卵巣癌における“hot spot”変異解析に基づく新規薬剤の探索

2015 Fiscal Year Annual Research Report

• Project/Area Number: 25462590
• Research Institution: Kyoto University
• Principal Investigator: 松村 謙臣 京都大学, 医学(系)研究科(研究院), 准教授 (20452336)
• Co-Investigator(Kenkyū-buntansha): 森 誠一 公益財団法人がん研究会, その他部局等, 研究員 (10334814) ; 小西 郁生 京都大学, 医学(系)研究科(研究院), 教授 (90192062)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 卵巣がん / 遺伝子発現解析 / バイオマーカー / 分子標的療法

Outline of Annual Research Achievements

卵巣癌は診断時には進行例が多く、手術のみでは完治せず、化学療法が必須である。しかし、化学療法を行っても、効果がない症例があり、その選別が重要である。またいったんは化学療法が奏功しても、再発し、最終的には薬物療法抵抗性となることが多い。卵巣癌の中で、卵巣高異型度漿液性腺癌(high-grade serous ovarian carcinoma; HGSOC)は、最も頻度が高く、予後不良の組織型である。そこで、我々は、HGSOCに対する、薬物療法感受性のバイオマーカーの探索、および、新規薬物療法の開発を研究の目的とした。
まず、自施設におけるHGSOC症例の病理組織像を検討すると、癌細胞が間質にばらけて浸潤する像を示す腫瘍は予後不良で、多数のリンパ球が浸潤する腫瘍は予後良好であった。The Cancer Genome Atlas (TCGA)データセットにおいて、卵巣漿液性腺癌の遺伝子変異、コピー数異常、遺伝子発現マイクロアレイデータを解析すると、遺伝子発現プロファイルによる分類が最も予後と関連していた。我々は、自施設のHGSOCの遺伝子発現マイクロアレイデータと比較検討し、HGSOCの遺伝子発現プロファイルを反映する病理組織細分類を樹立した。さらに、その分類がパクリタキセル感受性と相関することを示した。
パスウェイ解析の結果、卵巣漿液性腺癌において、BMPシグナルががん細胞の増殖亢進させることを見出した。そして、BMPシグナル経路阻害剤が治療薬として有望であることを示した。

