Kenzo Soejima - Academia.edu (original) (raw)

Papers by Kenzo Soejima

Introduction: Many anti-tumor drugs have been developed, however, prognosis of NSCLC remains poor... more Introduction: Many anti-tumor drugs have been developed, however, prognosis of NSCLC remains poor and new approaches for NSCLC treatment are expected. Lung is a unique organ whose epithelial cells are directly exposed to oxygen. Hyperoxia produces reactive oxygen species (ROS) and induces cell damage. Therefore we attempted to investigate the potential of hyperoxia as an anti-tumor treatment in NSCLC cells in this study. Methods: We used oxygen-concentration-adjustable incubators and validated effect of hyperoxia on various lung cancer cell lines in vitro. The effect of hyperoxia on cell proliferation, apoptosis and gene expression was evaluated using MTS assay, flowcytometry and cDNA microarray, respectively. Results: We found that the growth of lung cancer cell lines (A549, NCI-H1975) was inhibited by 50% of hyperoxia in a dose-dependent manner, while that of normal airway epithelial cells (NHBE, BEAS-2B) was not. Two independent pathway analysis using cDNA microarray revealed the activation of NF-kB and AMPK pathways, and the production of nitric oxide and ROS in hyperoxia (50%) treated lung cancer cell lines compared to untreated ones. The combined treatment with ABT-263, Bcl-2 inhibitor, and hyperoxia (50%) induced synergistic growth inhibition and apoptosis in NCI-H1975 and SK-MES-1 cells. Moreover, the combination of ABT-263 and activator of either ROS, NF-kB or AMPK also showed synergistic growth inhibition in those cells. Conclusions: Hyperoxia (50%) showed anti-tumor effect in NSCLC cell lines through the activation of NF-kB and AMPK pathways, and the production of ROS. The effect was augumented in combination with Bcl-2 inhibitor. Hyperoxia may be a treatment option for NSCLC patients. Citation Format: Junko Hamamoto, Hiroyuki Yasuda, Ichiro Nakachi, Michael G. Edwards, Masayoshi Miyawaki, Makoto Nishino, Aoi Kuroda, Tetsuo Tani, Daisuke Arai, Kota Ishioka, Ichiro Kawada, Katsuhiko Naoki, Tomoko Betsuyaku, Kenzo Soejima. Hyperoxia may be a treatment option for NSCLC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3006. doi:10.1158/1538-7445.AM2015-3006

Purpose: Alectinib is a highly selective ALK inhibitor and showed a striking efficacy in non-smal... more Purpose: Alectinib is a highly selective ALK inhibitor and showed a striking efficacy in non-small cell lung cancers (NSCLC) harboring EML4-ALK gene rearrangement. Recently, it was reported that alectinib had an objective response rate of 93.5% in ALK positive patients in a clinical study. However, cancer cells usually acquire resistance to molecular-targeted drugs. The mechanisms of acquired resistance to alectinib are not yet well clarified. The purpose of this study is to clarify the mechanism of acquired resistance to alectinib in ALK translocated lung cancer cells. Experimental design: We have established alectinib resistant cells (H3122-AR) from H3122, which harbors EML4-ALK rearrangement, by long term exposure to alectinib. The mechanism of acquired resistance to alectinib in H3122-AR cells was evaluated in vitro by cDNA sequencing of ALK tyrosine kinase (TK) domain, or by phospho-RTK array to estimate activation of bypass pathway. The efficacy of combination therapy targeting ALK and EGFR was evaluated in vitro and in vivo by using alectinib, afatinib, or siRNA for EGFR. For in vivo experiment, we used mouse xenograft model. Human tumor samples were evaluated by immunohistochemistry. Results: No additional mutation in ALK TK domain was found by cDNA sequencing. Phospho-RTK array revealed that the phosphorylation level of EGFR was increased in H3122-AR cells compared with H3122 parental cells, which was subsequently confirmed by western blotting. We found no additional mutation in EGFR TK domain by cDNA sequencing. Among 5 ligands for EGFR, the expression of TGFα was significantly increased in H3122-AR cells compared with H3122 parental cells. We found the phosphorylation level of EGFR was decreased in TGFα gene knockdown, therefore TGFα and EGFR contributed to the acquired resistance to alectinib. The combination therapy targeting ALK and EGFR by using alectinib, afatinib in vitro and in vivo, or siRNA for EGFR in vitro showed efficacy. We found the increased phosphorylation of EGFR after long term ALK-TKI treatment was also detected in human tumor samples. Conclusion: Activation of EGFR signaling pathway through TGFα overexpression induces acquired resistance to alectinib in ALK-translocated lung cancer cells. Citation Format: Tetsuo Tani, Hiroyuki Yasuda, Junko Hamamoto, Aoi Kuroda, Daisuke Arai, Kota Ishioka, Keiko Ohgino, Ichiro Kawada, Katsuhiko Naoki, Hayashi Yuichiro, Tomoko Betsuyaku, Kenzo Soejima. Activation of EGFR bypass signaling through TGFα overexpression induces acquired resistance to alectinib in ALK-translocated lung cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 746. doi:10.1158/1538-7445.AM2015-746

