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Suzuki A.,Tokyo Medical University | Wakaguri H.,University of Tokyo | Yamashita R.,Tohoku University | Kawano S.,Database Systems | And 4 more authors.
Nucleic Acids Research | Year: 2015

DBTSS (http://dbtss.hgc.jp/) was originally constructed as a collection of uniquely determined transcriptional start sites (TSSs) in humans and some other species in 2002. Since then, it has been regularly updated and in recent updates epigenetic information has also been incorporated because such information is useful for characterizing the biological relevance of these TSSs/downstream genes. In the newest release, Release 9, we further integrated public and original single nucleotide variation (SNV) data into our database. For our original data, we generated SNV data from genomic analyses of various cancer types, including 97 lung adenocarcinomas and 57 lung small cell carcinomas from Japanese patients as well as 26 cell lines of lung cancer origin. In addition, we obtained publically available SNV data from other cancer types and germline variations in total of 11,322 individuals. With these updates, users can examine the association between sequence variation pattern in clinical lung cancers with its corresponding TSS-seq, RNA-seq, ChIP-seq and BS-seq data. Consequently, DBTSS is no longer a mere storage site for TSS information but has evolved into an integrative platform of a variety of genome activity data. © The Author(s) 2014.


Suzuki A.,Tokyo Medical University | Makinoshima H.,Exploratory Oncology Research and Clinical Trial Center | Wakaguri H.,University of Tokyo | Esumi H.,Exploratory Oncology Research and Clinical Trial Center | And 6 more authors.
Nucleic Acids Research | Year: 2014

Here we conducted an integrative multi-omics analysis to understand how cancers harbor various types of aberrations at the genomic, epigenomic and transcriptional levels. In order to elucidate biological relevance of the aberrations and their mutual relations, we performed whole-genome sequencing, RNA-Seq, bisulfite sequencing and ChIP-Seq of 26 lung adenocarcinoma cell lines. The collected multi-omics data allowed us to associate an average of 536 coding mutations and 13,573 mutations in promoter or enhancer regions with aberrant transcriptional regulations. We detected the 385 splice site mutations and 552 chromosomal rearrangements, representative cases of which were validated to cause aberrant transcripts. Averages of 61, 217, 3687 and 3112mutations are located in the regulatory regions which showed differential DNA methylation, H3K4me3, H3K4me1 and H3K27ac marks, respectively. We detected distinct patterns of aberrations in transcriptional regulations depending on genes. We found that the irregular histone marks were characteristic to EGFR and CDKN1A, while a large genomic deletion and hyper-DNA methylation were most frequent for CDKN2A. We also used the multi-omics data to classify the cell lines regarding their hallmarks of carcinogenesis. Our datasets should provide a valuable foundation for biological interpretations of interlaced genomic and epigenomic aberrations. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.


Suzuki S.,Nagoya University | Shibata K.,Nagoya University | Kikkawa F.,Nagoya University | Nakatsura T.,Exploratory Oncology Research and Clinical Trial Center
Human Vaccines and Immunotherapeutics | Year: 2014

Carcinoembryonic antigen glypican-3 (GPC3) is expressed by > 40% of ovarian clear cell carcinoma (CCC) and is a promising immunotherapeutic target. We previously reported the safety of and immunological and clinical responses to a GPC3-derived peptide vaccine in a phase I clinical trial of patients with advanced hepatocellular carcinoma (HCC). Although the efficacy of the GPC3-derived peptide vaccine against HCC patients was evaluated, other GPC3-positive cancer patients have not yet been investigated. Therefore, we conducted a phase II trial to evaluate the clinical outcome of ovarian CCC patients treated with a GPC3-derived peptide vaccine. The GPC3 peptide was administered at a dose of 3 mg per body. Patients received an intradermal injection of the GPC3 peptide emulsified with incomplete Freund's adjuvant. Vaccinations were performed biweekly from the first until the 6th injection and were then repeated at 6-week intervals after the 7th injection. Treatment continued until disease progression. We herein present two patients with chemotherapy-refractory ovarian CCC who achieved a significant clinical response in an ongoing trial of a GPC3 peptide vaccine. Case 1, a 42-year-old patient with advanced recurrent ovarian CCC with liver and retroperitoneal lymph node metastases, received the HLA-A24-restricted GPC3 peptide vaccine. Contrast-enhanced CT at week 10 revealed a partial response (PR) using RECIST criteria. Case 2 was a 67-year-old female with multiple lymph node metastases. She was injected with the HLA-A2-restricted GPC3 peptide vaccine. According to RECIST , PR was achieved at week 37. The stabilization of their diseases over one year provided us with the first clinical evidence to demonstrate that GPC3 peptide-based immunotherapy may significantly prolong the overall survival of patients with refractory ovarian CCC. © 2014 Landes Bioscience.


