Seiji Yano

Kanazawa University, Kanazawa, Ishikawa, Japan

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Publications (213)829.1 Total impact

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    ABSTRACT: Targeted therapies are effective in subsets of lung cancers with EGFR mutations and anaplastic lymphoma kinase (ALK) translocations. Large-scale genomics have recently expanded the lung cancer landscape with FGFR1 amplification found in 10-20% of squamous cell carcinomas (SCCs). However, the response rates have been low for biomarker-directed fibroblast growth factor receptor (FGFR) inhibitor therapy in SCC, which contrasts to the relatively high rates of response seen in EGFR mutant and ALK-translocated lung cancers treated with epidermal growth factor receptor (EGFR) inhibitors and ALK inhibitors, respectively. In order to better understand the low response rates of FGFR1-amplified lung cancers to FGFR inhibitors, relationships between gene copy number, mRNA expression and protein expression of FGFR1 were assessed in cell lines, tumor specimens and data from The Cancer Genome Atlas. The importance of these factors for the sensitivity to FGFR inhibitors was determined by analyzing drug screen data and conducting in vitro and in vivo experiments. We report that there was a discrepancy between FGFR1 amplification level and FGFR1 protein expression in a number of these cell lines, and the cancers with unexpectedly low FGFR1 expression were uniformly resistant to the different FGFR inhibitors. Further interrogation of the receptor tyrosine kinase activity in these discordant cell lines revealed co-activation of HER2 and platelet-derived growth factor receptor-α (PDGFRα) caused by gene amplification or ligand overexpression maintained phosphoinositide 3-kinase (PI3K) and MEK/ERK signaling even in the presence of FGFR inhibitor. Accordingly, co-inhibition of FGFR1 and HER2 or PDGFRα led to enhanced drug responses. In contrast, FGFR1-amplified high FGFR1 protein-expressing lung cancers are sensitive to FGFR inhibitor monotherapy by downregulating ERK signaling. Addition of a PI3K inhibitor to these high FGFR1 protein-expressing cancers further sensitized them to FGFR inhibitor. These data reveal that biomarker-directed trials for FGFR1-amplified SCC require assessment of FGFR1 protein expression and uncover novel therapeutic strategies for FGFR1-amplified SCC with low FGFR1 protein expression.Oncogene advance online publication, 9 November 2015; doi:10.1038/onc.2015.426.
    Oncogene 11/2015; DOI:10.1038/onc.2015.426 · 8.46 Impact Factor
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    ABSTRACT: Small-cell lung cancer (SCLC) accounts for nearly 15% of lung cancer cases and exhibits aggressive clinical behavior characterized by rapid growth and metastatic spread to multiple organs. About 70% of patients with SCLC present with extensive disease and distant metastases at diagnosis. HSP90 is a 90-kDa molecular chaperone whose association is required for the stability and function of its numerous “client proteins.” Here, we assessed the therapeutic potential of the HSP90 inhibitor 17-DMAG in SCLC. Notably, 17-DMAG hindered the viability of human SCLC cell lines—regardless of their chemosensitivity—via the decreased expression of client proteins, including the proto-oncogene c-Raf_(also known as RAF1). In an in vivo imaging model of SCLC multiple-organ metastasis with the human SCLC cell line SBC-5, treatment with 17-DMAG remarkably inhibited the formation of metastatic sites in the liver, but was ineffective in hindering the progression of bone lesions. The latter was likely the result of activation of osteoclasts. IGF-1, which is supposed to be rich in bone environment, preserved c-Raf expression and maintained viability of SBC-5 cells treated with 17-DMAG. Furthermore, the combined use of a bisphosphonate with 17-DMAG significantly attenuated the progression of metastases in both the liver and the bone. These findings suggest that therapeutic effects of HSP90 inhibitors may be organ-specific and should be carefully monitored in SCLC clinical trials. This article is protected by copyright. All rights reserved.