Journal of Clinical Oncology, May 20, 2015

e19039 Background: No consensus has been reached regarding the treatment order and timing of EGFR... more e19039 Background: No consensus has been reached regarding the treatment order and timing of EGFR-TKI and cytotoxic chemotherapy for EGFR mutation-positive non-small cell lung cancer (NSCLC) patien...

Background. Fibroblast growth factor 9 (FGF9) is a member of the FGF family, which modulates cell... more Background. Fibroblast growth factor 9 (FGF9) is a member of the FGF family, which modulates cell proliferation, differentiation and motility. Recent studies show that activation of FGF signals including FGF9 is associated with pathogenesis of several cancers. In lung cancer, some reports showed that FGF9 indirectly promoted the growth of lung adenocarcinoma and the intensity of FGF9 staining was positively correlated with the status of disease and the degree of lymph node metastasis in lung adenocarcinoma patients. However, the direct effect of FGF9 on the development and growth of lung cancer has not been clear. Purpose. The purpose of this study is to clarify the role of FGF9 in NSCLC. Method. First, we have performed in vitro analysis to clarify the role of FGF9 in NSCLC. FGF9 was introduced by retroviral infection to make stable cell lines. The cell lines which express no or low FGF9 were selected for the study, namely A549, PC9 and H1975. Overexpression of FGF9 in these cells was confirmed at mRNA and protein levels. Tumorigenic potential was evaluated by soft agar colony formation assay. The effect on proliferation of NSCLC cells was evaluated by MTS proliferation assay. Next, patients survival analysis was also performed to evaluate the effect of FGF9 on the prognosis of NSCLC patients. NSCLC specimens were obtained from 91 patients who underwent surgical resection at Department of Thoracic Surgery, Keio University Hospital from 2001 through 2006 with written informed consent. We have performed cDNA microarray gene expression analysis. Patient survival data was evaluated by genes expression profile. Results. Of the cells studied, A549 with FGF9 overexpression (A549-FGF9) cells significantly increased the anchorage independent colony formation ability compared with A549-empty cells. The numbers of the colonies were significantly higher in A549-FGF9, and the size of the colonies was bigger compared with A549-empty. For patient study, we found 10 out of 91 (11.0%) NSCLC patients overexpressed FGF9. We found FGF9 overexpression was associated with significantly worse prognosis (p=0.001). While none of other FGFs and FGFRs was associated with the prognosis of the patients. Three-year survival rate of FGF9-high patient group and FGF9-low patient group were 40% and 88% respectively. The rate of relapse was significantly higher in FGF9-high patients compared with FGF9-low patients, 60% vs 36.2% (p=0.016). Conclusion. Our in vitro and clinical data indicate that FGF-9 may promote tumorigenic potential, and can be a prognostic indicator in NSCLC patients. Citation Format: Kota Ishioka, Kenzo Soejima, Hiroyuki Yasuda, Keiko Ohgino, Satoshi Yoda, Takashi Sato, Junko Hamamoto, Daisuke Arai, Tetsuo Tani, Aoi Kuroda, Katsuhiko Naoki, Tomoko Betsuyaku. FGF9 overexpression promotes tumorigenic potential of non-small cell lung cancer (NSCLC) cells, and is associated with poor prognosis in NSCLC patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5257. doi:10.1158/1538-7445.AM2013-5257

