Education 【 display / non-display 】

Education 【 display / non-display 】

• 2011

  -

  2015

  Sapporo Medical University   Graduate School of Medicine   医学研究科  

• 2003

  -

  2009

  Sapporo Medical University   School of Medicine   医学科  

Research Experience 【 display / non-display 】

Research Experience 【 display / non-display 】

• 2018.04

  -

  Now

  Sapporo Medical University   腫瘍内科学講座   助教

  助教

• 2016.04

  -

  2018.03

  Massachusetts General Hospital   GI Unit   Postdoctoral Research Fellow

  Postdoctoral Research Fellow

• 2015.04

  -

  2016.03

  Sapporo Medical University   腫瘍内科学講座  

• 2011.04

  -

  2015.03

  Sapporo Medical University   Graduate School of Medicine   大学院生

  大学院生

• 2009.04

  -

  2011.03

  Sapporo Medical University   Hospital   臨床研修医

  臨床研修医

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Research Areas 【 display / non-display 】

Research Areas 【 display / non-display 】

• Life sciences   Tumor diagnostics and therapeutics  

Affiliation 【 display / non-display 】

Affiliation 【 display / non-display 】

• -  

Papers 【 display / non-display 】

Papers 【 display / non-display 】

• Synergistic antitumor effect of histone deacetylase class IIa inhibitor with lenvatinib in hepatocellular carcinoma.

  Ryo Ito, Koji Miyanishi, Tomohiro Kubo, Kota Hamaguchi, Takahiro Osuga, Shingo Tanaka, Hiroyuki Ohnuma, Kazuyuki Murase, Kohichi Takada, Minoru Nagayama, Yasutoshi Kimura, Toru Mizuguchi, Ichiro Takemasa, Junji Kato

  Hepatology international   17 ( 3 ) 735 - 744  2023.06  [International journal]

  　View Summary

  BACKGROUND: Histone deacetylase (HDAC) class I and IIa are highly expressed in hepatocellular carcinoma (HCC) and associated with decreased survival. However, clinically used pan and class I inhibitors have serious adverse events. In this study, we assessed the antitumor effects and tolerability of class IIa HDAC inhibitor (HDACI) with lenvatinib, which is a standard therapy for HCC. METHODS AND RESULT: Combination therapy with class IIa HDACI and lenvatinib exerted synergistic antitumor effect in human HCC cell lines. In mouse models, this therapy showed significant antitumor effects, and few adverse events occurred. In immunoblotting, the expression of fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) was high in cell lines that showed a high antitumor effect. In addition, class IIa HDACI administration decreased the expression of FGFR4. In the small interfering RNA (siRNA) analysis, knockdown of HDAC9, which is an isoform of HDAC class IIa, reduced the expression of FGFR4 and induced apoptosis. Immunohistochemistry of human clinical specimens showed a positivity rate of 32% for FGFR4 and 84% for HDAC9 in HCC, and all FGFR4-positive patients were HDAC9 positive. CONCLUSION: Class IIa HDACI and lenvatinib combination therapy induces apoptosis by downregulating FGFR4 and blocking the FGFR signaling in FGFR4-positive HCC cell lines and has demonstrated synergistic antitumor effects and safety. This combination therapy overcomes the problems of conventional therapies and will be beneficial for FGFR4-positive HCC patients.

  DOI PubMed

• Association between Hepatic Oxidative Stress Related Factors and Activation of Wnt/β-Catenin Signaling in NAFLD-Induced Hepatocellular Carcinoma.

  Kota Hamaguchi, Koji Miyanishi, Takahiro Osuga, Shingo Tanaka, Ryo Ito, Hiroki Sakamoto, Tomohiro Kubo, Hiroyuki Ohnuma, Kazuyuki Murase, Kohichi Takada, Minoru Nagayama, Yasutoshi Kimura, Toru Mizuguchi, Ichiro Takemasa, Junji Kato

  Cancers   14 ( 9 )  2022.04  [International journal]