    International Journal of Cancer 09/2015; DOI:10.1002/ijc.29858 · 5.09 Impact Factor
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    ABSTRACT: Diffuse malignant mesothelioma (DMM) is a tumor of serosal membranes with propensity for progressive local disease. Since current treatment options are largely ineffective, novel therapeutic strategies based on molecular mechanisms and the disease characteristics are needed to improve the outcomes of patients with this disease. Akt kinase-interacting protein Aki1 (Freud-1/CC2D1A) is a scaffold protein for the PI3K/PDK1/Akt signaling module that helps determines receptor signal selectivity for EGFR. Aki1 has been suggested as a therapeutic target but its potential has yet to be evaluated in a tumor setting. Here we report evidence supporting its definition as a therapeutic target in DMM. In cell based assays, Aki1 silencing decreased cell viability and caused cell cycle arrest of multiple DMM cell lines via effects on the PKA/CREB1 signaling pathway. Blocking CREB activity phenocopied Aki1 silencing. Clinically, Aki1 was expressed in most human DMM specimens where its expression correlated with phosphorylated CREB1. Notably, Aki1 siRNA potently blocked tumor growth in an orthotopic implantation model of DMM when administered directly into the pleural cavity of tumor-bearing mice. Our findings suggest an important role for the Aki1/CREB axis in DMM pathogenesis and provide a preclinical rationale to target Aki1 by intrathoracic therapy in locally advanced tumors. Copyright © 2015, American Association for Cancer Research.
    Cancer Research 08/2015; DOI:10.1158/0008-5472.CAN-15-0858 · 9.33 Impact Factor
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    ABSTRACT: There is a high death rate of lung cancer patients. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in some lung adenocarcinoma patients with EGFR mutations. However, a significant number of patients show primary and acquire resistance to EGFR-TKIs. Although the Akt kinase is commonly activated due to various resistance mechanisms, the key targets of Akt remain unclear. Here, we show that the Akt-β-catenin pathway may be a common resistance mechanism. We analyzed gene expression profiles of gefitinib-resistant PC9M2 cells that were derived from gefitinib-sensitive lung cancer PC9 cells and do not have known resistance mechanisms including EGFR mutation T790M. We found increased expression of Axin, a β-catenin target gene, increased phosphorylation of Akt and GSK3, accumulation of β-catenin in the cytoplasm/nucleus in PC9M2 cells. Both knockdown of β-catenin and treatment with a β-catenin inhibitor at least partially restored gefitinib sensitivity to PC9M2 cells. Lung adenocarcinoma tissues derived from gefitinib-resistant patients displayed a tendency to accumulate β-catenin in the cytoplasm. We provide a rationale for combination therapy that includes targeting of the Akt-β-catenin pathway to improve the efficacy of EGFR-TKIs.
    Scientific Reports 08/2015; 5:13076. DOI:10.1038/srep13076 · 5.58 Impact Factor
  • Hiromichi Ebi · Hiroshi Kotani · Seiji Yano ·

    Cancer Research 08/2015; 75(15 Supplement):749-749. DOI:10.1158/1538-7445.AM2015-749 · 9.33 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):3555-3555. DOI:10.1158/1538-7445.AM2015-3555 · 9.33 Impact Factor
  • Azusa Tanimoto · Seiji Yano ·

    Nippon rinsho. Japanese journal of clinical medicine 02/2015; 73 Suppl 2:256-60.