Background: Fibroblast growth factor (FGF)-9 is a member of the FGF family, which modulates cell ... more Background: Fibroblast growth factor (FGF)-9 is a member of the FGF family, which modulates cell proliferation, differentiation and motility. Recent studies show that activation of FGF signals including FGF-9 is associated with pathogenesis of several cancers, however its clinicopathological and biological significance in non-small cell lung cancer (NSCLC) is unclear. The purpose of this study is to clarify the characteristics of FGF-9-expressing NSCLC. Methods: We evaluated expression of FGF-9 in completely resected NSCLC and corresponding non-tumorous lung samples using cDNA microarray combining with quantitative RT-PCR for confirmation, and compared with clinical pathological parameters and survival. We also evaluated altered gene expression patterns between FGF-9-high and -low NSCLCs. Results: The expression of FGF-9 increased compared with the corresponding non-cancerous lung tissues in 13 (13.2%) of 98 NSCLCs. Histologically, 10 out of 13 FGF9-high NSCLC were adenocarcinoma, while none of them were squamous cell carcinoma. The relationship between FGF-9 expression and sex, smoking history or clinical stage was not observed. On the other hand, postoperative recurrence rates and 3-year survival rates were 40% vs. 21% and 54% vs. 92% (p=0.002) for FGF9-high vs. -low NSCLC patients, respectively. The overall survival rate was also significantly worse in FGF9-high NSCLC (p=0.023). The specific gene expression pattern of FGF-9-high NSCLC will be also presented. Conclusion: Our data indicate that FGF-9 may be a novel unfavorable prognostic indicator and a candidate for therapeutic targets of NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4585. doi:1538-7445.AM2012-4585

MicroRNAs, the small and noncoding RNAs, regulate the translation of specific protein-coding gene... more MicroRNAs, the small and noncoding RNAs, regulate the translation of specific protein-coding genes. Accumulated evidence strongly suggests that microRNAs play important and complex roles in human cancers, including lung cancer. We previously reported that miR-375 expression was low in squamous cell carcinoma (SCC) and high in adenocarcinoma (AC) of lung cancer. The target gene of miR-375 in non-small cell lung cancer (NSCLC) has not been elucidated. The purpose of this study was to identify a target of miR-375 and clarify the function of miR-375 in NSCLC. Candidate genes of miR-375 targets were determined using the prediction databases and also previous findings about the different gene expression between SCC and AC. We focused on claudin-1 (CLDN1), which has four putative target sites of miR-375 in its 3′-untranslated region (UTR). CLDN1 was reported to express high in SCC and low in AC opposite to miR-375. We evaluated miR-375 and CLDN1 expression levels by quantitative polymerase chain reaction (qPCR) and Western blotting in 12 NSCLC cell lines. The effect of miR-375 overexpression upon the CLDN1 expression was evaluated in 5 NSCLC cell lines by transfecting miR-375 precursor. It showed that the expression of CLDN1 messenger RNA and protein were attenuated by miR-375 overexpression. Luciferase reporter assay was performed to confirm direct interaction between miR-375 and CLDN1. We cloned 3′-UTR of CLDN1 cDNA into the downstream of a luciferase reporter gene and co-transfected this vector into A549 cells with miR-375 precursor. MiR-375 overexpression resulted in a 3-fold repression of luciferase activity (p < 0.001). To ascertain the clinical validity, we analyzed the relationship between miR-375 and CLDN1 expression in 63 clinical samples of NSCLC. There was a negative correlation between miR-375 and CLDN1 expression (r = -0.35, p = 0.005). In addition, we analyzed the correlation between miR-375 expression and overall survival in the same samples. High miR-375 expression correlated with poor survival in NSCLC (p = 0.043). To investigate the reason why high miR-375 expression lead to poor survival, wound healing assay was performed to evaluate the effect of miR-375 overexpression on the cell migration in SK-MES-1 cells. The cell migration was promoted by miR-375 overexpression, suggesting the high potential of invasion and metastasis in NSCLC expressing high level of miR375. In conclusion, we found that CLDN1 is a novel target of miR-375, and high miR-375 expression leads to poor survival in NSCLC. Citation Format: Satoshi Yoda, Kenzo Soejima, Hiroyuki Yasuda, Takashi Sato, Daisuke Arai, Keiko Ohgino, Kota Ishioka, Tetsuo Tani, Ayano Oashi, Aoi Kuroda, Makoto Nishino, Masayoshi Miyawaki, Junko Hamamoto, Katsuhiko Naoki, Tomoko Betsuyaku. Claudin-1, a novel target of miR-375 in non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5195. doi:10.1158/1538-7445.AM2014-5195