Sawada Y.,Exploratory Oncology Research and Clinical Trial Center | Sawada Y.,Yokohama City University | Yoshikawa T.,Exploratory Oncology Research and Clinical Trial Center | Shimomura M.,Exploratory Oncology Research and Clinical Trial Center | And 3 more authors.
International Journal of Oncology | Year: 2015

Novel treatment modalities are required urgently in patients with hepatocellular carcinoma (HCC). A vaccine that induces cytotoxic T lymphocytes (CTLs) is an ideal strategy for cancer, and glypican-3 (GPC3) is a potential option for HCC. Blocking the programmed death-1 (PD-1)/PD-L1 pathway is a rational strategy to overcome tumor escape and tolerance toward CTLs. In the present study, we investigated whether anti-PD-1 blocking antibodies (αPD-1 Ab) enhanced the number of vaccine-induced peptide-specific CTLs in peripheral blood mononuclear cells (PBMCs) following the administration of GPC3 peptide vaccine to both patients and in a mouse model. The inhibitory receptor PD-1 was highly expressed in ex vivo GPC3-specific CTLs isolated from the PBMCs of vaccinated HCC patients. In vitro, interferon-γ induced PD-L1 expression in liver cancer cell lines. In addition, PD-1 blockade increased the number of GPC3-specific CTLs, which degranulate against liver cancer cell lines. In vivo experiments using tumor-bearing mouse models showed that the combination therapy of peptide vaccine and αPD-1 Ab suppressed tumor growth synergistically. PD-1 blockade increased the number of peptide-specific tumor-infiltrating T cells (TILs) and decreased the expression of inhibitory receptors on TILs. This study demonstrated that PD-1/PD-L1 blockade augmented the antitumor effects of a peptide vaccine by increasing the immune response of vaccine-induced CTLs, and provided a foundation for the clinical development of a combination therapy using a GPC3 peptide vaccine and αPD-1 Ab.


Nishikawa H.,Exploratory Oncology Research and Clinical Trial Center
Oncology | Year: 2015

Cancer immunotherapy is now becoming a promising modality of cancer treatment upon the clinical successes of adoptive T-cell transfer and immune checkpoint blockade. At the 30th Nagoya International Cancer Treatment Symposium, Marcel R.M. van den Brink (Memorial Sloan Kettering Cancer Center, MSKCC, New York, N.Y., USA) showed novel strategies to control malignant relapse and graft-versus-host disease, both major obstacles for clinical benefits in allogeneic hematopoietic stem cell transplantation. Alexander M. Lesokhin (MSKCC, New York, N.Y., USA) presented an overview of immune checkpoint blockade, particularly focusing on hematologic malignancies stressing the importance of immunomonitoring to identify biomarkers. © 2015 S. Karger AG, Basel.


Shitara K.,National Cancer Center Hospital East | Ohtsu A.,Exploratory Oncology Research and Clinical Trial Center
Expert Review of Gastroenterology and Hepatology | Year: 2014

In recent years, various molecular target agents have been investigated for gastric cancer. VEGF is one of the most potent angiogenic factors and is a signaling molecule secreted by many solid tumors. High VEGF expression is one of the characteristic features of gastric carcinomas, thus targeting VEGF is considered a promising strategy for gastric cancer. Ramucirumab, an anti-VEGF receptor antibody, has proven to be effective for previously treated advanced gastric cancer. Details of ramucirumab, including two pivotal Phase III studies, will be discussed in this review. Ramucirumab, with or without chemotherapy, improved survival in gastric cancer after previous systemic chemotherapy, thus becoming the standard of care for this patient population. Optimal timing of ramucirumab use and adequate biomarkers for patient selection as well as mechanism of resistance should be explored in future research. © 2015 Informa UK, Ltd.