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    ABSTRACT: EML4-ALK lung cancer accounts for approximately 3%–7% of non-small cell lung cancer cases. To investigate the molecular mechanism underlying tumor progression and targeted drug sensitivity/resistance in EML4-ALK lung cancer, clinically relevant animal models are indispensable. In this study, we found that the lung adenocarcinoma cell line A925L expresses an EML4-ALK gene fusion (variant 5a, E2:A20) and is sensitive to the ALK inhibitors crizotinib and alectinib. We further established highly tumorigenic A925LPE3 cells, which also have the EML4-ALK gene fusion (variant 5a) and are sensitive to ALK inhibitors. By using A925LPE3 cells with luciferase gene transfection, we established in vivo imaging models for pleural carcinomatosis, bone metastasis, and brain metastasis, all of which are significant clinical concerns of advanced EML4-ALK lung cancer. Interestingly, crizotinib caused tumors to shrink in the pleural carcinomatosis model, but not in bone and brain metastasis models, while alectinib showed remarkable efficacy in all three models, indicative of the clinical efficacy of these ALK inhibitors. Our in vivo imaging models of multiple organ sites may provide useful resources to analyze further the pathogenesis of EML4-ALK lung cancer and its response and resistance to ALK inhibitors in various organ microenvironments.This article is protected by copyright. All rights reserved.
    Cancer Science 01/2015; 106(3). DOI:10.1111/cas.12600 · 3.52 Impact Factor

  • Cancer Science 01/2015; 106(1). DOI:10.1111/cas.12590 · 3.52 Impact Factor
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    ABSTRACT: The insulin-like growth factor 2 gene (IGF2) is an imprinting gene, which mediates cell growth and apoptosis. The loss of imprinting (LOI) of IGF2 has been associated with the development of cancer. In the present study, loss LOI of IGF2 in lung cancer was analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in combination with DNA sequencing of samples collected by laser capture microdissection. The status of each sample was assigned as imprinting when PCR-RFLP revealed only one band or sequence with a single peak; otherwise, the case was classified as LOI. LOI was identified in eight out of 13 adenocarcinoma cases (62%), but was not detected in any of the nine squamous cell carcinoma cases (0%). These results suggest that IGF2 LOI is involved in the molecular pathogenesis of lung adenocarcinoma, but not squamous cell carcinoma, and that LOI may be detected through increased IGF2 expression levels.
    Oncology letters 12/2014; 8(6):2561-2564. DOI:10.3892/ol.2014.2572 · 1.55 Impact Factor
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    ABSTRACT: Malignant pleural mesothelioma (MPM) is a rare and highly aggressive neoplasm that arises from the pleural, pericardial or peritoneal lining. Although surgery, chemotherapy, radiotherapy and combinations of these therapies are used to treat MPM, the median survival of such patients is dismal. Therefore, there is a compelling need to develop novel therapeutics with different modes of action. Ganglioside GM2 is a glycolipid that has been shown to be overexpressed in various types of cancer. However, there is currently no literature regarding the use of GM2 as a potential therapeutic target in cases of MPM. In this study, we evaluated the efficacy of the anti-GM2 antibody BIW-8962 as an anti-MPM therapeutic using in vitro and in vivo assays. Consequently, the GM2 expression in the MPM cell lines was confirmed using flow cytometry. In addition, eight of 11 cell lines were GM2-positive (73%), although the GM2 expression was variable. BIW-8962 showed a significant ADCC activity against the GM2-expressing MPM cell line MSTO-211H, the effect of which depended on the antibody concentration and effector/target ratio. In an in vivo orthotropic mouse model using MSTO-211H cells, BIW-8962 significantly decreased the incidence and size of tumors. Additionally, the GM2 expression was confirmed in the MPM clinical specimens. Fifty-eight percent of the MPM tumors were positive for GM2, with individual variation in the intensity and frequency of staining. These data suggest that anti-GM2 antibodies may become a therapeutic option for MPM patients This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Cancer Science 11/2014; 106(1). DOI:10.1111/cas.12575 · 3.52 Impact Factor