Japanese Journal of Clinical Oncology, Jan 22, 2015

Objective: This Phase II study was conducted to evaluate the efficacy and safety of S-1 and irino... more Objective: This Phase II study was conducted to evaluate the efficacy and safety of S-1 and irinotecan combination therapy as a second-line treatment in patients with advanced non-small cell lung cancer. Methods: Irinotecan was administered at 60 mg/m 2 on Days 1 and 8. Oral S-1 was administered on Days 1-14 every 3 weeks at 80 mg/day for patients with a body surface area of <1.25 m 2 , 100 mg/day for patients with a body surface area of 1.25-1.5 m 2 and 120 mg/day for patients with a body surface area of >1.5 m 2. The primary endpoint was response rate, while the secondary endpoints were progression-free survival, overall survival and safety. Results: Thirty-one patients were enrolled in this study. The response and disease control rates were 6.5 and 58.1%, respectively. Progression-free survival and median survival time were 2.8 and 12.6 months, respectively. Grade 3-4 adverse events were reported for 29.0% of the patients. Hematological toxicities of Grade 3 or 4 included leukopenia (9.7%), neutropenia (9.7%), febrile neutropenia (3.2%), thrombopenia (3.2%) and anemia (6.5%). Non-hematological toxicities of Grade 3 or 4 included pneumonitis (6.5%), diarrhea, colitis, dyspnea, rash, oral mucositis, anorexia and pulmonary thromboembolism/deep vein thrombosis (3.2% each). Conclusions: S-1 and irinotecan combination therapy at the present dose and schedule exhibited only modest efficacy with mild toxicities in previously treated patients with non-small cell lung cancer. No further clinical investigation with current dose and schedules is warranted for patients with non-small cell lung cancer who failed first-line platinum-based doublet chemotherapy.

Supplementary Table S1. Mutation signature analysis. Supplementary Table S2. Baseline characteris... more Supplementary Table S1. Mutation signature analysis. Supplementary Table S2. Baseline characteristics of the transdifferentiated SCLC patients included in this study. Supplementary Table S3. Intensity of EGFR and Ki67 staining in lung cancer tissues obtained from the indicated patients. Supplementary Table S4. Baseline characteristics of the primary SCLC patients included in this study. Supplementary Table S5. Genetic alterations of the indicated lung cancer cell lines. Supplementary Figure S1. FGF9 immunohistochemistry staining in lung cancer cell lines. Supplementary Figure S2. List of the mutated genes before and after transdifferentiation. Supplementary Figure S3. Gene ontology term analysis in the context of upregulated (A) and downregulated (B) genes. Supplementary Figure S4. Computed tomography images of the patients (Case2-4) during the course of gefitinib therapy. Supplementary Figure S5. EGFR, Ki67 and FGFR1 immunohistochemistry staining of tissues from Cases #5 and #6. Su...

Journal of Clinical Oncology, 2012

e18058 Background: Both CPT-11 and S-1, which contains a prodrug of 5-FU, have moderate activity ... more e18058 Background: Both CPT-11 and S-1, which contains a prodrug of 5-FU, have moderate activity against NSCLC as a single agent and the combination of these agents have been reported to possess marked synergistic effects and tolerability in several gastrointestinal cancers. So the combination of CPT-11 and S-1 will be a promising alternative for the second line treatment of NSCLC patients. We have previously reported the phase I study of this combination and determined the recommended doses of these agents. This study was conducted as a phase II trial to evaluate the efficacy and safety of CPT-11 and S-1 for NSCLC patients who had previously treated. Methods: :This trial was open-label, multicenter study. NSCLC patients who had received one prior chemotherapy with performance status 0-1 were enrolled. Primary endopoint was response rate and secondary endpoints were progression free survival, overall survival, 1-year survival rate and adverse events. CPT-11 (60mg/m2 on days1, 8) and...

