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M. Nishimura



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    P1.01 - Poster Session 1 - Cancer Biology (ID 143)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.01-014 - Effects of combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor and the histone deacetylase inhibitor on NSCLC cells. (ID 2680)

      12:32 - 12:46  |  Author(s): M. Nishimura

      • Abstract

      Background
      EZH2, a polycomb group protein, has histone methyltransferase activity, and is involved in malignant transformation of several cancers. We have previously shown that an EZH2 inhibitor, DZNep, inhibits growth of non-small cell lung cancer (NSCLC) cell lines via G1 arrest and apoptosis. Recent studies have shown that EZH2-mediated gene silencing requires a recruitment of the histone deacetylase (HDAC) activity. Co-treatment with DZNep and an HDAC inhibitor has been shown to induce apoptosis synergistically in AML, ovarian cancers and renal cancers. However, the effect of combined therapy with DZNep and an HDAC inhibitor on NSCLC cells has not been reported.

      Methods
      We evaluated the effect of combined therapy with DZNep and an HDAC inhibitor, SAHA, on four human NSCLC cell lines, H1299, H1975, A549 and PC-3. Cell proliferation of untreated or drug-treated cells was measured by MTT assay. Percentage of apoptotic cells was measured using FITC-conjugated annexin V with a flow cytometer. Western blot analysis was performed on total cell lysates.

      Results
      Co-treatment with DZNep and SAHA inhibited cell proliferation synergistically, and reduced EZH2 expression and histone H3 lysine 27 trimethylation more effectively compared with each agent alone. The co-treatment greatly induced accumulation of p27[ Kip1] and decrease in cyclin A expression. Flow cytometry analysis demonstrated that the apoptotic fraction was increased in an additive or synergistic manner by the combination therapy. These effects were more evident in H1975 and PC-3 cells with EGFR mutation, in which expression of EGFR and phosphorylation of EGFR, AKT and ERK1/2 were markedly decreased by the co-treatment.

      Conclusion
      Combined epigenetic therapy with an EZH2 inhibitor and an HDAC inhibitor may represent an effective strategy for NSCLCs.

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    P2.10 - Poster Session 2 - Chemotherapy (ID 207)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.10-017 - Efficacy of Pemetrexed in advanced non-small cell lung cancer with asymptomatic brain metastases (ID 1118)

      09:30 - 09:30  |  Author(s): M. Nishimura

      • Abstract

      Background
      Conventionally, the role of chemotherapy in brain metastases (BM) from non-small cell lung cancer (NSCLC) remains limited. However, some cases in which brain metastases (BM) are responsive to Pemetrexed (PEM) have been recognized recently.

      Methods
      We conducted a retrospective analysis of 74 advanced NSCLC patients who had received PEM-containing regimens in our institution from January 2006 to May 2013.

      Results
      Twenty-seven patients had been diagnosed as having BM before starting chemotherapy of PEM-containing regimens. The patient characteristics were: male/female = 12/15; median age (range) = 63 (25-85) years; smoking status: ever/never = 13/14; performance status: 0/1/2 = 0/26/1; histology: adenocarcinoma/NSCLC-NOS = 26/1; EGFR mutation status: positive/negative/unknown = 12/12/3; prior EGFR-TKI therapy: yes/no = 13/14 ; response to prior EGFR-TKI: CR/PR/SD/PD = 1/8/3/1. Fourteen patients had received any local treatments for BM, consisting of 7 whole brain radiotherapy (WBRT), 6 stereotactic radiotherapy (SRT), 2 stereotactic radiosurgery (SRS) and 2 brain surgery. The PEM-containing regimens administered were; CDDP+PEM/CBDCA+PEM/PEM alone = 2/9/16. The lines of chemotherapy was; 1st/2nd/3rd/4th or later = 5/7/9/6. They received the chemotherapy for a median cycle of 3 cycles (range 1-15). The overall response rate (ORR) was 14.8% (4/27) in total and the cranial response rate regarding BM was 14.8%(4/27), consisting of 1 CR and 3 PR. Of 13 patients who received prior EGFR-TKI, the cranial response rate was 23.1% (3/13). Of 17 patients without any prior local treatments for BM or with disease progression of BM after the prior local treatment, the cranial response rate was 23.5% (4/17).

      Conclusion
      The PEM-containing regimens might be a promising therapy for asymptomatic BM in NSCLC including those who showed resistance to EGFR-TKI.