Research Products

• [Journal Article] Prediction of taxane and platinum sensitivity in ovarian cancer based on gene expression profiles. (2016)
  • Author(s): Murakami R, Matsumura N, Brown JB, Wang Z, Yamaguchi K, Abiko K, Yoshioka Y, Hamanishi J, Baba T, Koshiyama M, Mandai M, Yamada R, Konishi I
  • Journal Title: Gynecol Oncol Volume: 141 Pages: 49-56
  • DOI: 10.1016/j.ygyno.2016.02.027.
  • Peer Reviewed
• [Journal Article] The BMP signaling pathway leads to enhanced proliferation in serous ovarian cancer-a potential therapeutic target. (2016)
  • Author(s): Peng J, Yoshioka Y, Mandai M, Matsumura N, Baba T, Yamaguchi K, Hamanishi J, Kharma B, Murakami R, Abiko K, Murphy SK, Konishi I
  • Journal Title: Mol Carcinog Volume: 55 Pages: 335-345
  • DOI: 10.1002/mc.22283.
  • Peer Reviewed
• [Journal Article] Chemotherapy Induces Programmed Cell Death-Ligand 1 Overexpression via the Nuclear Factor-κB to Foster an Immunosuppressive Tumor Microenvironment in Ovarian Cancer. (2015)
  • Author(s): Peng J, Hamanishi J, Matsumura N, Abiko K, Murat K, Baba T, Yamaguchi K, Horikawa N, Hosoe Y, Murphy SK, Konishi I, Mandai M
  • Journal Title: Cancer Res Volume: 75 Pages: 5034-5045
  • DOI: 10.1158/0008-5472.CAN-14-3098.
  • Peer Reviewed
• [Journal Article] Ovarian clear cell carcinoma meets metabolism; HNF-1β confers survival benefits through the Warburg effect and ROS reduction. (2015)
  • Author(s): Mandai M, Amano Y, Yamaguchi K, Matsumura N, Baba T, Konishi I
  • Journal Title: Oncotarget Volume: 6 Pages: 30704-30714
  • DOI: 10.18632/oncotarget.5228.
  • Peer Reviewed
• [Journal Article] Safety and Antitumor Activity of Anti-PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer. (2015)
  • Author(s): Hamanishi J, Mandai M, Ikeda T, Minami M, Kawaguchi A, Murayama T, Kanai M, Mori Y, Matsumoto S, Chikuma S, Matsumura N, Abiko K, Baba T, Yamaguchi K, Ueda A, Hosoe Y, Morita S, Yokode M, Shimizu A, Honjo T, Konishi I
  • Journal Title: J Clin Oncol Volume: 33 Pages: 4015-4022
  • DOI: 10.1200/JCO.2015.62.3397.
  • Peer Reviewed
• [Journal Article] Metabolic alterations caused by HNF1β expression in ovarian clear cell carcinoma contribute to cell survival (2015)
  • Author(s): Amano Y, Mandai M, Yamaguchi K, Matsumura N, Kharma B, Baba T, Abiko K, Hamanishi J, Yoshioka Y, Konishi I
  • Journal Title: Oncotarget Volume: 6 Pages: 26002-26017
  • DOI: 10.18632/oncotarget.4692.
  • Peer Reviewed
• [Journal Article] Venous thromboembolism, interleukin-6 and survival outcomes in patients with advanced ovarian clear cell carcinoma. (2015)
  • Author(s): Matsuo K, Hasegawa K, Yoshino K, Murakami R, Hisamatsu T, Stone RL, Previs RA, Hansen JM, Ikeda Y, Miyara A, Hiramatsu K, Enomoto T, Fujiwara K, Matsumura N, Konishi I, Roman LD, Gabra H, Fotopoulou C, Sood AK
  • Journal Title: Eur J Cancer Volume: 51 Pages: 1978-1988
  • DOI: 10.1016/j.ejca.2015.07.012.
  • Peer Reviewed
• [Journal Article] IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer. (2015)
  • Author(s): Abiko K, Matsumura N, Hamanishi J, Horikawa N, Murakami R, Yamaguchi K, Yoshioka Y, Baba T, Konishi I, Mandai M
  • Journal Title: Br J Cancer Volume: 112 Pages: 1501-1509
  • DOI: 10.1038/bjc.2015.101.
  • Peer Reviewed
• [Presentation] Integrated analysis of single nucleotide variants and copy number variants in ovarian clear cell adenocarcinoma (2015)
  • Author(s): Noriomi Matsumura、Ryuusuke Murkami、Koichiro Higasa、Takanobu Tsutsumi、J. B. Brown、Junzo Hamanishi、Ken Yamaguchi、Kaoru Abiko、Tsukasa Baba、Masafumi Koshiyama、Ryo Yamada、Fumihiko Matsuda、Yasushi Okuno、Ikuo Konishi
  • Organizer: 第53回日本癌治療学会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2015-10-29 – 2015-10-31
  • Invited
• [Presentation] 卵巣癌の微小免疫環境解析と抗PD-1抗体療法の展望 (2015)
  • Author(s): 濱西 潤三、万代 昌紀、松村 謙臣、安彦 郁、村上 隆介、馬場 長、山口 建、小西 郁生
  • Organizer: 第53回日本癌治療学会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2015-10-29 – 2015-10-31
  • Invited
• [Presentation] Identification through functional genomics screening of factors whose downregulation enhances the side population in ovarian cancer. (2015)
  • Author(s): Noriomi Matsumura, Koji Yamanoi, Susan K Murphy, Junzo Hamanishi, Kaoru Abiko, Ken Yamaguchi, Tsukasa Baba, Masafumi Koshiyama, Ikuo Konishi
  • Organizer: An AACR Special Conference on Advances in Ovarian Cancer Research
  • Place of Presentation: Hyatt Regency Orland
  • Year and Date: 2015-10-17 – 2015-10-20
  • Int'l Joint Research
• [Presentation] Chemoimmunotherapy with PD-1 blockade and paclitaxel induce a potent antitumor immunity in ovarian cancers. (2015)
  • Author(s): Junzo Hamanishi, Jin Peng, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Ikuo Konishi, Masaki Mandai
  • Organizer: An AACR Special Conference on Advances in Ovarian Cancer Research
  • Place of Presentation: Hyatt Regency Orland
  • Year and Date: 2015-10-17 – 2015-10-20
• [Presentation] Inhibition of Snail-induced EMT promotes anti-tumor immune response in ovarian cancer. (2015)
  • Author(s): Mana Taki, Kaoru Abiko, Noriomi Matsumura, Tsukasa Baba, Junzo Hamanishi, Naoki Horikawa, Ikuo Konishi
  • Organizer: An AACR Special Conference on Advances in Ovarian Cancer Research
  • Place of Presentation: Hyatt Regency Orland
  • Year and Date: 2015-10-17 – 2015-10-20
• [Presentation] Expression of VEGF in ovarian cancer suppresses tumor immunity through recruitment of myeloid derived suppressor cells. (2015)
  • Author(s): Naoki Horikawa, Kaoru Abiko, Noriomi Matsumura, Junzo Hamanishi, Susan K Murphy, Tsukasa Baba, Ken Yamaguchi, Masafumi Koshiyama, Ikuo Konishi
  • Organizer: An AACR Special Conference on Advances in Ovarian Cancer Research
  • Place of Presentation: Hyatt Regency Orland
  • Year and Date: 2015-10-17 – 2015-10-20