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Y. Shi



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    MO12 - Prognostic and Predictive Biomarkers III (ID 96)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO12.05 - A new biomarker Heat shock protein 90 alpha as therapeutic monitor and predictor for lung cancer patients (ID 2628)

      10:30 - 12:00  |  Author(s): Y. Shi

      • Abstract
      • Presentation
      • Slides

      Background
      Heat shock proteins are a group of proteins termed stress proteins. The family of Hsp90 includes Hsp90α and Hsp90β, but only Hsp90α has been described to be extracellular, and the presence of Hsp90α on cell surface has been shown to correlate with malignancy in cancer patients, especially with the tumor metastasis. However, to the best of our knowledge, no large clinical samples have been reported to verify above standpoint. The aim of the present multicenter clinical study was to evaluate the expression level of Hsp90α in lung cancer patients and whether Hsp90α was monitor and predictor for response to therapy in lung cancer.

      Methods
      A total of 2284 lung cancer patients were enrolled in this study which was randomly assigned into two groups as static and dynamic groups. The static group (2036 samples) consisted of healthy subjects (592 samples), lung cancer (1046 samples), non-cancerous lesions of the lung patients(361 samples ) and other cancer patients(37 samples). Samples of peripheral blood from all subjects were collected in sterile EDTA-K2-coated vials. Whereas the dynamic group included lung cancer patients who received surgical treatment and underwent chemotherapy, with number of above mentioned parts 79 and 169, respectively. For surgical patients, plasma samples were collected at following time points: 3 days before surgery, 3-7 days after surgery and 3 days after clinical efficacy evaluation. Similarly, plasma samples of chemotherapy patients were also collected before treatment, after each chemotherapy cycle until the forth cycle. The concentrations of Hsp90α in plasma were measured by enzyme-linked immunosorbent assay.

      Results
      The concentration of Hsp90α in lung cancer patients was significantly higher than in other control groups (P <0.05). The cut-off value was 56.33 ng/mL for diagnosis, with high sensitivity and specificity (72.18% and 78.70%, respectively). Advanced lung cancer (stage III-Ⅳ) patients were with higher Hsp90α levels than the early patients(stage I-II) (251.38 ng/ml vs 111.50ng/ml, P<0.001), no significant relationship was found between non-small cell lung cancer（NSCLC,910 samples）patients and small cell lung cancer （SLCL, 136 samples）patients, and patients with adenocarcinoma(537 samples) and squamouscarcinoma (218 samples). Furthermore, a statistically significant association was observed between pre-operative and post-operative patients in surgical patients group (P<0.01). In chemotherapy patients group, Hsp90α level was correlated significantly with the effect of treatment [concentration of Hsp90α was higher in progressive disease(PD)group than in partial response(PR)/stable disease(SD) group].

      Conclusion
      This study firstly developed large clinical samples and elucidated the role of Hsp90α in the lung cancer patients. The cut-off value of 56.33 ng/mL was recommended to assess the expression level of Hsp90α in lung cancer patients. Hsp90α may be a potential biomarker for therapeutic monitor and prediction for lung cancer.

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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 - 16:30  |  Author(s): Y. Shi

      • 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.