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Author Notes:

E-mail: jcbrand@emory.edu

Conceived and designed the experiments: SAB CL GL JCB AIM PMV FRK. Performed the experiments: SAB CL GL JCB. Analyzed the data: SAB CL GL JK KG JCB PMV AIM. Contributed reagents/materials/analysis tools: SY. Contributed to the writing of the manuscript: SAB JCB PMV FRK.

The authors' have read the journal's policy and the authors of this manuscript have the following competing interests: the Suntrust Scholar Award was an unconditional philanthropic gift of Suntrust Bank to the Winship Cancer Institute of Emory University to support pilot projects. The authors never had a direct connection with this commercial source. Rather, the authors' project was chosen by the Director of the Winship Cancer institute for funding based on the results of a peer review. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

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Research Funding:

Support was provided by the Veterans' Health Administration Career Development Award 7-IK2BX001283-03 to JCB; NCI- 5 P50 CA128613-02 Career Development Project to JCB; NCI-P30CA138292 pilot grant to JCB; CHEST Foundation/Lungevity Foundation Clinical Lung Cancer Research Award to JCB; Uniting against Lung Cancer / Lungevity Foundation Research Award to JCB; SunTrust Scholar Award to JCB; Cohen Family Scholar Award to JCB; and Elsa U Pardee Foundation Research Award to JCB. This research project was supported in part by the Emory University Integrated Cellular Imaging Microscopy Core and the Biostatistics and Bioinformatics Shared Resource of the Winship Cancer Institute of Emory University under award number P30CA138292.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Department of Veterans Affairs. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • CELL LUNG-CANCER
  • EPIGENETIC INACTIVATION
  • MESENCHYMAL TRANSITION
  • POOR-PROGNOSIS
  • GENE
  • SENSITIVITY
  • EXPRESSION
  • RESISTANCE
  • INHIBITORS
  • CHEMORESISTANCE

Aberrant Promoter Methylation of Caveolin-1 Is Associated with Favorable Response to Taxane-Platinum Combination Chemotherapy in Advanced NSCLC

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PLoS ONE

Volume:

Volume 9, Number 9

Publisher:

, Pages e107124-e107124

Type of Work:

Article | Final Publisher PDF

Abstract:

Purpose Aberrant promoter DNA methylation can serve as a predictive biomarker for improved clinical responses to certain chemotherapeutics. One of the major advantages of methylation biomarkers is the ease of detection and clinical application. In order to identify methylation biomarkers predictive of a response to a taxane-platinum based chemotherapy regimen in advanced NSCLC we performed an unbiased methylation analysis of 1,536 CpG dinucleotides in cancer-associated gene loci and correlated results with clinical outcomes. Methods We studied a cohort of 49 patients (median age 62 years) with advanced NSCLC treated at the Atlanta VAMC between 1999 and 2010. Methylation analysis was done on the Illumina GoldenGate Cancer panel 1 methylation microarray platform. Methylation data were correlated with clinical response and adjusted for false discovery rates. Results Cav1 methylation emerged as a powerful predictor for achieving disease stabilization following platinum taxane based chemotherapy (p = 1.21E-05, FDR significance = 0.018176). In Cox regression analysis after multivariate adjustment for age, performance status, gender, histology and the use of bevacizumab, CAV1 methylation was significantly associated with improved overall survival (HR 0.18 (95%CI: 0.03–0.94)). Silencing of CAV1 expression in lung cancer cell lines(A549, EKVX)by shRNA led to alterations in taxane retention. Conclusions CAV1 methylation is a predictor of disease stabilization and improved overall survival following chemotherapy with a taxane-platinum combination regimen in advanced NSCLC. CAV1 methylation may predict improved outcomes for other chemotherapeutic agents which are subject to cellular clearance mediated by caveolae.

Copyright information:

© 2014 Brodie et al.

This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits distribution, public display, and publicly performance, distribution of derivative works, making multiple copies, provided the original work is properly cited. This license requires copyright and license notices be kept intact, credit be given to copyright holder and/or author.

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