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Tetsunari Hase
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-91 - Exosomal Analysis of ALK Rearrangements by Spin Column with Porous Glass Filter (ID 2206)
10:15 - 18:15 | Author(s): Tetsunari Hase
- Abstract
Background
ALK rearrangements account for about 3-5% of non-small cell lung cancer (NSCLC). ALK-tyrosin kinase inhibitors (TKI) demonstrated robust efficacy compared with cytotoxic chemotherapy in patients with ALK alterations detected in the tumor tissues. Identifying ALK rearrangement was performed using tissue samples, which are not always available. The spin column with porous glass filter has been developed by Nagoya university and AGC Inc, resulting in highly efficient and easy to use exosome isolation. The exosomes contain various molecules of their cell of origin, including proteins and RNA. The purpose of this study was to explore the spin column to capture exosome and detect ALK alterations in exosomal RNA from blood.
Method
The supernatant of cell culture medium (H3122, H2228) and plasma samples from 3 patients with ALK-positive NSCLC were passed through the filter using a conventional centrifugation. Exosome captured in the filter was lysed with reagent for RNA extraction. The total RNA was retrotranscripted by random primers. The ALK rearrangement in the exosome were determined by RT-qPCR and DNA sequencing.
Result
EML4-ALK variant 1 and 3 were detected in exosome from 500μL of culture supernatant of H3122 and H2228, respectively. In the analysis of exosome in plasma from patients with EML4-ALK determined by fluorescence in situ hybridization and immunohistochemistry, EML4-ALK variant 1 was successfully detected in all cases.
Conclusion
Exosome remains relatively stable in the blood, making it an attractive target for liquid biopsy. Our preliminary results showed potential capability in the detection of ALK alteration in exosomes from blood. These findings require confirmation in further studies with a larger number of patients with ALK-positive NSCLC.
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-23 - UHRF1 as a Potential Therapeutic Target for KRAS Mutated Non-Small Cell Lung Cancer (ID 687)
10:15 - 18:15 | Author(s): Tetsunari Hase
- Abstract
Background
KRAS mutation occurring in approximately 20% of non-small cell lung cancer (NSCLC) functions as a driver oncogene and it serves as a potential therapeutic target. However, development of KRAS-targeted drugs has not been successful primarily because of difficulty in pharmacologically inhibiting a constitutively activated KRAS signaling. Activation of several driver oncogenes including mutant KRAS in normal cells causes cellular senescence, leading to permanent cell cycle arrest, which is termed oncogene-induced senescence (OIS). Thus, KRAS mutated cancers are thought to acquire additional alterations that allow bypassing OIS and such alterations could be good targets for them. With this background, we designed the present study to identify therapeutic targets whose inhibition cause growth suppression in KRAS mutated NSCLC through inducing OIS.
Method
We established cdk4/hTERT-immortalized normal human bronchial epithelial cell (HBEC) that expresses mutant KRAS upon tetracycline treatment (designated HBEC-RIN). A semi-genome wide shRNA library (DECIPHER) targeting 5,000 genes was transduced in HBEC- RIN. Each shRNA vector is barcoded with unique sequence for quantification. Two weeks after culturing the cells, we extracted genomic DNA from cells at two points: before (point#1) and after (point #2) tetracycline treatment. The barcodes of DNA were sequenced with NGS at a depth of 20 million reads. The effects of senescence-bypass were determined by dividing the normalized barcode abundance at point #2 by that of point#1. The significance of change of each gene was determined by performing t-test to compare replicates of shRNA with a given gene with those of luciferase. Senescence was evaluated by senescence associated b-gal staining. Three KRAS mutated lung cancer cell lines (A549, H2009, and H460) were used to examine effects of silencing candidates of OIS-bypassing genes. Association between prognosis and expression of candidate genes in NSCLC patients was analyzed with several online datasets.
Result
We drew a volcano plot from results of a shRNA screen. We selected genes based on significant average suppressive effects. In the present study, we focused on Ubiquitin-like, containing PHD and RING finger domains, 1 (UHRF1) because we were able to confirm OIS-bypassing ability of this gene in HBEC-RIN by its transient silencing with synthetic siRNA. Colorimetric growth and colony formation assays showed that UHRF1 knockdown suppresses cell growth and colony formation in H2009 but not in A549 or H460. Importantly, we found that expression of UHRF1 mRNA correlated with worse prognosis in patients with NSCLC in multiple independent datasets, suggesting its potential as a prognostic marker.
