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Masaoki Ito
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MA10 - Emerging Technologies for Lung Cancer Detection (ID 129)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Screening and Early Detection
- Presentations: 1
- Now Available
- Moderators:Fabrizio Bianchi, Marcelo Sanchez
- Coordinates: 9/08/2019, 15:15 - 16:45, Dublin (1997)
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MA10.11 - Sensitivity and Optimal Clinicopathological Features of Genetic Targeted Liquid Biopsy in pN0M0 Lung Adenocarcinoma (Now Available) (ID 788)
15:15 - 16:45 | Presenting Author(s): Masaoki Ito
- Abstract
- Presentation
Background
Liquid biopsy for diagnosis of early-stage lung cancer is still challenging. The optimal marker and methodology has not been established. In Asia, almost 40-50% of lung adenocarcinomas harbor the EGFR mutation and L858R is a representative of a somatic EGFR mutation. We evaluated the usefulness of the EGFR somatic mutation in liquid biopsy using droplet digital PCR (ddPCR), which is a sensitivity device to detect several types of genetic mutations.
Method
We examined weather L858R could be detected from preoperative ctDNA by ddPCR. Cases without EGFR mutation (wild type) were utilized as negative control. All involved cases underwent surgical resection after preoperative HRCT and PET-CT. Serum for ctDNA extraction was collected before the operation. L858R in the primary site was confirmed by resected surgical specimen. Clinicopathological features (e.g.: whole and invasive tumor size on HRCT, SUV max on PET-CT, histological subtype) were also explored for an optimal liquid biopsy candidate.
Result
Forty-five pN0M0 lung adenocarcinoma patients harboring L858R were enrolled. Twenty-one and 24 cases showed part-solid and pure solid appearance on HRCT, respectively. Median whole and invasive tumor size on HRCT was 21 and 19 mm, respectively. 91.1% (41/45) cases were clinical stage IA1-IB and 97.8% (44/45) cases were pathological stage IA1-IB. In wild type cases, positive droplet for L858R was almost completely undetectable. Whereas, L858R was significantly detected in 7 EGFR mutant cases (sensitivity is 15.56%, 7/45). Among 7 positive cases, 6 cases showed pure solid appearance in preoperative HRCT. Except for pure solid appearance, there was no significant features related to the positive result. If cases are limited to pure solid appearance, 25.0% (6/24) of cases could be diagnosed by liquid biopsy. Even small-sized tumors (1.1 cm in diameter) or tumors with slight accumulation on PET-CT (SUV max 0.5) could be detected if it showed pure solid appearance on HRCT.
Conclusion
L858R can be a definitive marker for liquid biopsy using ddPCR in pN0M0 lung adenocarcinoma. 15.56% (7/45) of cases were diagnosed in pN0M0 cases. Limited to pure solid tumor, 25.0% (6/24) could be detected. Liquid biopsy can be a useful diagnostic option, especially for tumors with pure solid appearance.
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P1.03 - Biology (ID 161)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.03-14 - HLA-E and FAT1 in Head and Neck and Lung Cancer. The Effect of Osimertinib or Olmutinib with Artesunate (Dihydroartemisinin) (ID 912)
09:45 - 18:00 | Author(s): Masaoki Ito
- Abstract
Background
Cisplatin and cetuximab have little effect in head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinoma (LSCC). HLA-E expression suppressed the cetuximab effect and HLA-E is overexpressed in both HNSCC and LSCC. In addition, FAT1 inactivating mutations are present in 30% of HNSCCs and 19% of LSCCs. Dihydroartemisinin (DHA) inhibits STAT3 and increases cisplatin effect in HNSCC. Osimertinib and olmutinib increase intracellular accumulation of doxorubicin by blocking the efflux function of ABC transporters. We posit that osimertinib or olmutinib, plus DHA, could have activity in the HNSCC cell lines, FaDu and CAL27, with loss of FAT1 expression.
Method
Osimertinib and olmutinib plus DHA were tested in the FaDu and CAL27 cell lines. Tumor cell proliferation assays (MTTs) and mouse xenografts were performed, and western blotting analysis was carried out. FaDu CTXR clone #3 (cetuximab-resistant, a gift from Bhola) and SCCNC4 (EGFR exon 20 S768_D770 dup, a gift from Hermsen) were also examined.
Result
1. DHA decreased HLA-E protein levels in a dose dependent manner in the FaDu CTXR.
2. DHA was able to induce the expression of FAT1 in FaDu and CAL27 cells.
3. Osimertinib plus DHA had a synergistic effect (<1, Combination index (CI)=0.468 and 0.593 in FaDu and CAL27, respectively). Olmutinib with DHA was also synergistic (CI=0.773 and 0.762 in FaDu and CAL27).