Kojima M.,Exploratory Oncology Research and Clinical Trial Center | Ochiai A.,Exploratory Oncology Research and Clinical Trial Center
Pathology International | Year: 2016

Clinical outcomes of colorectal cancer are influenced not by tumor size, but by spread into the bowel wall. Although assessment of serosal involvement is an important pathological feature for classification of colon cancer, its diagnostic consistency has been questioned. Using elastic staining, we assessed elastic laminal invasion (ELI) for more objective stratification of deep tumor invasion around the peritoneal surface. In addition, pathological characteristic features of marked tumor budding, fibrosis, and macrophage infiltration in the tumor area with ELI was elucidated. This characteristic tumor area was termed cancer microenvironment formed by peritoneal elastic laminal invasion (CMPI). We elucidated histoanatomical layer-dependent heterogeneity of fibroblast in colonic tissue. Furthermore, subperitoneal fibroblasts (SPFs) play a crucial role in tumor progression and metastasis in CMPI. Our ELI and CMPI concept contributes not only to objective pathological diagnosis, but also sheds light on biological research of special cancer microenvironments detectable in human colorectal cancers. Herein, we describe the diagnostic utility of ELI and morphological alteration in advanced colorectal cancers to determine the phenomenon that occurs when tumors invade around the peritoneal surface. Next, biological research of CMPI is reviewed to stress the importance of pathological research to establish new biological concepts. © 2016 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.


Umemura S.,National Cancer Center Hospital East | Tsuchihara K.,Exploratory Oncology Research and Clinical Trial Center | Goto K.,National Cancer Center Hospital East
Japanese Journal of Clinical Oncology | Year: 2015

The molecular profiling of small-cell lung cancer is challenging because of the difficulty in obtaining suitable tumor samples for integrative genomic analysis. While an urgent need exists for well-defined and effective therapeutic targets in small-cell lung cancer, no significant improvement has been made in treating this disease over the past 30 years. Recently, three reports describing comprehensive genomic analyses of small-cell lung cancer have been published. These reports have provided a framework of biologically relevant genes in small-cell lung cancer and have demonstrated that the genomic landscape of small-cell lung cancer was almost equivalent between Asian and Caucasian populations. Of note, these three comprehensive genomic analyses and other molecular analyses of small-cell lung cancer have contributed to the identification of patient populations that may benefit from promising targeted agents, such as those affecting the PI3K/AKT/mTOR pathway, FGFR1, RET or AURORA kinase inhibitors. Targeting small-cell lung cancer cells with tumor suppressor gene alteration based on synthetic lethality is also promising. The present review provides an overviewof the biologically relevant genetic alterations and targeted therapies of small-cell lung cancer focusing on recent discoveries that could impact the management of small-cell lung cancer. © The Author 2015. Published by Oxford University Press. All rights reserved.


PubMed | Exploratory Oncology Research and Clinical Trial Center and University of Tokyo
Type: | Journal: Scientific reports | Year: 2017

Tumor initiating cells (TICs) are characterized by high clonal expansion capacity. We previously reported that podoplanin is a TIC-specific marker for the human squamous cell carcinoma cell line A431. The aim of this study is to explore the molecular mechanism underlying the high clonal expansion potential of podoplanin-positive A431cells using Fucci imaging. Single podoplanin-positive cells created large colonies at a significantly higher frequency than single podoplanin-negative cells, whereas no difference was observed between the two types of cells with respect to cell cycle status. Conversely, the cell death ratio of progenies derived from podoplanin-positive single cell was significantly lower than that of cells derived from podoplanin-negative cells. Single A431 cells, whose podoplanin expression was suppressed by RNA interference, exhibited increased cell death ratios and decreased frequency of large colony forming. Moreover, the frequency of large colony forming decreased significantly when podoplanin-positive single cells was treated with a ROCK (Rho-associated coiled-coil kinase) inhibitor, whereas no difference was observed in single podoplanin-negative cells. Our current study cleared that high clonal expansion capacity of podoplanin-positive TICs populations was the result of reduced cell death by podoplanin-mediated signaling. Therefore, podoplanin activity may be a therapeutic target in the treatment of squamous cell carcinomas.


PubMed | Juntendo University, National Cancer Center Hospital and Exploratory Oncology Research and Clinical Trial Center
Type: Journal Article | Journal: Molecular and clinical oncology | Year: 2017

Combination therapy with S-1 and cisplatin (CDDP) is the standard chemotherapy for advanced gastric cancer in Japan; however, its administration requires hospitalization for hydration to prevent nephrotoxicity from CDDP. By contrast, NC-6004 appears to reduce the renal toxicity of CDDP and may be used on an outpatient basis. Thus, the effects of combined treatment with S-1 and NC-6004 were compared with those of S-1 and CDDP in a human gastric cancer model.

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