  　View Summary

  We investigated the association between iron overload, oxidative stress (8-oxo-7,8-dihydroguanine: 8-oxo-dG scores), Wnt/β-catenin pathway activation (expression of glutamine synthetase: GS), and tumor hyperintensity in the Gd-EOB-DTPA-enhanced MRI hepatobiliary phase (relative enhancement ratio: RER). This was a retrospective analysis of 94 hepatocellular carcinoma (HCC) patients who underwent surgical resection. In HBV-, HCV-, and alcohol-associated HCC, serum ferritin levels in the high and low RER groups were equivalent. In contrast, ferritin levels were elevated in the 'high RER' group of patients with nonalcoholic fatty liver disease (NAFLD)-HCC. As predictors of GS positivity, high RER had a sensitivity of 57.2% and a specificity of 100%. High serum ferritin had a sensitivity of 85.7% and a specificity of 85.7%. All cases with serum ferritin ≥275.5 ng/mL and high RER were 8-oxo-dG- and iron staining-positive. Additionally, GS positivity was seen in all cases with "serum ferritin levels above the upper limits or iron staining-positive" and '8-oxo-dG high' cases. Therefore, combining serum ferritin levels with RER may increase the accuracy with which activated Wnt/β-catenin signaling is predicted in NAFLD-HCC. We suggest that 8-oxo-dG accumulates following increased oxidative stress due to hepatic tissue iron deposition; this may activate Wnt/β-catenin signaling and trigger carcinogenesis.

  DOI PubMed

• A case of acute exacerbation of chronic hepatitis C during the course of adrenal Cushing's syndrome

  Takahiro Osuga, Koji Miyanishi, Kota Hamaguchi, Shingo Tanaka, Hiroyuki Ohnuma, Kazuyuki Murase, Kohichi Takada, Junji Kato

  Clinical Case Reports ( Wiley )  10 ( 2 )  2022.02

  DOI

• A Case of Unresectable Combined Hepatocellular-Cholangiocarcinoma Successfully Treated with Lenvatinib.

  Takahiro Osuga, Koji Miyanishi, Ryo Ito, Shingo Tanaka, Kota Hamaguchi, Hiroyuki Ohnuma, Kazuyuki Murase, Kohichi Takada, Minoru Nagayama, Yasutoshi Kimura, Taro Sugawara, Shintaro Sugita, Ichiro Takemasa, Tadashi Hasegawa, Junji Kato

  Case reports in oncology   15 ( 1 ) 318 - 325  2022  [International journal]

  　View Summary

  A 77-year-old man was referred to our hospital because of a hepatic tumor. Blood biochemistry showed elevated serum alfa-fetoprotein, protein induced by vitamin K absence-II, and carbohydrate antigen 19-9 levels. Gd-EOB-DTPA-enhanced magnetic resonance imaging revealed a 95-mm-sized tumor in liver S7. The tumor showed heterogeneous hyperintensity in the arterial phase, slightly washed out from the portal vein phase, and hypointensity in the hepatocellular phase. Post-enlargement segmental resection was performed, and the pathological diagnosis was combined hepatocellular cholangiocarcinoma. Seven months after surgery, multiple liver tumors were found, and biopsy revealed combined hepatocellular-cholangiocarcinoma. Hepatic arterial infusion chemotherapy with cisplatin was initiated. However, the patient developed a pulmonary abscess, which was treated with antibiotics. He then underwent treatment with lenvatinib, 11 months after surgery. At 8 weeks follow-up, a complete response (according to the modified Response Evaluation Criteria in Solid Tumors [RECIST]) and a partial response (RECIST version 1.1) was noted. To the best of our knowledge, thus far, only a single case of lenvatinib treatment of unresectable mixed liver cancer has been reported. In that case, lenvatinib was used as a third-line treatment. The present report is the first to describe lenvatinib as a first-line therapy for unresectable combined hepatocellular-cholangiocarcinoma, which resulted in a meaningful response. This case provides useful insights into the choice of appropriate drug treatment in this disease in the absence of randomized controlled trials of drug treatment.

  DOI PubMed

• MUTYH is associated with hepatocarcinogenesis in a non-alcoholic steatohepatitis mouse model

  Hiroki Sakamoto, Koji Miyanishi, Shingo Tanaka, Ryo Ito, Kota Hamaguchi, Akira Sakurada, Masanori Sato, Tomohiro Kubo, Takahiro Osuga, Kazuyuki Murase, Kohichi Takada, Yusaku Nakabeppu, Masayoshi Kobune, Junji Kato

  Scientific Reports ( Springer Science and Business Media LLC )  11 ( 1 )  2021.12

