu and Kashmir, India
| | - Waseem Raja Dar
- Department of Medicine, Oncology Division, Sher-i-Kashmir Institute of Medical Science, Soura, Jammu and Kashmir, India
| | - Sheikh Aijaz Aziz
- Department of Medicine, Oncology Division, Sher-i-Kashmir Institute of Medical Science, Soura, Jammu and Kashmir, India
| | - Abdul Rashid Lone
- Department of Medicine, Oncology Division, Sher-i-Kashmir Institute of Medical Science, Soura, Jammu and Kashmir, India
| | - Najeeb Ullah Sofi
- Department of Medicine, Oncology Division, Sher-i-Kashmir Institute of Medical Science, Soura, Jammu and Kashmir, India
| | - Imtiyaz Ahmad Dar
- Department of Medicine, Oncology Division, Sher-i-Kashmir Institute of Medical Science, Soura, Jammu and Kashmir, India
| | - Muzamil Latief
- Department of Medicine, Oncology Division, Sher-i-Kashmir Institute of Medical Science, Soura, Jammu and Kashmir, India
| | - Faheem Arshad
- Department of Medicine, Oncology Division, Sher-i-Kashmir Institute of Medical Science, Soura, Jammu and Kashmir, India
| | - Moomin Hussain
- Department of Medicine, Oncology Division, Sher-i-Kashmir Institute of Medical Science, Soura, Jammu and Kashmir, India
| | - Mir Hussain
- Department of Medicine, Oncology Division, Sher-i-Kashmir Institute of Medical Science, Soura, Jammu and Kashmir, India
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Palmer M, Geurink J, Hahn K, Kolesar J. Clinical pharmacology and determinates of response to gefitinib in non-small cell lung cancer. J Oncol Pharm Pract 2016. [DOI: 10.1191/1078155204jp130oa] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Objective. Provide a review and update of gefitinib (Iressa®), including recent data on mutations in the epidermal growth factor receptor (EGFR) and possible implications in non-small cell lung cancer patients. Data sources. Primary literature and review articles were researched using Pub-Med. Articles through June 2004 were considered for preparation of the review. All clinical trials with published results and articles reporting EGFR mutations were considered for inclusion by the authors. Conclusions. Gefitinib is a novel EGFR tyrosine kinase inhibitor approved for treatment of chemo-resistant NSCLC. Response rates of 10-19% have been observed in clinical trials with no improvement when combined with chemotherapy. Currently, gefitinib is used as a single agent for advanced NSCLC that is resistant to chemotherapy. Mutations in EGFR correlating with response to gefitinib have recently been described. Based on these early results, genetic testing of NSCLC patients upon diagnosis could predict response to gefitinib. Early treatment of NSCLC patients positive for EGFR mutations with gefitinib remains to be tested.
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Lung Adenocarcinoma Staging Using the 2011 IASLC/ATS/ERS Classification: A Pooled Analysis of Adenocarcinoma In Situ and Minimally Invasive Adenocarcinoma. Clin Lung Cancer 2016; 17:e57-e64. [DOI: 10.1016/j.cllc.2016.03.009] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 03/22/2016] [Accepted: 03/22/2016] [Indexed: 11/20/2022]
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Fernández-López C, Expósito-Hernández J, Arrebola-Moreno JP, Calleja-Hernández MÁ, Expósito-Ruíz M, Guerrero-Tejada R, Linares I, Cabeza-Barrera J. Trends in phase III randomized controlled clinical trials on the treatment of advanced non-small-cell lung cancer. Cancer Med 2016; 5:2190-7. [PMID: 27449070 PMCID: PMC5055155 DOI: 10.1002/cam4.782] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Revised: 04/29/2016] [Accepted: 05/02/2016] [Indexed: 12/02/2022] Open
Abstract
The objective of this review was to analyze trends in outcomes and in the quality of phase III randomized controlled trials on advanced NSCLC published between 2000 and 2012, selecting 76 trials from a total of 122 retrieved in a structured search. Over the study period, the number of randomized patients per trial increased by 14 per year (P = 0.178). The sample size significantly increased between 2000 and 2012 in trials of targeted agents (460.1 vs. 740.8 patients, P = 0.009), trials of >1 drug (360.4 vs. 584.8, P = 0.014), and those including patients with good performance status (675.3 vs. 425.6; P = 0.003). Quality of life was assessed in 46 trials (60.5%), and significant improvements were reported in 10 of these (21.7%). Platinum-based regimens were the most frequently investigated (86.8% of trials). Molecular-targeted agents were studied in 25.0% of chemotherapy arms, and the percentage of trials including these agents increased each year. The median (interquartile range) overall survival (MOS) was 9.90 (3.5) months with an increase of 0.384 months per year of publication (P < 0.001). A statistically significant improvement in MOS was obtained in only 13 (18.8%) trials. The median progression-free survival was 4.9 (1.9) months, with a nonsignificant increase of 0.026 months per year (P > 0.05). There has been a continuous but modest improvement in the survival of patients with advanced NSCLC over the past 12 years. Nevertheless, the quality of clinical trials and the benefit in outcomes should be carefully considered before the incorporation of novel approaches into clinical practice.