4. Osimertinib plus DHA was validated in vivo in FaDu and CAL27 mice xenografts with significant tumor regression.
5. Osimertinib plus DHA suppress the expression of onco-effectors: STAT3, Src, YAP and AXL.
6. Osimertinib plus DHA was also synergistic in SCCNC4 (CI=0.596).
Conclusion
The findings indicate that DHA can revert resistance to cetuximab by repressing the expression of HLA-E. The combination of DHA plus osimertinib was active in the parental FaDu, but not in FaDu CTXR. For tumors with lack of FAT1 expression, the use of DHA reactivates FAT1 and YAP1 inhibition was noted. DHA has been tested for the treatment of systemic lupus erythematosus (SLE), orally, daily for 2 years. The results encourage development of clinical trials with DHA to re-sensitize HNSCC and LSCC cells to cetuximab-based therapy.
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P1.17 - Treatment of Early Stage/Localized Disease (ID 188)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.17-08 - mRNA Expression Level of Receptor Tyrosine Kinases and Non-Receptor Tyrosine Kinases as a Recurrence Risk in Resected Adenocarcinoma of the Lung (ID 786)
09:45 - 18:00 | Presenting Author(s): Masaoki Ito
- Abstract
Background
The profile of receptor tyrosine kinases (RTK) and non-receptor tyrosine kinases (non-RTK) is crucial for tumor genesis and therapeutic strategy in several types of cancer. We previously reported that elevated mRNA expression level of some RTKs/non-RTKs (AXL, CDCP1, STAT3, YAP1) were related to poorer prognosis in lung adenocarcinoma patients receiving EGFR-TKI. The prognostic impact of RTKs/non-RTKs is unclear in early-stage lung cancer. This study aims to explore the usefulness of RTK and non-RTK to detect the risk of recurrence in resected NSCLC, especially in EGFR mutant adenocarcinoma.
Method
We retrospectively collected pathologic N0-2 adenocarcinoma cases resected in Japanese and Spanish institutions. mRNA expression levels of RTK or non-RTK (STAT3, YAP1, AXL, CDCP1, MET, SHP2, and EGFR) in surgical specimens were evaluated and the impact of expression level on recurrence-free survival (RFS) was compared. The oncological significance on RTK or non-RTK was validated in vitro.
Result
Among enrolled 268 cases, 100 cases (37.3%) harbored EGFR mutation. Forty-five EGFR mutation positive cases recurred and cases with higher mRNA expression level of EGFR showed worse RFS. In addition, higher expression of CDCP1 or SHP2 indicated poorer RFS in EGFR mutation positive cases. In vitro, combination of SHP099 (SHP2 inhibitor) and osimertinib showed synergism in EGFR mutation positive cell line (Combination index was 0.62).
Conclusion
Higher expression of SHP2 and CDCP1 is potential risk of recurrence in EGFR mutant lung adenocarcinoma. The synergism of SHP2 inhibitor plus EGFR-TKI suggests that the expression level of SHP2 is involved in tumorigenesis and is a promising predictor for recurrence in EGFR mutant lung adenocarcinoma.
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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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P2.03-45 - PKCι-PAK1 Pathway Modulates Sensitivity to Therapy in EGFR, KRAS Mutant Adenocarcinoma and Squamous Cell Carcinoma (ID 789)
10:15 - 18:15 | Presenting Author(s): Masaoki Ito
- Abstract
Background
p21-activated kinase 1 (PAK1) stimulates growth and metastasis in several types of tumors, including non-small cell lung cancer (NSCLC). Protein kinase C iota (PKCi) is an enzyme highly expressed in NSCLC that regulates PAK1 signaling. To understand intrinsic and acquired resistance to different MAPK signaling inhibitors, we explored PKCι-PAK1 signaling in EGFR/KRAS mutant adenocarcinoma or squamous cell carcinoma (SCC) cell lines by combination therapy using PAK1 inhibitor and PKCι inhibitor.
Method
Three lung cancer cell lines were used: HCC827 and H23 lung adenocarcinoma cells that carries EGFR and KRAS mutations, respectively, and H520 (PAK1 amplified squamous cell carcinoma). Cell viability assays and western blotting were applied to evaluate the effect of IPA-3 (PAK1 inhibitor) plus auranofin (PKCι inhibitor). Since IPA-3 is only for laboratory use, we explored alternative PAK-1 inhibitor and tested combination effect with auranofin.