  　View Summary

  Non-alcoholic steatohepatitis (NASH)-related HCC is associated with oxidative stress. However, the mechanisms underlying the development of NASH-related HCC is unclear. MUTYH is one of the enzymes that is involved in repair of oxidative DNA damage. The aim of this study was to investigate the association between MUTYH and NASH-related hepatocarcinogenesis. MUTYH wild-type (Mutyh^+/+), heterozygous (Mutyh^+/−), and MUTYH-null (Mutyh^−/−) mice were fed a high-fat high-cholesterol (HFHC) diet or HFHC + high iron diet (20 mice per group) for 9 months. Five of 20 Mutyh^−/− mice fed an HFHC + high iron diet developed liver tumors, and they developed more liver tumors than other groups (especially vs. Mutyh^+/+ fed an HFHC diet, P = 0.0168). Immunohistochemical analysis revealed significantly higher accumulation of oxidative stress markers in mice fed an HFHC + high iron diet. The gene expression profiles in the non-tumorous hepatic tissues were compared between wild-type mice that developed no liver tumors and MUTYH-null mice that developed liver tumors. Gene Set Enrichment Analysis identified the involvement of the Wnt/β-catenin signaling pathway and increased expression of c-Myc in MUTYH-null liver. These findings suggest that MUTYH deficiency is associated with hepatocarcinogenesis in patients with NASH with hepatic iron accumulation.

  DOI

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Misc 【 display / non-display 】

Misc 【 display / non-display 】

• Neoadjuvant chemotherapy with docetaxel, nedaplatin, and fluorouracil for resectable esophageal cancer: A phase II study.

  Hiroyuki Ohnuma, Yasushi Sato, Naotaka Hayasaka, Teppei Matsuno, Chisa Fujita, Masanori Sato, Takahiro Osuga, Masahiro Hirakawa, Koji Miyanishi, Tamotsu Sagawa, Koshi Fujikawa, Motoh Ohi, Yutaka Okagawa, Yasushi Tsuji, Michiaki Hirayama, Tatsuya Ito, Takayuki Nobuoka, Ichiro Takemasa, Masayoshi Kobune, Junji Kato

  Cancer science   109 ( 11 ) 3554 - 3563  2018.11  [International journal]

  　View Summary

  Cisplatin plus 5-fluorouracil is regarded as standard neoadjuvant chemotherapy for esophageal squamous cell carcinoma (ESCC) in Japan, but the prognosis remains poor. We have previously described how definitive chemoradiotherapy with docetaxel, nedaplatin, and 5-fluorouracil (DNF) led to a very high response rate and promising survival times. We therefore undertook a phase II trial to evaluate the feasibility and efficacy of neoadjuvant DNF. The study included patients with clinical stage Ib-III ESCC. Chemotherapy consisted of i.v. docetaxel (30 mg/m2 ) and nedaplatin (50 mg/m2 ) on days 1 and 8, and a continuous infusion of 5-fluorouracil (400 mg/m2 /day) on days 1-5 and 8-12, every 3 weeks. After three courses of chemotherapy, esophagectomy was carried out. The primary end-point was the completion rate of the protocol treatment. Twenty-eight patients were enrolled (cStage Ib/II/III, 2/3/23) and all received at least two cycles of chemotherapy. Twenty-five patients underwent surgery, all of whom achieved an R0 resection, leading to a completion rate of 89.3%. The overall response rate was 87.0%. A pathological complete response was confirmed in eight (32.0%) cases. Grade 3/4 adverse events included leukopenia (32.1%), neutropenia (39.3%), febrile neutropenia (10.7%), thrombocytopenia (10.7%), and diarrhea (14.3%), but were manageable. Treatment-related deaths and major surgical complications did not occur. Estimated 2-year progression-free and overall survival rates were 70.4% and 77.2%, respectively. Thus, DNF therapy was well tolerated and deemed feasible, with a strong tumor response in a neoadjuvant setting for ESCC. This trial is registered with the University Hospital Medical Information Network (UMIN ID: 000014305).

  DOI PubMed

• 進行食道癌に対するdocetaxel、nedaplatin、5-FU、放射線同時併用療法(DNF-R)の第I/II相試験

  大沼 啓之, 佐藤 康史, 大須賀 崇裕, 林 毅, 佐藤 勉, 宮西 浩嗣, 小船 雅義, 瀧本 理修, 加藤 淳二, 佐川 保, 堀 正和, 染谷 正則, 中田 健生, 坂田 耕一

  北海道医学雑誌 ( 北海道医学会 )  90 ( 2 ) 152 - 153  2015.11

• Docetaxel, cisplatin and S-1 (DCS) combination chemotherapy for gastric cancer patients with peritoneal metastasis: a multi-institute retrospective study

  Y. Sato, H. Ohnuma, M. Hirakawa, T. Osuga, Y. Okagawa, T. Sagawa, Y. Takahashi, M. Takahashi, M. Maeda, S. Katsuki, M. Hirayama, S. Kikuchi, K. Murase, K. Takada, T. Sato, K. Miyanishi, M. Kobune, R. Takimoto, T. Takayama, J. Kato

  EUROPEAN JOURNAL OF CANCER ( ELSEVIER SCI LTD )  51   S431 - S431  2015.09

  Research paper, summary (international conference)  