The oncologist, 2018

Prognostic understanding in advanced cancer patients and their caregivers may have an impact on t... more Prognostic understanding in advanced cancer patients and their caregivers may have an impact on the delivery of effective care. The aims of this study were to explore prognostic understanding at diagnosis in both patients with advanced lung cancer and their caregivers and to investigate correlates of their understanding. A total of 193 patients with newly diagnosed advanced lung cancer and their 167 caregivers were enrolled at 16 hospitals in Japan. We assessed their perceptions of prognosis and goals of therapy and examined their associations with their sociodemographic characteristics, clinical status, quality of life, mood symptoms, and the status of disclosure of information by their treating physicians. One fifth of patients and caregivers (21.7% and 17.6%, respectively) mistakenly believed that the patients' cancer was "completely curable." Substantial proportions of them (16.9% and 10.3%, respectively) mistakenly believed that the primary goal of therapy was to ...

Clinical lung cancer, May 1, 2018

Nivolumab, an immune checkpoint inhibitor, is now a standard treatment for previously treated adv... more Nivolumab, an immune checkpoint inhibitor, is now a standard treatment for previously treated advanced non-small-cell lung cancer based on the results from phase III clinical trials. We evaluated the real-world efficacy and safety of nivolumab in a nonselected population and identified the clinical characteristics that influence efficacy. A total of 142 patients with advanced non-small-cell lung cancer who were administered nivolumab at Keio University and affiliated hospitals in Japan from January to July 2016 were enrolled. The treatment efficacy and adverse events were retrospectively reviewed, and the clinical characteristics associated with the nivolumab response were evaluated using univariate and stratified analyses and the Cochran-Mantel-Haenszel test. The objective response rate was 17.0% (95% confidence interval [CI], 12.0%-24.0%), the median progression-free survival (PFS) was 58 days (95% CI, 50-67 days), and the proportion of patients with adverse events of any grade wa...

Molecular cancer research : MCR, 2017

Activation of the EGFR pathway is one of the mechanisms inducing acquired resistance to anaplasti... more Activation of the EGFR pathway is one of the mechanisms inducing acquired resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) such as crizotinib and alectinib. Ceritinib is a highly selective ALK inhibitor and shows promising efficacy in non-small cell lung cancers (NSCLC) harboring the ALK gene rearrangement. However, the precise mechanism underlying acquired resistance to ceritinib is not well-defined. This study set out to clarify the mechanism in ALK-translocated lung cancer and to find the preclinical rationale overcoming EGFR pathway-induced acquired resistance to ALK-TKIs. To this end, ceritinib-resistant cells (H3122-CER) were established from the H3122 NSCLC cell line harboring the ALK gene rearrangement via long-term exposure to ceritinib. H3122-CER cells acquired resistance to ceritinib through EGFR bypass pathway activation. Furthermore, H3122 cells that became resistant to ceritinib or alectinib through EGFR pathway activation showed cross-re...

Molecular and clinical oncology, 2017

The aim of this study was to assess the efficacy and safety of erlotinib, an epidermal growth fac... more The aim of this study was to assess the efficacy and safety of erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), as second- or third-line treatment for elderly Japanese patients with non-small-cell lung cancer (NSCLC). The patients eligible for this phase II trial were aged ≥70 years, had stage III/IV or recurrent NSCLC, and had previously received 1 or 2 chemotherapy regimens that did not include EGFR-TKIs. The patients received erlotinib at a dose of 150 mg/day. The primary endpoint was overall response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicity. A total of 38 patients with a median age of 76 years were enrolled. The majority of the patients were men (66%), had an Eastern Cooperative Oncology Group performance status of 1 (58%), stage IV disease (66%) and adenocarcinoma (74%). Of the 35 patients, 13 (34%) had tumors with EGFR mutations. The ORR was 26.3% (95% confidence inter...

