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Masashi Kondo



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    P1.03 - Biology (Not CME Accredited Session) (ID 935)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.03-13 - eIF2β, A Subunit of Translation-Initiation Factor EIF2, as a Potential Therapeutic Target for Non-Small Cell Lung Cancer (ID 11293)

      16:45 - 18:00  |  Author(s): Masashi Kondo

      • Abstract
      • Slides

      Background

      To identify potential therapeutic targets for non-small cell lung cancer (NSCLC), we recently performed a semi-genome wide shRNA screen in a NSCLC cell line H460 . Through this approach, we identified multiple potential targets for NSCLC (Kakumu et al. Cancer Sci, 2017). In the present study, to search for genes with more generalized potential as therapeutic targets, we did shRNA screen using the alternative NSCLC cell line H358 and combined its results with those of our previous screen.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      19 NSCLC cell lines, two cdk4/hTERT-immortalized normal human bronchial epithelial (HBEC) cell lines and primary NHBE culture were used. A semi-genome wide shRNA screen was performed with the DECIPHER library in H358, and its results were integrated with those of our previous screen in H460. Gene silencing was done with RNA interference followed by growth and cell cycle analyses.

      4c3880bb027f159e801041b1021e88e8 Result

      24 genes overlapped between results of two shRNA screens in H460 and H358 and we identified these as more generalized targets. Gene-annotation enrichment analysis showed that the RNA transport pathway including three genes is one of the overrepresented pathways in the 24 genes. Among the three genes, we determined to focus on eIF2β, a subunit of translation-initiation factor EIF2 because other two genes included in the RNA transport pathway, XPO1 and RAN are well characterized therapeutic targets for human cancers including lung cancer. eIF2β protein was more abundantly expressed in all the 19 lung cancer cell lines analyzed than in NHBE used as a control. To determine the clinical relevance of eIF2β in lung cancer, we examined eIF2β mRNA expression in lung adenocarcinoma tissues using TCGA dataset. These analyses showed significantly higher expression of eIF2β mRNA in lung adenocarcinoma tissues than in normal adjacent tissues. Importantly, we found that expression of eIF2β mRNA correlated with worse prognosis in patients with lung adenocarcinoma in multiple independent datasets, suggesting its potential as a prognostic marker. Next, we examined the effects of eIF2β knockdown on the growth of the H460 and H1975. Colorimetric growth and colony formation assays showed that eIF2β knockdown in H460 and H1975 suppresses cell growth and colony formation.

      8eea62084ca7e541d918e823422bd82e Conclusion

      eIF2β is highly expressed in NSCLC cells, and its expression correlates with poor prognosis in patients with lung adenocarcinoma. Knockdown of eIF2β caused G1 arrest in lung cancer cell lines. These results suggest that eIF2β is a potential therapeutic target for NSCLC and that it is a prognostic marker for lung adenocarcinoma.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.03-18 - Mechanobiology of Lung Cancer Cells: Regulation of PD-L1 Expression by Matrix Stiffness (ID 11153)

      16:45 - 18:00  |  Author(s): Masashi Kondo

      • Abstract
      • Slides

      Background

      Expression of programmed death-ligand 1 (PD-L1) in tumor cells plays an important role in mechanisms underlying evasion of an immune check point system. PD-L1 expression is regulated by multiple mechanisms such as the tumor microenvironment. Lung cancer tissue with increased deposition of extracellular matrix is much stiffer than normal lung tissue. There is emerging evidence that the matrix stiffness of cancer tissue affects the phenotypes and properties of cancer cells. Nevertheless, the effects of substrate rigidity on expression of PD-L1 in lung cancer cells remain elusive. This study was designed to determine whether substrate stiffness affects the regulation of PD-L1 in lung cancer cells.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We evaluated PD-L1 expression levels in HCC827 human lung cancer cell line. Commercially available polyacrylamide hydrogels of different stiffnesses bound to 6-well polystyrene plates or polystyrene dishes coated with type I collagen were utilized. We used 2 and 25 kPa gels as substrates of normal (soft) human lung and cancer-associated (stiff) tissue. Western blotting and Immunofluorescence staining were performed for evaluating PD-L1 expression levels. A colorimetric viability assay was performed for evaluating of PD-L1 expression and cell proliferation by using transfection with short interfering RNA (siRNA) for PD-L1.

      4c3880bb027f159e801041b1021e88e8 Result

      Expression of PD-L1 protein was higher on the stiffer substrates (25 kPa gel and plastic dish) than on the soft 2 kPa gel. PD-L1 expression was reduced by detachment of cells adhering to the substrate. Interferon-γ enhanced expression of PD-L1 protein cultured on stiff (25 kPa gel and plastic dishes) and soft (2 kPa gel) substrates and in the cell adhesion-free condition. As the stiffness of substrates increased, formation of actin stress fiber and cell growth were enhanced. Transfection of the cells with siRNA for PD-L1 inhibited cell growth without affecting stress fiber formation. Treatment of the cells with cytochalasin D, an inhibitor of actin polymerization, significantly reduced PD-L1 protein levels.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Stiff substrates enhanced PD-L1 expression via actin cytoskeleton-dependent mechanisms in HCC827 lung cancer cell line. It is suggested that stiffness as a tumor environment regulates PD-L1 expression, which leads to evasion of the immune system and tumor growth.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.01-34 - Short Hydration Regimen with a Modified Dose of Magnesium Supplementation for Lung Cancer Patients Receiving Cisplatin-Based Chemotherapy (ID 12290)

      12:00 - 13:30  |  Author(s): Masashi Kondo

      • Abstract

      Background

      Intravenous administration of magnesium is recommended for patients receiving high-dose cisplatin with a short hydration regimen in terms of protection against cisplatin-induced nephrotoxicity. However, the optimal dose of the magnesium supplementation has not been clarified. The aim of this trial was to investigate the safety and efficacy of short hydration regimen with 20mEq of magnesium supplementation for lung cancer patients receiving cisplatin-based chemotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The key eligibility criteria included cytologically or histologically proven lung cancer, candidates for cisplatin (≥60 mg/m2) based chemotherapy or chemoradiotherapy, no prior chemotherapy, age ranged 20 and 75 years old and adequate renal function. Cisplatin was administered with pre-hydration containing 20 mEq of magnesium sulfate. Mannitol was administered just before the cisplatin infusion as an enforced diuresis. The primary endpoint was the proportion of patients without a Grade 2 or higher elevation in creatinine. The study was registered at UMIN-CTR as UMIN000011687.

      4c3880bb027f159e801041b1021e88e8 Result

      Forty patients with a median age of 66 years (range, 35-74) were enrolled in the study. Of these, 16 had adenocarcinoma, 12 had squamous cell carcinoma, 5 had small cell carcinoma, 2 had large cell carcinoma and 5 had other histology. The median baseline creatinine value was 0.71 mg/dl. The median dose of cisplatin at the first cycle was 80 mg/m2. Twenty-nine patients received cisplatin and vinorelbine as their most frequent regimen and 24 patients received 4 cycles of chemotherapy. In the first cycle, no patients developed Grade 2 creatinine toxicity. During the whole treatment period, one patient developed Grade 2 creatinine elevation, and thus, the proportion of patients without a Grade 2 or higher elevation in creatinine was 97.5% (95%CI 86.8‐99.9). Grade 1 hypermagnesemia was observed in 3 patients.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study indicates short hydration regimen with 20mEq of magnesium supplementation was safe and feasible for lung cancer patients receiving cisplatin-based chemotherapy without risk of severe nephrotoxicity.

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