• Accumulation of L-Fucose Is a Functional Target for Colorectal Cancer Therapy

  Junji Kato, Rishu Takimoto, Takahiro Osuga, Michihiro Ono, Yutaka Okagawa, Naoki Uemura, Yohei Arihara, Yasushi Sato, Fumito Tamura

  GASTROENTEROLOGY ( W B SAUNDERS CO-ELSEVIER INC )  148 ( 4 ) S948 - S948  2015.04

  Research paper, summary (international conference)  

• A phase I/II study of definitive chemoradiotherapy with docetaxel, nedaplatin, and 5-fluorouracil (DNF-R) for advanced esophageal cancer

  Yasushi Sato, Hiroyuki Ohnuma, Masahiro Hirakawa, Yutaka Okagawa, Takahiro Osuga, Kazuyuki Murase, Kohichi Takada, Yutaka Kawano, Satoshi Iyama, Tsuyoshi Hayashi, Tsutomu Sato, Koji Miyanishi, Rishu Takimoto, Masayoshi Kobune, Tamotsu Sagawa, Masakazu Hori, Masanori Someya, Koh-ichi Sakata, Tetsuji Takayama, Junji Kato

  JOURNAL OF CLINICAL ONCOLOGY ( AMER SOC CLINICAL ONCOLOGY )  33 ( 3 )  2015.01

  Research paper, summary (international conference)  

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Research Projects 【 display / non-display 】

Research Projects 【 display / non-display 】

• Novel strategies for the treatment of solid tumors with CAR and CIML NK cells

  Grant-in-Aid for Scientific Research (B)

  Project Year :

  2021.04

  -

  2024.03

   

  宮西 浩嗣, 久保 智洋, 加藤 淳二, 大須賀 崇裕, 田中 信悟, 濱口 孝太

  　View Summary

  Chimeric antigen receptor（CAR）を用いた遺伝子改変Ｔ細胞療法（CAR-T療法）は、Ｂ細胞性腫瘍に対して劇的な治療効果をもたらした。更にallogenic source を用いたCAR-NK 療法がB細胞性腫瘍に対してCAR-T療法と同等の効果があることが報告され、同治療ではCAR-T療法に比べ、cytokine release syndromeや重篤な神経毒性の出現が少なく、安全性が高いことが示された。しかしながら固形腫瘍、特に膵癌に対するCAR-NK療法の効果に関しては、造血器腫瘍に対するCD19 CAR療法の劇的な治療効果と比較すると抗腫瘍効果は限定的であり、その免疫阻害の克服方法が問われている。本研究においては、CARコンストラクトにIL-12/15/18を組み込んだ”armored CAR-NK”(IL-12/15/18を自己分泌する)を作製し、膵癌細胞株に対する抗腫瘍効果を検討することを目的とした。まず前段階としてIL-12/15/18でNK細胞を刺激して作製したCytokine Induced Memory Like (CIML) NK細胞が、実際に膵癌に対して抗腫瘍効果を発揮するかどうかを検討するため、複数の膵臓癌細胞株とCIML NK細胞を共培養し、7AADおよびAnnexin Vを用いてアポトーシスを解析したところ、コントロールNK細胞(IL-2での刺激のみ)と比較し、有意にアポトーシスを誘導することを示した。以上より当該年度の研究において、通常のCAT-NKと比較し、本研究で作成を予定しているarmored CAR-NKはより膵癌細胞に対してより高い効果を発揮できる可能性を示す貴重なデータを得られたと考える。

• 膵臓癌に対する抗がん剤の腫瘍指向性を持つ新規DDSの開発

  基盤研究(B)

  Project Year :

  2020.04

  -

  2023.03

   

  加藤 淳二, 大須賀 崇裕, 濱口 孝太, 宮西 浩嗣, 村瀬 和幸

  　View Summary

  きわめて予後不良の疾患である膵癌に対する新規治療戦略として、膵癌が単糖を取り込む性質に着目し、新規のドラッグデリバリーシステムを用いた薬剤の開発を進めている。すなわち単糖を抗がん剤内包リポソームに修飾し、高い腫瘍指向性が得られる抗がん剤の開発をこれまで類を見ない「多剤併用療法」で行うことが本研究の目的である。その有用性を証明し、英文での論文発表、特許を取得し、創薬へ繋げることを目標としている。初年度は、「1. 膵癌細胞におけるFDG取り込み機構の解明:FDG-FITCの膵癌細胞への導入, 2. 膵癌に対する多剤併用療法内包化FDG修飾抗がん剤内包リポソームの開発とin vitroでの検討:FDG修飾蛍光剤、抗がん剤の作製。蛍光物質内包FDG結合リポソームの膵癌細胞への導入。」について検討を行なった。膵癌細胞へのFDGの取り込みについてFCM等にて検討した。リポソームにFDGを結合することに成功し、膵癌細胞への取り込みについてFCMあるいは蛍光顕微鏡にて確認を行なった。担癌モデルマウスの作成、FDG結合リポソーム内包抗がん剤の開発も成功した。昨年度は、「in vivoでの検討(担癌モデルマウスへの蛍光内包リポソームの集積）」を行なった。腫瘍組織にFDG結合Cy5.5内包リポソームが集積していることが確認された。本年度は、抗がん剤内包リポソームでの治療効果の確認)と組織学的検討を行なう予定である。