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    ABSTRACT: Introduction: The BIM deletion polymorphism in intron 2 was found in a significant percent of the Asian population. Patients with epidermal growth factor receptor (EGFR) mutant lung cancers harboring this BIM polymorphism have shorter progression free survival and overall response rates to EGFR tyrosine kinase inhibitors. However, the association between the BIM deletion polymorphism and lung cancer risk is unknown. Methods: The BIM deletion polymorphism was screened by polymerase chain reaction in 765 lung cancer cases and 942 healthy individuals. Results: Carriers possessing one allele of the BIM polymorphism were observed in 13.0% of control cases and 12.8% of lung cancer cases, similar to incidence rates reported earlier in healthy individuals. Homozygote for the BIM polymorphism was observed in four of 942 healthy controls and three of 765 lung cancer cases. The frequency of the BIM deletion polymorphism in lung cancer patients was not related to age, sex, smoking history, or family history of lung cancer. The BIM deletion polymorphism was found in 30 of 212 patients with EGFR wild type lung cancers and 16 of 120 patients with EGFR mutant lung cancers. The frequency of the BIM polymorphism is similar between cancers with wild type EGFR and mutated EGFR (p = 0.78). Conclusion: The BIM deletion polymorphism was not associated with lung cancer susceptibility. Furthermore, the BIM polymorphism is not associated with EGFR mutant lung cancer.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 11/2014; 10(1). DOI:10.1097/JTO.0000000000000371 · 5.28 Impact Factor
  • Shinji Takeuchi · Seiji Yano ·
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    ABSTRACT: Gefitinib and erlotinib, which are epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs), are highly effective against lung tumors with EGFR activating mutations. However, in 20-30% of cases, there is intrinsic resistance, and even if the treatment is effective, resistance is acquired in one to several years. Possible mechanisms of acquired resistance to EGFR-TKI, thus far, include a gatekeeper mutation of EGFR, activation of an alternate pathway, activation of EGFR downstream signals, transformation to small cell lung cancer, and epithelial-mesenchymal transition (EMT). Recently, BIM (BCL2L11), which is a BH3-only proapoptotic member of the Bcl-2 protein family, was shown to play a central role in inducing apoptosis in response to EGFR-TKI treatment in EGFR mutant lung cancer cells. Moreover, when the expression of active BIM protein was low, there was resistance to apoptosis induction by EGFR-TKI treatment and early disease progression. A polymorphism of the BIM gene unique to East Asian people has been detected and is now attracting attention as a factor causing resistance to EGFR-TKI due to decreased BIM activity. Copyright © 2014 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
    Respiratory Investigation 11/2014; 52(6):348-356. DOI:10.1016/j.resinv.2014.10.002

  • Cancer Research 10/2014; 74(19 Supplement):2762-2762. DOI:10.1158/1538-7445.AM2014-2762 · 9.33 Impact Factor
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    ABSTRACT: Objectives: Akt kinase-interacting protein 1 (Aki1) has been reported to be a scaffold protein of the PI3K (phosphoinositide 3-kinase)/PDK1 (3-phosphoinositide-dependent protein kinase)/Akt pathway and to interact with epidermal growth factor receptor signaling. Although Aki1 has been reported to be expressed in lung cancer, the significance of its expression in pancreatic cancer has not been clarified. Methods: The expression of Aki1 and its associated proteins was assayed in pancreatic cancer cell lines, and its involvement in cell viability was examined by treatment with Aki1 small interfering RNA. We also assessed the immunohistochemical expression of Aki1 in tissue samples from 60 patients with pancreatic cancer. Results: All of the pancreatic cancer cell lines expressed Aki1 and its associated proteins at various levels. Treatment with Aki1 small interfering RNA or PI3K inhibitor inhibited the viability of Panc1 cells. Silencing of Aki1 in Panc1 cells reduced the phosphorylation of Akt and increased the phosphorylation of cleaved PARP. The Aki1 was expressed in 25 (42%) of the 60 pancreatic cancers, but there was no correlation between Aki1 expression and clinicopathologic parameters. We observed a statistically significant correlation between Aki1 and p-Akt expression (P = 0.016). Conclusions: Inhibition of the Aki1-Akt axis may be a therapeutic target in some patients with pancreatic cancer.