Result
IPA-3 plus auranofin was highly synergistic (Combination index was less than 0.4) in EGFR mutant adenocarcinoma (HCC827), KRAS mutant adenocarcinoma (H23) and SCC with PAK1 amplification (H520) cell lines in MTT assay and colony forming assay. We revealed OTSSP167 (a MELK inhibitor in phase I/II trials) inhibits phosphorylated PAK1 and combination of OTSSP167 plus auranofin showed similar synergism in the 3 cell lines. The combination of auranofin with either IPA-3 or OTSSP167 ablated EGFR phosphorylation and downstream signaling pathways: ERK, AKT, STAT3, YAP1 and inhibited the expression of RTKs: AXL, MET, and CDCP1.
Conclusion
The combination of IPA-3 plus auranofin is promising treatment in different subclasses NSCLC with driver EGFR or KRAS mutations, as well as SCC with PAK1 amplification. OTSSP167 also works as PAK1 inhibitor. The therapeutic effect of PAK-1 inhibitor and PKCι inhibitor was validated using OTSSP167 plus auranofin.
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YI03 - Scientific Mentoring (ID 109)
- Event: WCLC 2019
- Type: Young Investigator Session
- Track: Young Investigators
- Presentations: 1
- Now Available
- Moderators:Lizza Hendriks, Carme Obiols
- Coordinates: 9/08/2019, 10:30 - 12:00, Dublin (1997)
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YI03.04 - Oncology Fellows' Career Plans and Expectations (Now Available) (ID 3706)
10:30 - 12:00 | Presenting Author(s): Masaoki Ito
- Abstract
- Presentation
Abstract
I will discuss how I planned my fellow career and tips for achieving based on my own experience. My own career is short, at around 10 years, but I would be glad if my presentation could be of some service to fellows in the same position.
If you want to achieve something different than your current situation for your own career, then you gain qualifications, earn achievements such as publishing papers, participate in the academic community, or organize projects, but it is difficult to decide on the ultimate goal at an early stage. For young fellows to build a career, the process is more crucial than setting the outcome, therefore it is essential to know oneself, in addition to learning the latest information on thoracic oncology. Read articles, participate in academic conferences and train at other facilities as a means of understanding your own knowledge and competencies, rather than simply as a means of learning about thoracic oncology.
Although training at special facility will provide the smallest amount of information about thoracic oncology at one time, I believe it is the most efficient means of learning about oneself. This type of learning enables you to directly and simultaneously understand your disadvantages, advantages and characteristics. I have worked and researched at several hospitals and research institutes both in Japan and overseas. I made use of the scholarship system in the past to conduct clinical training in Spain, which enabled me to gain a wealth of clinical experience that I would not have been able to experience in Japan. I am currently affiliated with a research institute in Barcelona and have been involved in research there since 2017 under world-renowned supervisors. I contribute to joint research between Japan and Spain, and Spain and the US, and this, among other opportunities, has enabled me to learn a great deal at my current facility. This experience has not only strengthened my resolve about the new goals I want to achieve, it has also made me fully aware of areas where I am lacking.
For the training at a special facility, getting the grant is crucial. I have received some grant support from several academic associations including IASLC. The financial supports allowed me to gain and achieve ambitious aims. Through the project, I have been inspired and it brought me new ambitions. Although there are more and more opportunities of the grant in these days, winning is getting more competitive. Fortunately, I could receive grant support several times. However, I failed many times to get the support. To get the grant, I will show tips based on my own experience at my presentation.
If training at a special facility or getting the grant is difficult, I recommend continuing to participate at international conferences. This is also particularly important for learning the latest information about thoracic oncology. I have participated 13 times in international conferences to date, and have participated in the World Conference on Lung Cancer (WCLC) since the 13th congress held in 2009. I strongly recommend checking all the abstracts before attending the conference, preparing questions and discussing matters with as many people as possible during the conference. WCLC has research in all fields related to thoracic oncology, so it is relatively easy to make new acquaintances and partnership in your own field of research or interest. In this instance also, it is important to make presentations and receive as much input as possible, to clarify areas where you may be lacking and you have advantage, thus using this opportunity as efficiently as you can. Attending congress also gives you chances to get informed the grant opportunity and which facility is attractive for you to make training.
In summary, it is not easy to make decisions about your career, and often we are unaware when we are at a turning point. No one knows the correct answer. Building a career involves not only your own intentions, but also your situation and funds. The important thing is to focus on the quality of the process to ensure that you do not waste time, and to always be aware of your own strengths and weaknesses, and using or supplementing these characteristics to discover what you want to achieve and what you can achieve in your career.
Training at a special facility and keeping to join academic congress clearly enhance our academic career. It will give you new confidence to find or continue on your mission for thoracic oncology.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