• Developing a novel therapeutic strategy for advanced gastric cancer using the new genetic pathway of HIF-1 alpha.

  Grant-in-Aid for Early-Career Scientists

  Project Year :

  2019.04

  -

  2022.03

   

  Osuga Takahiro

  　View Summary

  In this study, we succeeded in culturing gastric cancer cells in a low oxygen state, and found that the number of tumor cells decreased in the low oxygen state compared to the normal oxygen state. Regarding the role of REL in hypoxia in gastric cancer, its inhibition alone could not inhibit the tumor's resistance to hypoxia. This may be due to the activation of other gene pathways by inhibiting REL, resulting in resistance to hypoxia. It was considered to be an important finding because it differs from previous studies on colorectal cancer. In addition, histological and clinical studies have revealed the characteristics of gastric cancer that occurs in smokers. Since there is a slight tendency in the relationship between smoking and HIF-1α, we plan to conduct positive histological analysis and patient background statistical analysis in the future.

• Development of a new treatment for colorectal cancer using the glucose metabolism characteristics.

  Grant-in-Aid for Scientific Research (B)

  Project Year :

  2017.04

  -

  2020.03

   

  Kato Junji

  　View Summary

  Metastatic / recurrent colorectal cancer is a disease with a poor prognosis, and the number of deaths continues to increase, and the development of more effective treatment methods is awaited. The FDG-PET examination, which utilizes the characteristics of increased sugar uptake in colorectal cancer, is useful for diagnosing colorectal cancer. Therefore, anticancer drugs using FDG as a carrier are promising as therapeutic agents for colorectal cancer. Therefore, we aimed to prepare an FDG-binding anticancer drug and examine its effect. A fluorescent reagent directly bound to FDG was prepared and examined, but no difference of anticancer effect from other sugar was observed. Considering that the stability of the reagent was a problem, we prepared a fluorescent reagent in which FDG was bound to liposomes, and found that it was taken up by cancer cells. In the future, we would like to promote the development of new anticancer agents that utilize this mechanism using FDG-binding liposomes.

• FUTを標的とした進行大腸癌に対する抗EMT療法の開発

  基盤研究(C)

  Project Year :

  2015.04

  -

  2016.03

   

  瀧本 理修, 加藤 淳二, 大須賀 崇裕, 岡川 泰, 佐藤 康史

  　View Summary

  大腸癌細胞の転移・浸潤には上皮間葉移行（EMT）が関与している．再発転移進行大腸癌の長期予後を改善するためには，悪性形質の一つである転移・浸潤を克服することが極めて重要である．そこで，申請者らは新規治療法の開発のために，がん細胞の転移を抑制する抗EMT療法を考案し基礎検討を実施した．申請者らはこれまでのpreliminaryな検討から，EMT亢進の機序として増殖因子受容体の糖鎖修飾が重要な役割を果たしていることを見出している．そこで，この糖鎖修飾を担う酵素の発現を各種大腸がん細胞株で検討し，これらの細胞株におけるEMTと糖鎖修飾酵素の関連性を比較した．その結果，糖鎖修飾酵素の中でFucosyltransferase（FUT）の発現が亢進している細胞株ではEMTも高まっていることが確認された．そこで，この糖鎖修飾分子を標的とした抗転移分子標的療法の可能性を検討した．その結果，FUT3, FUT6を抑制することによりEMT関連誘導分子の発現抑制とEMTの低下，浸潤能および遊走能が低下することが明らかとなった． 現在，糖鎖修飾酵素を抑制するsiRNAを作製し，その効率を検討した上でEMTに対する影響を検討する予定である．その上で，我々が開発した糖鎖修飾リポソームにFUTに対するsiRNAを搭載することで腫瘍特異性を高め，大腸ガン細胞を標的とすることで有害事象を軽減した抗転移抑制療法として臨床応用に向けた基礎的な検討を行い有用性を検証したい．

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