Functional analysis and development of novel treatment targeting for Nrf2 in hapatobiliary pancreatic cancer

2018 Fiscal Year Research-status Report

• Project/Area Number: 18K16370
• Research Institution: Kumamoto University
• Principal Investigator: 北野 雄希 熊本大学, 医学部附属病院, 非常勤診療医師 (40814760)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: 膵癌 / がん代謝 / 腫瘍免疫 / Nrf2 / PD-L1 / CD8 T細胞

Outline of Annual Research Achievements

がん細胞内では様々な代謝リプログラミングが生じ、がん細胞に有利な環境が作られている。Nuclear factor erythroid 2 related factor 2 (Nrf2)は従来、酸化ストレスや異物に対する生体防御機構を制御する転写因子とされていたが、近年がん代謝のmaster regulatorであると報告された。本研究の目的は肝胆膵領域癌において、がん代謝バイオマーカーとしてのNrf2の機能解析と新規治療法の開発であった。膵癌は様々な集学的治療を行うも予後は不良であり、さらに膵癌の大多数で見られるKras変異が、がん代謝に大きく関わっていることが知られている。これまでに我々は、In vitroの実験においてNrf2の発現が膵癌の腫瘍進展に大きく関わっていることを示し、パブリックデータベースにてNrf2高発現が予後不良であることを示した。また、がん代謝は腫瘍免疫と複雑に関連していることも知られており（Cell, 2015）、Nrf2もその制御に関わっていると報告された（Oncogene, 2018）。我々は臨床検体を用いて、膵癌においてCD8低発現・PD-L1高発現が予後不良であることを報告し（Cancer Sci, 2018）、パブリックデータベースにてNrf2とPD-L1発現が相関することを示している。今後、これらの知見に基づいてNrf2が腫瘍免疫を介して膵癌進展に与える影響について詳細に検討を行っていく予定である。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

臨床サンプルの発現解析、in vitro実験、in silico解析などを主に熊本大学で行っている。熊本大学では、膵癌における様々なMolecular data（KRAS変異、PIK3CA変異、BRAF変異、LINE-1 methylation level）のデータベース構築を行い、今後の更なる研究への地盤形成を行っており、それらとNrf2の相関関係の評価も可能である。さらに、これまでに膵癌が腫瘍免疫の観点から予後に与える影響を評価し、その結果を報告した。

Strategy for Future Research Activity

近年、Nrf2はがん代謝のregulatorだけでなく、腫瘍免疫やオートファジーとの相互作用も報告され、さらに注目を集めている（Cell 2015, Front oncol 2018）。Nrf2をがん代謝だけでなく、様々な観点から多面的に検討することでNrf2の本来の機能を理解し、治療開発に繋げることが必要と考える。また、膵癌だけでなく、胆管癌も同じく予後不良の疾患であり、有効な治療法も限られている。我々は胆管癌においても、腫瘍免疫が予後に与える影響を報告しており（Br J cancer 2018）、がん代謝との相互作用の解析も可能である。また近年、メタボローム解析や次世代シーケンサー解析も可能になったこともあり、これらを用いて肝胆膵領域癌の新規オンコメタボライトの同定を含めた統合的解析も重要であり、今後進めていく予定である。

