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S. Wang



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    P2.05 - Poster Session 2 - Preclinical Models of Therapeutics/Imaging (ID 158)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.05-015 - A novel CRM1 inhibitor targeting for NSCLC with EGFR-TKI resistance mutation (ID 2520)

      09:30 - 09:30  |  Author(s): S. Wang

      • Abstract

      Background
      Chromosome Region Maintenance 1 (CRM1) is a nuclear exporter which transports certain proteins from the nucleus to the cytoplasm, including tumor suppressor proteins (TSPs) and other modulators of proliferation. Overexpression of CRM1 correlates with cancer progression in several human cancers, suggesting that CRM1 could serve as a novel target for treatment of cancers. NSCLC is an aggressive carcinoma which is not yet curable. The aim of our study was to explore the therapeutic efficiency of novel drug-like CRM1 inhibitors in NSCLC in vitro and in vivo, and to investigate the cytotoxic mechanisms of CRM1 inhibitors in NSCLC cell lines with EGFR-TKI resistance mutation.

      Methods
      KPT-185 and KPT-276 are selective inhibitors of nuclear export (SINE) that block CRM1. Cell viability, apoptosis and cell cycle were evaluated in 6 NSCLC cell lines (H1975, H1650, A549, H2228, HCC827, H1650 Gefitinib Resistance (H1650GR)) after treated with KPT-185; expression level of CRM1 in NSCLC cell lines was detected after exposed to KPT-185; TSPs were detected by western blot to explore the possible mechanisms of KPT-185 inducing NSCLC cells growth inhibition and apoptosis. NOD-SCID mice bearing H1975 (epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistant) tumors were treated orally with KPT-276 (similar structure to KPT-185, but improved animal pharmacokinetics) to examine the efficacy and side-effects of KPT-276 in vivo.

      Results
      In 6 NSCLC cell lines, growth inhibition showed in a time- and dose-dependent way after treated with KPT-185. The EGFR TKI resistant cell lines H1975 and H150GR were sensitive to KPT-185. Cell apoptosis analysis showed that KPT-185 induced NSCLC cells apoptosis in a dose-dependent manner. Also, KPT-185 induced cell cycle arrest at the G1/S checkpoint in NSCLC cell lines. CRM1 protein expression of 6 NSCLC cell lines was down regulated when treated with KPT-185, which could be completely abolished by bortezomib. CRM1 inhibition by KPT-185 up-regulated the expression of proteins involved in apoptosis in NSCLC cell lines, and down-regulated the expression of EGFR and survivin. In the xenograft H1975 model, tumor growth was significantly inhibited in KPT-276 oral treatment group compared with vehicle control group and EGFR-TKI treatment group (P<0.01), and there was no significant loss in body weight or side-effects in KPT-276 treatment group.

      Conclusion
      SINE CRM1 inhibitors showed anti-tumor activity in NSCLC both in vitro and in vivo, especially in EGFR-TKI resistance cell lines, it could inhibit the growth of NSCLC, arrest cell cycle, reduce expression of CRM1 protein, and the anti-tumor activity of SINE is mainly through inducing cell apoptosis. SINE is a novel CRM1 inhibitor and a promising clinical candidate.

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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-051 - Clinical significance of pretreatment plasma biomarkers in advanced non-small cell lung cancer patients (ID 1160)

      09:30 - 09:30  |  Author(s): S. Wang

      • Abstract

      Background
      The use of biomarkers for selecting patients with non-small cell lung cancer (NSCLC) for treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is essential for achieving a satisfactory therapeutic outcome. EGFR mutations have been found to be predictive of response to EGFR-TKIs. The aim of this study was to explore whether biomarkers which can be identified in plasma, such as EGFR mutations, circulating free DNA, and levels of expressed cytokines are predictive for response to EGFR-TKIs and patient survival time.

      Methods
      Formalin-fixed and paraffin-embedded biopsies from tumor tissues and paired plasma samples were collected from 134 patients with advanced NSCLC, EGFR mutations in both types of specimens were assessed by an ARMS/Scorpion assay using real-time PCR. Expression levels of transforming growth factor-alpha and beta one (TGF-α and TGF-β1) were assessed using an enzyme-linked immunosorbent assay (ELISA). Concentrations of circulating free DNA were detected in both NSCLC patients and healthy subjects by a colorimetric assay using ultraviolet spectrometry. The clinical significance of EGFR mutations, levels of cytokines, and circulating free DNA was assessed in advanced NSCLC patients treated with EGFR-TKIs.

      Results
      EGFR somatic mutations were detected in the tumors from 68 of 134 (50.7%) advanced NSCLC patients, and EGFR mutations were detected in the plasma samples from 17 (12.7%) NSCLC patients. Also, the concentrations of circulating free DNA were higher in NSCLC patients than in healthy subjects (P<0.01). EGFR-TKI treatment produced significant effects on progression-free survival (PFS) and overall survival (OS) that were related to the presence of EGFR mutations detected in the tumor tissues (P<0.01).Patients with high levels of TGF-β1 showed shorter OS and worse response to EGFR-TKI treatment than patients with low TGF-β1 levels (P<0.01); however, patients with different expression levels of TGF-α showed no difference in either PFS or OS (P>0.05). Multivariate analysis showed that younger age, adenocarcinoma, never smoking and EGFR somatic mutation were associated with a longer PFS time, and adenocarcinoma, never smoking, low performance status (PS) score, EGFR somatic mutation and low levels of TGF-β1 were associated with greater OS (P<0.05).

      Conclusion
      Plasma levels of TGF-β1 may be a marker for predicting response to EGFR-TKIs and survival time in NSCLC patients, and levels of circulating free DNA could be a biomarker for differentiating between NSCLC patients and healthy individuals.