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Affiliation(s)
- Cristina Fernández-López
- Department of Pharmacy, Biosanitary Institute of Granada (ibs.GRANADA), University Hospitals of Granada/University of Granada, Granada, Spain.
| | | | | | - Miguel Ángel Calleja-Hernández
- Department of Pharmacy, Biosanitary Institute of Granada (ibs.GRANADA), University Hospitals of Granada/University of Granada, Granada, Spain
| | - Manuela Expósito-Ruíz
- Unit Research Support, Biosanitary Institute of Granada (ibs.GRANADA), University Hospitals of Granada/University of Granada, Granada, Spain
| | - Rosa Guerrero-Tejada
- Department of Oncology, Virgen de las Nieves Universitary Hospital, Granada, Spain
| | - Isabel Linares
- Department of Oncology, Virgen de las Nieves Universitary Hospital, Granada, Spain
| | - José Cabeza-Barrera
- Department of Pharmacy, Biosanitary Institute of Granada (ibs.GRANADA), University Hospitals of Granada/University of Granada, Granada, Spain
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49
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Lee SE, Lee SY, Park HK, Oh SY, Kim HJ, Lee KY, Kim WS. Detection of EGFR and KRAS Mutation by Pyrosequencing Analysis in Cytologic Samples of Non-Small Cell Lung Cancer. J Korean Med Sci 2016; 31:1224-30. [PMID: 27478332 PMCID: PMC4951551 DOI: 10.3346/jkms.2016.31.8.1224] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 04/10/2016] [Indexed: 02/02/2023] Open
Abstract
EGFR and KRAS mutations are two of the most common mutations that are present in lung cancer. Screening and detecting these mutations are of issue these days, and many different methods and tissue samples are currently used to effectively detect these two mutations. In this study, we aimed to evaluate the testing for EGFR and KRAS mutations by pyrosequencing method, and compared the yield of cytology versus histology specimens in a consecutive series of patients with lung cancer. We retrospectively reviewed EGFR and KRAS mutation results of 399 (patients with EGFR mutation test) and 323 patients (patients with KRAS mutation test) diagnosed with lung cancer in Konkuk University Medical Center from 2008 to 2014. Among them, 60 patients had received both EGFR and KRAS mutation studies. We compared the detection rate of EGFR and KRAS tests in cytology, biopsy, and resection specimens. EGFR and KRAS mutations were detected in 29.8% and 8.7% of total patients, and the positive mutation results of EGFR and KRAS were mutually exclusive. The detection rate of EGFR mutation in cytology was higher than non-cytology (biopsy or resection) materials (cytology: 48.5%, non-cytology: 26.1%), and the detection rate of KRAS mutation in cytology specimens was comparable to non-cytology specimens (cytology: 8.3%, non-cytology: 8.7%). We suggest that cytology specimens are good alternatives that can readily substitute tissue samples for testing both EGFR and KRAS mutations. Moreover, pyrosequencing method is highly sensitive in detecting EGFR and KRAS mutations in lung cancer patients.
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Affiliation(s)
- Seung Eun Lee
- Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
| | - So-Young Lee
- Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
| | - Hyung-Kyu Park
- Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
| | - Seo-Young Oh
- Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
| | - Hee-Joung Kim
- Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
| | - Kye-Young Lee
- Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
| | - Wan-Seop Kim
- Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
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50
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Lin JB, Lai FC, Li X, Tu YR, Lin M, Qiu ML, Luo RG, Liu B, Lin JW. Sequential treatment strategy for malignant pleural effusion in non-small cell lung cancer with the activated epithelial grow factor receptor mutation. J Drug Target 2016; 25:119-124. [PMID: 27282915 DOI: 10.1080/1061186x.2016.1200590] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
- Jian-Bo Lin
- Department of Thoracic Surgery, First Affiliated Hospital, Fujian Medical University, Fuzhou City, People’s Republic of China
| | - Fan-Cai Lai
- Department of Thoracic Surgery, First Affiliated Hospital, Fujian Medical University, Fuzhou City, People’s Republic of China
| | - Xu Li
- Department of Thoracic Surgery, First Affiliated Hospital, Fujian Medical University, Fuzhou City, People’s Republic of China
| | - Yuan-Rong Tu
- Lung Cancer Center, First Affiliated Hospital, Fujian Medical University, Fuzhou City, People’s Republic of China
| | - Min Lin
- Lung Cancer Center, First Affiliated Hospital, Fujian Medical University, Fuzhou City, People’s Republic of China
| | - Min-Lian Qiu
- Department of Thoracic Surgery, First Affiliated Hospital, Fujian Medical University, Fuzhou City, People’s Republic of China
| | - Rong-Gang Luo
- Department of Thoracic Surgery, First Affiliated Hospital, Fujian Medical University, Fuzhou City, People’s Republic of China
| | - Bo Liu
- Department of Thoracic Surgery, First Affiliated Hospital, Fujian Medical University, Fuzhou City, People’s Republic of China
| | - Jing-Wei Lin
- Lung Cancer Center, First Affiliated Hospital, Fujian Medical University, Fuzhou City, People’s Republic of China
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