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X. Han



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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-038 - The significance of ALK rearrangement in selected advanced non-small cell lung cancer: ALK expression provides insights into ALK target therapy (ID 2757)

      09:30 - 09:30  |  Author(s): X. Han

      • Abstract

      Background
      ALK rearrangements are detected in 3%~7% in unselected non-small cell lung cancer (NSCLC) and accurate determination of ALK rearrangements are the key importance to screen appropriate candidates for ALK inhibitor therapy. Previous studies showed that IHC could be a promising prescreening method. However, the correlation between IHC results and clinical outcomes had not been confirmed. This study aimed to elucidate clinical significance of ALK rearrangement in selected advanced NSCLC patients and evaluate a possible association between ALK expression and clinical outcomes in ALK positive crizotinib-treated patients.

      Methods
      ALK status was assessed by FISH, immunohistochemistry (IHC) and quantitative RT-PCR(qRT-PCR) in 173 selected advanced NSCLC patients who were aiming at undergoing ALK screening for crizotinib therapy. Clinicopathologic data, genotype status and survival outcomes were analyzed. In addtion, we correlated ALK expression with clinical outcomes in crizotinb treated patients including two patients with concurrent ALK rearrangement and EGFR mutation.

      Results
      ALK positive detection rate was 35.5% (59/166), 36.3% (61/168), 27.9% (34/122) by FISH, IHC and qRT-PCR, respectively. Among the 166 advanced NSCLC patients who were successfully underwent ALK screening by FISH, 20 patients with EGFR mutation, 87 patients with wild type status and 2 (3.4%, 2/59) patients with concurrent ALK rearrangement and EGFR mutation. Of the 59 patients with FISH-positive ALK rearrangement, 45 received crizotinib in the phase II clinical trial (PROFILE 1005), 8 were enrolled in the phase III clinical trial (PROFILE 1014) and 6 did not participate in any clinical trial. ALK-positive patients have distinct clinicopathological features. ALK FISH-positive and crizotinib-treated patients (PROFILE 1005) had a median progression-free survival (PFS) of 7.6 months and longer overall survival (OS) compared with crizotinib-naïve (P<0.0001) or wild type cohorts (P=0.0138), but there was no significant difference in OS compared with EGFR mutation patients(P=0.8959). ALK positive and negative patients divided by qRT-PCR in the ALK FISH crizotinib-treated patients had no different in clinical outcomes. ALK expression was not associated with PFS (P=0.792) and OS (P=0.325). However, when used IHC expression as a dichotomous variable, moderate and strong ALK expression had a decreased risk of death (P=0.026). The two patients with concurrent EGFR mutation and ALK rearrangement had difference in ALK expression, response to TKIs and crizotinib, and overall survival.

      Conclusion
      In the era of ALK-targeted inhibitors, enriching NSCLC patients according to clinicopathologic characteristics could highly improve ALK detection rate for molecular target therapy. IHC could be a supplementary method to provide more clues for clinical trial design and therapeutic strategies for NSCLC patients who harbor ALK rearrangement including patients with double genetic aberration of ALK and EGFR.

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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): X. Han

      • 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.