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K. Takayama



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    P1.07 - Immunology and Immunotherapy (ID 693)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      P1.07-044 - The Impact of Neutrophil/Lymphocyte Ratio as the Predictive Marker to Anti-PD-1 Antibody Treatment in NSCLC Patients (ID 9913)

      09:30 - 09:30  |  Author(s): K. Takayama

      • Abstract

      Background:
      Anti-Programmed death 1 (PD-1) antibody which enhances anti-tumor activity of cytotoxic T lymphocytes by blockade of PD-1/PD-L1 pathway has demonstrated improvement of survival in the patients with advanced non-small-cell lung cancer (NSCLC). PD-1 and its ligand PD-L1 is also known as key players in the formation of tumor microenvironment, closely related with inflammatory cytokines. Here, we retrospectively analyzed the potential of peripheral blood biomarkers for predicting outcome of anti-PD-1 antibody therapy.

      Method:
      Patients treated with anti-PD-1 antibody nivolumab from February 2016 to March 2017 in our hospital were selected. We investigated the tendency of differential leukocyte counts and c-reactive protein (CRP) in peripheral blood as inflammatory markers on the treatment progress with nivolumab.

      Result:
      19 patients were enrolled. Median age was 67, ECOG-PS 0 or 1 were 16 (84.2%). Histological subtypes were non-squamous 10 (52.6%), and squamous 9 (47.4%). Median follow-up was 7.2 months (range: 2.2-16.1 months), median progression free survival was 2.5 months. Disease control rate was 42.1%, and overall response rate was 26.3%. Of some parameters in peripheral blood, lower absolute lymphocyte count (ALC), higher absolute neutrophil count (ANC), neutrophil to lymphocyte ratio (NLR), and platelet lymphocyte ratio (PLR) at baseline were associated with shorter survival. Interestingly, patient with longer PFS decreased NLR at baseline and its parameter remained at low levels until disease progression.

      Conclusion:
      Lower pre-treatment ANC, NLR and PLR are associated with longer survival, and increased NLR during nivolumab therapy is reflect disease progression in NSCLC patients. We suggest that peripheral blood biomarkers may predict response and acquisition of resistance to anti-PD-1 therapy.

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    P3.03 - Chemotherapy/Targeted Therapy (ID 719)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 1
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      P3.03-002 - Histone Deacetylase Inhibition Enhances the Antitumor Activity of a MEK Inhibitor in Lung Cancer Cells Harboring RAS Mutations (ID 7917)

      09:30 - 09:30  |  Author(s): K. Takayama

      • Abstract

      Background:
      Non-small-cell lung cancer (NSCLC) can be identified by precise molecular subsets based on genomic alterations that drive tumorigenesis and include mutations in EGFR, KRAS, and various ALK fusions. However, despite effective treatment for EGFR and ALK, promising therapeutics have not been developed for patients with KRAS mutations. Therefore, novel therapeutic strategies for KRAS mutated cancer based on molecular mechanisms are needed to improve their prognosis. It has been reported that one way the RAS-ERK pathway contributes to tumorigenesis is by affecting stability and localization of FOXO3a protein, an important regulator of cell death and the cell cycle.

      Method:
      We used NSCLC cells with RAS mutation to evaluate the effect of a MEK inhibitor in combination with a HDAC inhibitor through the expression and localization of FOXO proteins in vitro and in vivo. Protein expression was examined by Western blotting.

      Result:
      Combined treatment with a MEK inhibitor and a HDAC inhibitor showed synergistic effects on cell viability of RAS mutated lung cancer cells through activation of FOXOs, with a subsequent increase in BIM and cell cycle inhibitors. Moreover, in a mouse xenograft model, the combination of belinostat and trametinib significantly decreases tumor formation through FOXOs by increasing BIM and increase in cell cycle inhibitors p21 and p27.

      Conclusion:
      These findings demonstrate that FOXOs might be one of the critical pathways in RAS driven lung cancer cells, suggesting that the dual molecular targeted therapy for MEK and HDACs may be promising as novel therapeutic strategy in NSCLC with specific populations of RAS mutations.