Causes of Carryover

試薬、消耗品の購入費及び研究データの管理、資料整理を行ってもらうための事務補佐員の雇用経費に充てたいと考える。

Research Products

• [Journal Article] PD-L1 expression enhancement by infiltrating macrophage-derived tumor necrosis factor-alpha leads to poor pancreatic cancer prognosis. (2019)
  • Author(s): Tsukamoto M, Imai K, Ishimoto T, Komohara Y, Yamashita Y, Nakagawa S, Umezaki N, Yamao T, Kitano Y, Miyata T, Arima K, Okabe H, Baba Y, Chikamoto A, Ishiko T, Hirota M, Baba H
  • Journal Title: Cancer Sci Volume: 110(1) Pages: 310-320
  • DOI: 10.1111/cas.13874.
  • Peer Reviewed / Open Access
• [Journal Article] A case of acute perforated cholecystitis with intracystic tumor thrombus of hepatocellular carcinoma. (2019)
  • Author(s): Nakao Y, Okabe H, Yamashita Y, Itoyama R, Yusa T, Kitano Y, Arima K, Miyata T, Nakagawa S, Imai K, Chikamoto A, Baba H
  • Journal Title: Int Canc Conf J Volume: 8(1) Pages: 43-45
  • Peer Reviewed
• [Journal Article] Clinical role of fludeoxyglucose (18F) positron emission tomography/computed tomography ((18)F-FDG PET/CT) in patients with pancreatic neuroendocrine tumors. (2019)
  • Author(s): Matsumoto T, Okabe H, Yamashita Y, Yusa T, Itoyama R, Nakao Y, Yamao T, Umzaki N, Tsukamoto M, Kitano Y, Miyata T, Arima K, Nitta H, Hayashi H, Imai K, Chikamoto A, Baba H
  • Journal Title: Surg Today Volume: 49(1) Pages: 21-26
  • DOI: 10.1007/s00595-018-1703-2
  • Peer Reviewed
• [Journal Article] Clinical significance of preoperative hepatocellular carcinoma with high lens culinaris agglutinin-reactive fraction of alpha-fetoprotein, but low alpha-fetoprotein. (2019)
  • Author(s): Yamao T, Yamashita Y, Imai K, Umezaki N, Tsukamoto M, Kitano Y, Arima K, Miyata T, Nakagawa S, Okabe H, Hayashi H, Chikamoto A, Ishiko T, Baba H
  • Journal Title: Anticancer Res Volume: 39(2) Pages: 883-889
  • DOI: 10.21873/anticanres.13189.
  • Peer Reviewed
• [Journal Article] Effectiveness of surgery for recurrent cholangiocarcinoma: A single center experience and brief literature review (2019)
  • Author(s): Kitano Yuki、Yamashita Yo-ichi、Nakagawa Shigeki、Okabe Hirohisa、Imai Katsunori、Chikamoto Akira、Baba Hideo
  • Journal Title: The American Journal of Surgery
  • DOI: 10.1016/j.amjsurg.2019.02.015
  • Peer Reviewed / Open Access
• [Journal Article] Multidisciplinary approach of liver metastases from colorectal cancer. (2019)
  • Author(s): Adam R, Kitano Y
  • Journal Title: Ann Gastroenterol Surg Volume: 3 Pages: 50-56
  • DOI: 10.1002/ags3.12227.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nrf2 promotes oesophageal cancer cell proliferation via metabolic reprogramming and detoxification of reactive oxygen species. (2018)
  • Author(s): Kitano Y, Baba Y, Nakagawa S, Miyake K, Iwatsuki M, Ishimoto T, Yamashita Y, Yoshida N, Watanabe M, Nakao M, Baba H
  • Journal Title: J Pathol Volume: 244(3) Pages: 346-357
  • DOI: 10.1002/path.5021.
  • Peer Reviewed
• [Journal Article] Tumour-infiltrating inflammatory and immune cells in patients with extrahepatic cholangiocarcinoma. (2018)
  • Author(s): Kitano Y, Okabe H, Yamashita Y, Nakagawa S, Saito Y, Umezaki N, Tsukamoto M, Yamao T, Yamamura K, Arima K, Kaida T, Miyata T, Mima K, Imai K, Hashimoto D, Komohara Y, Chikamoto A, Ishiko T, Baba H
  • Journal Title: Br J Cancer Volume: 118(2) Pages: 171-180
  • DOI: 10.1038/bjc.2017.401.
  • Peer Reviewed
• [Journal Article] Prognostic value of LINE-1 methylation level in 321 patients with primary liver cancer including hepatocellular carcinoma and intrahepatic cholangiocarcinoma. (2018)
  • Author(s): Miyata T, Yamashita Y, Baba Y, Harada K, Yamao T, Umezaki N, Tsukamoto M, Kitano Y, Yamamura K, Arima K, Nakagawa S, Okabe H, Imai K, Hashimoto D, Chikamoto A, Shimokawa M, Baba H
  • Journal Title: Oncotarget Volume: 9(29) Pages: 20795-20806
  • DOI: 10.18632/oncotarget.25124.
  • Peer Reviewed / Open Access
• [Journal Article] Controlling Nutritional Status (CONUT) score is a prognostic marker for gastric cancer patients after curative resection. (2018)
  • Author(s): Kuroda D, Sawayama H, Kurashige J, Iwatsuki M, Eto T, Tokunaga R, Kitano Y, Yamamura K, Ouchi M, Nakamura K, Baba Y, Sakamoto Y, Yamashita Y, Yoshida N, Chikamoto A, Baba H