Molecular cancer therapeutics, 2016

Alectinib is a highly selective ALK inhibitor and shows promising efficacy in non-small cell lung... more Alectinib is a highly selective ALK inhibitor and shows promising efficacy in non-small cell lung cancers (NSCLC) harboring the EML4-ALK gene rearrangement. The precise mechanism of acquired resistance to alectinib is not well defined. The purpose of this study was to clarify the mechanism of acquired resistance to alectinib in ALK-translocated lung cancer cells. We established alectinib-resistant cells (H3122-AR) from the H3122 NSCLC cell line, harboring the EML4-ALK gene rearrangement, by long-term exposure to alectinib. The mechanism of acquired resistance to alectinib in H3122-AR cells was evaluated by phospho-receptor tyrosine kinase (phospho-RTK) array screening and Western blotting. No mutation of the ALK-TK domain was found. Phospho-RTK array analysis revealed that the phosphorylation level of EGFR was increased in H3122-AR cells compared with H3122. Expression of TGFα, one of the EGFR ligands, was significantly increased and knockdown of TGFα restored the sensitivity to ale...

Cancer Research, 2014

Many of the patients with non-small cell lung cancer (NSCLC) who initially responded well to epid... more Many of the patients with non-small cell lung cancer (NSCLC) who initially responded well to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) will eventually relapse. The mechanisms of resistance to EGFR-TKIs is not yet fully clarified. The suppression of genes by DNA methylation is reported to be involved in the mechanism of tolerance to cytotoxic drugs. The purpose of this study is to identify epigenetically regulated genes and to clarify the contribution of epigenetic alteration to the acquired resistance to EGFR-TKI. We established gefitinib-resistant PC-9, which was originally gefitinib-sensitive lung cancer cell line, by serial long term exposure to gefitinib. We collected RNA and DNA from both gefitinib-sensitive and -resistant PC-9 cells and performed comprehensive analysis for DNA methylation and mRNA expression using infinium array and cDNA microarray, respectively. We identified 640 genes those DNA methylations were increased in gefitinib-resistan...

Oncotarget, Jan 15, 2015

EGFR mutated lung cancer accounts for a significant subgroup of non-small-cell lung cancer (NSCLC... more EGFR mutated lung cancer accounts for a significant subgroup of non-small-cell lung cancer (NSCLC). Over the last decade, multiple EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been developed to target mutated EGFR. However, there is little information regarding mutation specific potency of EGFR-TKIs against various types of EGFR mutations. The purpose of this study is to establish an in vitro model to determine the "therapeutic window" of EGFR-TKIs against various types of EGFR mutations, including EGFR exon 20 insertion mutations. The potency of 1st (erlotinib), 2nd (afatinib) and 3rd (osimertinib and rociletinib) generation EGFR-TKIs was compared in vitro for human lung cancer cell lines and Ba/F3 cells, which exogenously express mutated or wild type EGFR. An in vitro model of mutation specificity was created by calculating the ratio of IC50 values between mutated and wild type EGFR. The in vitro model identified a wide therapeutic window of afatinib for exon 19 dele...