Conclusion
These results suggest that UHRF1 is a potential therapeutic target for KRAS mutated NSCLC and that it is a prognostic marker for NSCLC.
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-21 - Serum CRP Decrease Has Predictive Value for Long-Term Disease Control by PD-1/ PD-L1 Inhibitors in Patients with NSCLC (ID 305)
10:15 - 18:15 | Author(s): Tetsunari Hase
- Abstract
Background
Several studies showed the predictive or prognostic value of systemic inflammatory markers such as C-reactive protein (CRP) in patients with non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 inhibitors. In OAK study, serum CRP decrease at 6 weeks from baseline was associated with the favorable clinical efficacy of atezolizumab, a PD-L1 inhibitor. However, the result is not validated in the clinical practice setting including patients treated with anti PD-1 antibodies. The aim of this study is to investigate the significance of serum CRP change from baseline as a biomarker in NSCLC patients treated with PD-1/PD-L1 inhibitors.
Method
The current study is a retrospective cohort study. NSCLC patients treated with anti-PD-1/PD-L1 inhibitors in 2nd or later line setting were reviewed at Nagoya University Hospital and Tosei General Hospital. Patients were divided into two groups by serum CRP change (Group 1; patients with serum CRP decrease at 6 weeks by >= 33% compared to the baseline, and Group 2; the others except Group 1).
Result
From January 2016 to September 2018, 124 advanced or recurrent NSCLC patients were enrolled. 34 (27.4%) patients were divided into Group 1 and 90 (72.6%) were into group 2, respectively. Group 1 showed statistically significant higher objective response rate compared with Group 2 (38.2% vs 7.0%, p< 0.01), and longer progression-free survival (PFS) (1-year PFS rate: 34.2% vs. 11.7%, HR of group 1 to group 2: 0.63 (95%CI: 0.39-0.98), p=0.04). Multivariate analysis also identified the CRP decrease as an independent favorable factor of PFS (adjusted HR of group 1 to group 2: 0.45 (95%CI: 0.26-0.77), p< 0.01). In contrast, PFS and OS were similar between the patients treated with PD-1 and PD-L1 inhibitors.
Conclusion
Serum CRP decrease at 6 weeks from baseline would have predictive value for long-term disease control by PD-1/PD-L1 inhibitors for NSCLC in the clinical practice setting.
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P2.18 - Treatment of Locoregional Disease - NSCLC (ID 191)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment of Locoregional Disease - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.18-18 - Impact of Combined Evaluation Using Tumor Volume and Metastatic Nodal Extent in Stage III NSCLC Treated with CRT (ID 310)
10:15 - 18:15 | Author(s): Tetsunari Hase
- Abstract
Background
Chemoradiotherapy (CRT) is the standard treatment for patients with unresectable stage III non-small cell lung cancer (NSCLC). In those, gross tumor volume (GTV) and number of metastatic nodal stations were proposed as possible prognostic factors, while TNM stage classification (stage IIIA vs. stage IIIB/IIIC) did not show significant prognostic impact. However, these evidences remain controversial. The aim of this study was to investigate the prognostic impact of GTV and metastatic nodal extent.
Method
We retrospectively reviewed stage III NSCLC patients treated with CRT at our institution between October 2005 and December 2018. Simplified GTV (sGTV) was calculated by oval volume formula. We confirmed statistically significant association between sGTV and standard GTV as previous preparation. Metastatic nodal extent was divided into limited nodal extent (≤ND2a) (defined as "LN") or extensive nodal extent (>ND2a)(defined as "EN"). Prognostic impact of sGTV and metastatic nodal extent was evaluated by univariate and multivariate analysis.
Result
58 patients were enrolled in this study. Median progression-free survival (PFS) of all patients were 9.0 months. In univariate analysis, patients with sGTV>90cm3 had shorter PFS compared to those with sGTV≤90cm3 (median PFS: 6.7 vs. 11.7, p=0.03). Further, patients with sGTV>90cm3 and EN showed poorer PFS (HR 3.3; 95% CI,1.40-7.87; p<0.01) and OS (HR 3.3, 95% CI: 1.18-9.32, p<0.01) in univariate analysis. Multivariate analysis also showed an independent poor prognosis in patients with sGTV>90cm3 and EN (adjusted HR of PFS: 3.6, 95% CI: 1.49-8.71, p<0.01, adjusted HR of OS 4.1, 95% CI: 1.37-12.6, p=0.01).
Conclusion
Combined evaluation using sGTV and metastatic nodal extent can be a useful stratified factor for clinical trial in patients with stage III NSCLC.