  • Journal Title: Gastric Cancer Volume: 21(2) Pages: 204-212
  • DOI: 10.1007/s10120-017-0744-3.
  • Peer Reviewed
• [Journal Article] Enhancer of zeste homolog 2 (EZH2) regulates tumor angiogenesis and predicts recurrence and prognosis of intrahepatic cholangiocarcinoma. (2018)
  • Author(s): Nakagawa S, Okabe H, Ouchi M, Tokunaga R, Umezaki N, Higashi T, Kaida T, Arima K, Kitano Y, Kuroki H, Mima K, Nitta H, Imai K, Hashimoto D, Yamashita Y, Chikamoto A, Baba H
  • Journal Title: HPB (Oxford) Volume: 20(10) Pages: 939-948
  • DOI: 10.1016/j.hpb.2018.03.018.
  • Peer Reviewed
• [Journal Article] Number of acinar cells at the pancreatic stump predicts pancreatic fistula after pancreaticoduodenectomy. (2018)
  • Author(s): Umezaki N, Hashimoto D, Nakagawa S, Kitano Y, Yamamura K, Chikamoto A, Matsumura F, Baba H
  • Journal Title: Surg Today Volume: 48(8) Pages: 790-795
  • DOI: 10.1007/s00595-018-1656-5.
  • Peer Reviewed
• [Journal Article] Clinical usefulness of postoperative C-reactive protein/albumin ratio in pancreatic ductal adenocarcinoma. (2018)
  • Author(s): Arima K, Yamashita Y, Hashimoto D, Nakagawa S, Umezaki N, Yamao T, Tsukamoto M, Kitano Y, Yamamura K, Miyata T, Okabe H, Ishimoto T, Imai K, Chikamoto A, Baba H
  • Journal Title: Am J Surg Volume: 216(1) Pages: 111-115
  • DOI: 10.1016/j.amjsurg.2017.08.016.
  • Peer Reviewed
• [Journal Article] Hepatic resection followed by hepatic arterial infusion chemotherapy for hepatocellular carcinoma with intrahepatic dissemination. (2018)
  • Author(s): Kuramoto K, Beppu T, Nitta H, Imai K, Masuda T, Miyata T, Koga Y, Kitano Y, Kaida T, Nakagawa S, Okabe H, Hayashi H, Hashimoto D, Yamashita Y, Chikamoto A, Kikuchi K, Baba H
  • Journal Title: Anticancer Res Volume: 38(1) Pages: 525-531
  • Peer Reviewed
• [Journal Article] Predicting poorly differentiated hepatocellular carcinoma that meets the milan criteria. (2018)
  • Author(s): Koga Y, Beppu T, Miyata T, Kitano Y, Tsuji A, Nakagawa S, Arima K, Kuramoto K, Okabe H, Imai K, Hayashi H, Nitta H, Yamashita Y, Chikamoto A, Ishiko T, Baba H
  • Journal Title: Anticancer Res Volume: 38(7) Pages: 4093-4099
  • DOI: 10.21873/anticanres.12699.
  • Peer Reviewed
• [Journal Article] A case of 15-year recurrence-free survival after microwave coagulation therapy for liver metastasis from gastric cancer. (2018)
  • Author(s): Kinoshita K, Beppu T, Miyata T, Kuramoto K, Yoshida Y, Umesaki N, Kitano Y, Nakagawa S, Okabe H, Nitta H, Imai K, Hayashi H, Yamashita Y, Komori H, Horino K, Misumi A, Baba H
  • Journal Title: Anticancer Res Volume: 38(3) Pages: 1595-1598
  • Peer Reviewed
• [Journal Article] Multiple primary cancers in patients with pancreatic cancer. (2018)
  • Author(s): Yamamura K, Hashimoto D, Kitano Y, Kuroda D, Eto T, Arima K, Kaida T, Miyata T, Nakagawa S, Imai K, Yamashita Y, Chikamoto A, Matsumura F, Baba H
  • Journal Title: Am Surg Volume: 84(12) Pages: e514-e516
• [Journal Article] Microvascular invasion of single small hepatocellular carcinoma </=3 cm: Predictors and optimal treatments. (2018)
  • Author(s): Yamashita Y, Imai K, Yusa T, Nakao Y, Kitano Y, Nakagawa S, Okabe H, Chikamoto A, Ishiko T, Yoshizumi T, Aishima S, Maehara Y, Baba H
  • Journal Title: Ann Gastroenterol Surg Volume: 2(3): Pages: 197-203
  • DOI: 10.1002/ags3.12057.
  • Peer Reviewed / Open Access
• [Journal Article] Cystic gastric metastasis from pancreatic cancer. (2018)
  • Author(s): Umezaki N, Hashimoto D, Nakagawa S, Yamao T, Tsukamoto M, Kitano Y, Arima K, Yamamura K, Miyata T, Okabe H, Chikamoto A, Matsumura F, Baba H
  • Journal Title: Surg Case Rep Volume: 4(1) Pages: 31
  • DOI: 10.1186/s40792-018-0443-2.
  • Peer Reviewed / Open Access
• [Journal Article] Complete remission of advanced hepatocellular carcinoma following transient chemoembolization and portal vein ligation. (2018)
  • Author(s): Koga Y, Beppu T, Imai K, Kuramoto K, Miyata T, Kitano Y, Nakagawa S, Okabe H, Okabe K, Yamashita Y, Chikamoto A, Baba H
  • Journal Title: Surg Case Rep Volume: 4(1) Pages: 102
  • DOI: 10.1186/s40792-018-0510-8.
  • Peer Reviewed / Open Access