Cancer Research, 2015

Background: Angiogenesis plays an important role for tumor maintenance, progression, and metastas... more Background: Angiogenesis plays an important role for tumor maintenance, progression, and metastasis. BIBF1120 is a multiple tyrosine kinase inhibitor, targeting VEGFR, FGFR and PDGFR, and is known as an anti-angiogenic agent. The mechanism by which anti-angiogenic agents suppress the growth of tumors is supposed to be induction of under-nutrition. However, no study has demonstrated the regional differences in the nutrition status of tumors treated by anti-angiogenic agents. Imaging MS is a novel technology that quantitatively visualizes the distribution of hundreds of metabolites in the selected area of tissues. Aim: The aim of this study is to evaluate the efficacy of BIBF1120 in lung cancer cells, and to examine whether BIBF1120 induces under-nutrition status in association with suppressed angiogenesis in xenograft models of lung cancer using Imaging MS. Method: We used lung cancer cell lines driven by several types of histology, PC9, H1975, H3122, A549, H69, and H520. The efficacy of BIBF1120 was evaluated by MTS assay and mouse xenograft model. We treated the xenografted mice with BIBF1120 or vehicle for 4 weeks and harvested xenograft tumors. Micro vessel density and percentage of apoptosis cells in the tumors was evaluated by immunohistochemistry using anti-Ki-67 antibody and anti-cleaved caspase 3 antibody, respectively. The effect of BIBF1120 on metabolic status in xenograft tumors was evaluated by imaging MS. Result: BIBF1120 inhibited the growth of all of the xenograft tumors tested, although it did not directly affect the proliferation rate of those cells in vitro. BIBF1120-treated tumors exhibited significantly lower micro vessel density compared to the vehicle-treated tumors (p Conclusion: To our knowledge, this is the first report to demonstrate the effect of BIBF1120 on the nutrition status of tumor cells in a site-specific manner. Citation Format: Daisuke Arai, Kenzo Soejima, Hiroyuki Yasuda, Kota Ishioka, Shizuko Kagawa, Junko Hamamoto, Katsuhiko Naoki, Katsura Emoto, Yuki Sugiura, Makoto Suematsu, Tomoko Betsuyaku. Visualizing the effect of BIBF1120 in lung cancer cells by imaging-massspectrometry (MS). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1365. doi:10.1158/1538-7445.AM2015-1365

Cancer Research, 2013

Many of the patients with non-small cell lung cancer (NSCLC) with sensitive epidermal growth fact... more Many of the patients with non-small cell lung cancer (NSCLC) with sensitive epidermal growth factor receptor (EGFR)-mutation who initially responded well to EGFR-tyrosine kinase inhibitors (TKIs) eventually relapse. In spite of many studies over the last few years to elucidate this mechanism of acquired resistance to EGFR-TKIs, approximately 30% of the mechanisms of acquired resistance are still unknown. Recently autocrine signaling of fibroblast growth factors (FGFs) and their receptors (FGFRs) has been demonstrated in NSCLC cell lines. And several studies suggest that the FGF-FGFR autocrine growth pathway could be an important mechanism for intrinsic resistance to EGFR-TKIs in NSCLC cell lines with wild-type EGFR. But until now, no report has clarified the role of FGF-FGFR pathway in acquired resistance to EGFR-TKIs in NSCLC cell lines with sensitive EGFR mutations. We have established a gefitinib-resistant cell line (PC9 GR), by serial exposure of gefitinib to PC9, an originally ...

Cancer Research, 2014

The American journal of case reports, Jan 14, 2015

Increasing evidence has indicated that Staphylococcus aureus pneumonia complicated with influenza... more Increasing evidence has indicated that Staphylococcus aureus pneumonia complicated with influenza virus infection is often fatal. In these cases, disease severity is typically determined by susceptibility to antimicrobial agents and the presence of high-virulence factors that are produced by Staphylococcus aureus, such as Panton-Valentine leukocidin (PVL). We describe a rare case of fatal community-acquired pneumonia caused by methicillin-sensitive Staphylococcus aureus (MSSA), which did not secrete major high-virulence factors and coexisted with influenza type B infection. The 32-year-old previously healthy male patient presented with dyspnea, high fever, and cough. His roommate had been diagnosed with influenza B virus infection 3 days earlier. Gram-positive clusters of cocci were detected in the patient's sputum; therefore, he was diagnosed with severe pneumonia and septic shock, and was admitted to the intensive care unit. Despite intensive antibiotic and antiviral treatment...

Journal of Clinical Oncology, May 20, 2015

Japanese Journal of Clinical Oncology, Jan 22, 2015

Journal of Clinical Oncology, 2012

The oncologist, 2018

Clinical lung cancer, May 1, 2018

Molecular cancer research : MCR, 2017

Molecular and clinical oncology, 2017

Molecular cancer therapeutics, 2016

Cancer Research, 2014

Oncotarget, Jan 15, 2015

Cancer Research, 2015

Cancer Research, 2013

Cancer Research, 2014

The American journal of case reports, Jan 14, 2015