    Pancreas 07/2014; 43(7). DOI:10.1097/MPA.0000000000000168 · 2.96 Impact Factor
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    ABSTRACT: Alectinib is a new generation ALK inhibitor with activity against the gatekeeper L1196M mutation that showed remarkable activity in a phase I/II study with echinoderm microtubule associated protein-like 4 (EML4) - anaplastic lymphoma kinase (ALK) non-small cell lung cancer (NSCLC) patients. However, alectinib resistance may eventually develop. Here, we found that EGFR ligands and HGF, a ligand of the MET receptor, activate EGFR and MET, respectively, as alternative pathways, and thereby induce resistance to alectinib. Additionally, the heat shock protein 90 (Hsp90) inhibitor suppressed protein expression of ALK, MET, EGFR, and AKT, and thereby induced apoptosis in EML4-ALK NSCLC cells, even in the presence of EGFR ligands or HGF. These results suggest that Hsp90 inhibitors may overcome ligand-triggered resistance to new generation ALK inhibitors and may result in more successful treatment of NSCLC patients with EML4-ALK.
    Oncotarget 06/2014; 5(13). DOI:10.18632/oncotarget.2055 · 6.36 Impact Factor
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    ABSTRACT: Met activation by gene amplification and its ligand, hepatocyte growth factor (HGF), imparts resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant lung cancer. We recently reported that Met activation by HGF stimulates the production of vascular endothelial growth factor (VEGF) and facilitates angiogenesis, which indicates that HGF induces EGFR-TKI resistance and angiogenesis. This study aimed to determine the effect of triple inhibition of EGFR, Met, and angiogenesis on HGF-triggered EGFR-TKI resistance in EGFR-mutant lung cancer. Three clinically approved drugs, erlotinib (an EGFR inhibitor), crizotinib (an inhibitor of anaplastic lymphoma kinase and Met), and bevacizumab (anti-VEGF antibody), and TAS-115, a novel dual TKI for Met and VEGF receptor 2, were used in this study. EGFR-mutant lung cancer cell lines PC-9, HCC827, and HGF-gene-transfected PC-9 (PC-9/HGF) cells were examined. Crizotinib and TAS-115 inhibited Met phosphorylation and reversed erlotinib resistance and VEGF production triggered by HGF in PC-9 and HCC827 cells in vitro. Bevacizumab and TAS-115 inhibited angiogenesis in PC-9/HGF tumors in vivo. Moreover, the triplet erlotinib, crizotinib, and bevacizumab, or the doublet erlotinib and TAS-115 successfully inhibited PC-9/HGF tumor growth and delayed tumor regrowth associated with sustained tumor vasculature inhibition even after cessation of the treatment. These results suggest that triple inhibition of EGFR, HGF/Met, and VEGF/VEGF receptor 2, by either a triplet of clinical drugs or TAS-115 combined with erlotinib, may be useful for controlling progression of EGFR-mutant lung cancer by reversing EGFR-TKI resistance and for inhibiting angiogenesis.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 06/2014; 9(6):775-83. DOI:10.1097/JTO.0000000000000170 · 5.28 Impact Factor
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    ABSTRACT: Mutations in Kirsten rat-sarcoma (KRAS) are well appreciated to be major drivers of human cancers through dysregulation of multiple growth and survival pathways. Similar to many other non-kinase oncogenes and tumor suppressors, efforts to directly target KRAS pharmaceutically have not yet materialized. As a result, there is broad interest in an alternative approach to develop therapies that induce synthetic lethality in cancers with mutant KRAS, therefore exposing the particular vulnerabilities of these cancers. Fueling these efforts is our increased understanding into the biology driving KRAS mutant cancers, in particular the important pathways that mutant KRAS governs to promote survival. In this mini-review, we summarize the latest approaches to treat KRAS mutant cancers and the rationale behind them. This article is protected by copyright. All rights reserved.
