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K. Shilo



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    ORAL 42 - Drug Resistance (ID 160)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL42.05 - <em>SMARCA4</em>/BRG1 Is a Biomarker for Predicting Efficacy of Cisplatin-Based Chemotherapy in Non-Small Cell Lung Cancer (NSCLC) (ID 849)

      18:30 - 20:00  |  Author(s): K. Shilo

      • Abstract
      • Slides

      Background:
      Adjuvant platinum-based chemotherapy remains a primary treatment of non-small-cell lung cancer (NSCLC); however, identification of predictive biomarkers is critically needed to improve the selection of patients who derive the most benefit. In this study, we hypothesized that decreased expression of SMARCA4/BRG1, a known regulator of transcription and DNA repair, is a predictive biomarker of increased sensitivity to platinum-based therapies in NSCLC. Moreover, this study also sought to confirm the prognostic role of SMARCA4/BRG1 in NSCLC.

      Methods:
      The prognostic value of SMARCA4 expression levels was tested using a microarray dataset from the Director’s Challenge Lung Study (n=440). Its predictive significance was determined using a gene expression microarray dataset (n=133) from the JBR.10 trial, and RT-PCR data from 69 patients enrolled on the MADe-IT trial and 33 platinum-treated patients from an institutional cohort.

      Results:
      In the Director's challenge study, low expression of SMARCA4 was found to be associated with poor overall survival compared to high and intermediate expression (P = 0.006). Upon multivariate analysis, compared to high, low SMARCA4 expression predicted an increased risk of death and confirmed its prognostic significance (HR=1.75; P=0.002). In the JBR.10 trial, improved five-year disease-specific survival was noted only in patients with low SMARCA4 expression when treated with adjuvant cisplatin/vinorelbine (HR 0.1, P= 0.001 (low); HR 1.1 , P= 0.762 (high)). An interaction test showed significance (P=0.007). In addition, a trend toward improved progression-free survival was noted only in patients with low SMARCA4 receiving a carboplatin- versus a non-carboplatin-based regimen in the MADe-IT trial. Figure 1 Fig1. Low SMARCA4 correlates with improved disease-specific survival with adjuvant cisplatin-based chemotherapy in the JBR.10 trial.



      Conclusion:
      Although decreased expression of SMARCA4/BRG1 is significantly associated with worse prognosis, it is a novel significant predictive biomarker for increased sensitivity to platinum-based chemotherapy in NSCLC patients.

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    P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      P1.08-004 - Aki1 as a Potential Therapeutics Target in CREB1 Signaling in Malignant Mesothelioma (ID 234)

      09:30 - 17:00  |  Author(s): K. Shilo

      • Abstract

      Background:
      Malignant pleural mesothelioma (MPM) is an aggressive tumor arising from the mesothelial cells of serosal membranes. Since current treatment options are largely ineffective, novel therapeutic strategies based on molecular mechanisms and the disease characteristics are needed to improve its prognosis. Akt kinase-interacting protein 1 (Aki1)/Freud-1/CC2D1A known as a scaffold protein of PI3K/PDK1/Akt that determines receptor signal selectivity for EGFR has been suggested as a therapeutic target in lung cancer. The aim of this study was to elucidate the role of Aki1 and its potential for treatment of MPM.

      Methods:
      We tested the effects of the treatment with Aki1 or CREB1 siRNAs on cell viability by MTT assay, cell cycle by FACS analysis, cell signaling by WB, and CREB transcriptional activity in 7 MPM cells and 1 mesothelial cells using in vitro experiments. We investigated the efficacy of Aki1 siRNA against growth of 211H cells in an orthotropic implantation model using SCID mice. We further examined Aki1 and p-CREB1 expressions in MPM tumors from 35 patients by TMA specimens and from 33 patients by the tissues.

      Results:
      Cell based assay showed that silencing of Aki1 inhibited cell viability and caused cell arrest of some of MPM cells but not mesothelial cells. Importantly, we identified that the efficacy of Aki1 is regulated by CREB1 signaling which is involved in cell viability, cell cycle, and transcriptional activity. Aki1 and phosphorylated CREB1 were frequently expressed in MPM patients (65/68 cases) (30/35 cases), respectively. Furthermore, the expression of Aki1 correlated with phosphorylation of CREB1 (Spearman rank correlations = 0.521; p = 0.002). Furthermore, direct application of Aki1 siRNA into the pleural cavity significantly inhibited growth of 211H cells compared with that of control siRNA in an orthotropic implantation model using SCID mice.

      Conclusion:
      Our data suggest an important role of Aki1/CREB axis in pathogenesis of MPM and provide a rationale for targeting Aki1 by intrathoracic therapy in locally advanced tumors.