    Cancer Science 02/2014; 105(5). DOI:10.1111/cas.12383 · 3.52 Impact Factor
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    ABSTRACT: The mTOR inhibitor temsirolimus has antitumor and antiangiogenic activity against several carcinomas, yet few reports document the efficacy of temsirolimus against malignant pleural mesothelioma (MPM). Therefore, we evaluated the efficacy of temsirolimus and the antiangiogenic effect of temsirolimus in the treatment of MPM. We examined the efficacy of temsirolimus alone and the efficacy of the combination of temsirolimus and cisplatin or pemetrexed against four MPM cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The effect of temsirolimus on the production of proangiogenic cytokines by MPM cell lines was examined by enzyme-linked immunosorbent assay (ELISA). Expression of mTOR and proangiogenic cytokines in clinical specimens from MPM patients was determined by immunohistochemistry. Temsirolimus inhibited cell viability and suppressed cell proliferation of all MPM cell lines. Combined treatment with temsirolimus and cisplatin inhibited the viability of all MPM cell lines more effectively than temsirolimus alone. Temsirolimus strongly inhibited the phosphorylation of p70s6k, a downstream molecule of mTOR, in all MPM cell lines and led to an increase in the levels of cleaved caspase-3 in the H226 and Y-meso14 cells. Temsirolimus also inhibited the production of vascular endothelial growth factor (VEGF) and platelet-derived growth factor-AA (PDGF-AA). Phosphorylated mTOR and high expression of VEGF and PDGF were detected in 2 and 3, respectively, out of the 5 MPM specimens. These results suggest that temsirolimus has activity against MPM cells by inhibition of cell proliferation and angiogenesis, and may be beneficial for a subset of MPM patients with high mTOR expression.
    Oncology Reports 12/2013; 31(3). DOI:10.3892/or.2013.2948 · 2.30 Impact Factor
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    ABSTRACT: Although EGF receptor tyrosine kinase inhibitors (EGFR-TKI) have shown dramatic effects against EGFR mutant lung cancer, patients ultimately develop resistance by multiple mechanisms. We therefore assessed the ability of combined treatment with the Met inhibitor crizotinib and new generation EGFR-TKIs to overcome resistance to first-generation EGFR-TKIs. Lung cancer cell lines made resistant to EGFR-TKIs by the gatekeeper EGFR-T790M mutation, Met amplification, and HGF overexpression and mice with tumors induced by these cells were treated with crizotinib and a new generation EGFR-TKI. The new generation EGFR-TKI inhibited the growth of lung cancer cells containing the gatekeeper EGFR-T790M mutation, but did not inhibit the growth of cells with Met amplification or HGF overexpression. In contrast, combined therapy with crizotinib plus afatinib or WZ4002 was effective against all three types of cells, inhibiting EGFR and Met phosphorylation and their downstream molecules. Crizotinib combined with afatinib or WZ4002 potently inhibited the growth of mouse tumors induced by these lung cancer cell lines. However, the combination of high dose crizotinib and afatinib, but not WZ4002, triggered severe adverse events. Our results suggest that the dual blockade of mutant EGFR and Met by crizotinib and a new generation EGFR-TKI may be promising for overcoming resistance to reversible EGFR-TKIs but careful assessment is warranted clinically.
    PLoS ONE 12/2013; 8(12):e84700. DOI:10.1371/journal.pone.0084700 · 3.23 Impact Factor

Publication Stats

6k Citations
829.10 Total Impact Points


  • 2008-2015
    • Kanazawa University
      • Division of Medical Oncology
      Kanazawa, Ishikawa, Japan
  • 2009-2013
    • Kanazawa Medical University
      Kanazawa, Ishikawa, Japan
  • 1994-2008
    • The University of Tokushima
      • • Department of Internal Medicine and Molecular Therapeutics
      • • Department of Internal Medicine
      • • School of Medicine
      Tokusima, Tokushima, Japan
  • 2000-2004
    • University of Texas MD Anderson Cancer Center
      • Department of Cancer Biology
      Houston, TX, United States
    • University of Houston
      Houston, Texas, United States