Development of a novel assay for prediction of response to anti-EGFR antibody therapy in colorectal cancer

• Project/Area Number: 24590674
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Hokkaido University
• Principal Investigator: Hatanaka Yutaka 北海道大学, 大学病院, 特任講師 (30589924)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 分子標的治療 / 治療抵抗性 / コンパニオン診断 / 大腸癌 / 治療効果予測

Outline of Final Research Achievements

In this study, we attempted to develop a novel method to predict response to anti-EGFR therapy in colorectal cancer. A sensitive EGFR detection method using cetuximab and the simplified surrogate method were successfully established. However, these methods failed to enrich any responders to the therapy in RAS/BRAF wild-type colorectal cancer. We therefore explored novel predictive markers for the therapy by a comprehensive analysis of two different cell lines, KRAS wild-type and mutant, and identified twelve genes that changed between these cells. It is suggested that these candidate genes including a membrane protein related to nucleic acid metabolism might be predictive markers of anti-EGFR therapy.

Research Products

• [Journal Article] ZEB1 expression is associated with prognosis of intrahepatic cholangiocarcinoma (2016)
  • Author(s): Terashita K, Chuma M, Hatanaka Y, Hatanaka K, Mitsuhashi T, Yokoo H, Ohmura T, Ishizu H, Muraoka S, Nagasaka A, Tsuji T, Yamamoto Y, Kurauchi N, Shimoyama N, Toyoda H, Kumada T, Kaneoka Y, Maeda A, Ogawa K, Natsuizaka M, Kamachi H, Kakisaka T, Kamiyama T, Taketomi A, Matsuno Y, Sakamoto N
  • Journal Title: J Clin Pathol Volume: in press Issue: 7 Pages: 593-599
  • DOI: 10.1136/jclinpath-2015-203115
  • Peer Reviewed
• [Journal Article] Stromal Palladin Expression Is an Independent Prognostic Factor in Pancreatic Ductal Adenocarcinoma (2016)
  • Author(s): Sato D, Tsuchikawa T, Mitsuhashi T, Hatanaka Y, Marukawa K, Morooka A, Nakamura T, Shichinohe T, Matsuno Y, Hirano S
  • Journal Title: PLoS One Volume: 11 Issue: 3 Pages: e0152523-e0152523
  • DOI: 10.1371/journal.pone.0152523
  • NAID: 120005757988
  • Peer Reviewed / Open Access
• [Journal Article] Comparative genetic analysis of a rare synchronous collision tumor composed of malignant pleural mesothelioma and primary pulmonary adenocarcinoma. (2016)
  • Author(s): Naka T, Hatanaka Y, Marukawa K, Okada H, Hatanaka KC, Sakakibara-Konishi J, Oizumi S, Hida Y, Kaga K, Mitsuhashi T, Matsuno Y
  • Journal Title: Diagn Pathol Volume: 11 Issue: 1 Pages: 1-6
  • DOI: 10.1186/s13000-016-0488-0
  • NAID: 120005766752
  • Peer Reviewed / Open Access
• [Journal Article] Clinical significance of tumor-infiltrating immune cells focusing on BTLA and Cbl-b in patients with gallbladder cancer. (2015)
  • Author(s): Oguro S, Ino Y, Shimada K, Hatanaka Y, Matsuno Y, Esaki M, Nara S, Kishi Y, Kosuge T, Hiraoka N.
  • Journal Title: Cancer Sci Volume: Dec;106(12) Issue: 12 Pages: 1750-60
  • DOI: 10.1111/cas.12825
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] EGFR inhibitors prevent induction of cancer stem-like cells in esophageal squamous cell carcinoma by suppressing epithelial-mesenchymal transition. (2015)
  • Author(s): Sato F, Kubota Y, Natsuizaka M, Maehara O, Hatanaka Y, Marukawa K, Terashita K, Suda G, Ohnishi S, Shimizu Y, Komatsu Y, Ohashi S, Kagawa S, Kinugasa H, Whelan KA, Rustgi AK, Nakagawa H, Sakamoto N.
  • Journal Title: Cancer Biol Ther Volume: in press
  • Peer Reviewed
• [Journal Article] Immunohistochemical Validation and Expression Profiling of NKG2D Ligands in a Wide Spectrum of Human Epithelial Neoplasms. (2015)
  • Author(s): Fujita H, Hatanaka Y, Sutoh Y, Suzuki Y, Oba K, Hatanaka KC, Mitsuhashi T, Otsuka N, Fugo K, Kasahara M, Matsuno Y.
  • Journal Title: J Histochem Cytochem. Volume: 63 Issue: 3 Pages: 217-227
  • DOI: 10.1369/0022155414563800
  • Peer Reviewed / Open Access
• [Journal Article] CTNNB1 mutational analysis of solid-pseudopapillary neoplasms of the pancreas using endoscopic ultrasound-guided fine-needle aspiration and next-generation deep sequencing. (2014)
  • Author(s): Kubota Y, Kawakami H, Natsuizaka M, Kawakubo K, Marukawa K, Kudo T, Abe Y, Kubo K, Kuwatani M, Hatanaka Y, Mitsuhashi T, Matsuno Y, Sakamoto N.
  • Journal Title: J Gastroenterol. Volume: in press Issue: 2 Pages: 203-210
  • DOI: 10.1007/s00535-014-0954-y
  • NAID: 120005693897
  • Peer Reviewed
• [Journal Article] High level expression of AMAP1 protein correlates with poor prognosis and survival after surgery of head and neck squamous cell carcinoma patients. (2014)
  • Author(s): Sato H, Hatanaka KC, Hatanaka Y, Hatakeyama H, Hashimoto A, Matsuno Y, Fukuda S, Sabe H.
  • Journal Title: Cell Commun Signal. Volume: 12 Issue: 1 Pages: 17-17
  • DOI: 10.1186/1478-811x-12-17
  • NAID: 120005438264
  • Peer Reviewed / Open Access
• [Journal Article] Intratumoral distribution of EGFR-amplified and EGFR-mutated cells in pulmonary adenocarcinoma. (2014)
  • Author(s): Soma S, Tsuta K, Takano T, Hatanaka Y, Yoshida A, Suzuki K, Asamura H, Tsuda H
  • Journal Title: Pathol Res Pract Volume: 210 Issue: 3 Pages: 155-60
  • DOI: 10.1016/j.prp.2013.11.008
  • Peer Reviewed
• [Journal Article] Differential expression of progesterone receptor, FOXA1, GATA3, and p53 between pre- and postmenopausal women with estrogen receptor-positive breast cancer. (2014)
  • Author(s): Hosoda M, Yamamoto M, Nakano K, Hatanaka KC, Takakuwa E, Hatanaka Y, Matsuno Y, Yamashita H
  • Journal Title: Breast Cancer Res Treat. Volume: 144 Issue: 2 Pages: 249-61
  • DOI: 10.1007/s10549-014-2867-0
  • NAID: 120005600744
  • Peer Reviewed
• [Journal Article] p53 accumulation is a strong predictor of recurrence in estrogen receptor-positive breast cancer patients treated with aromatase inhibitors. (2014)
  • Author(s): Yamamoto M, Hosoda M, Nakano K, Jia S, Hatanaka KC, Takakuwa E, Hatanaka Y, Matsuno Y, Yamashita H
  • Journal Title: Cancer Sci Volume: 105 Issue: 1 Pages: 81-8
  • DOI: 10.1111/cas.12302
  • NAID: 120005411143
  • Peer Reviewed
• [Journal Article] 免疫組織化学－診断と治療選択の指針：病理診断のための検査室の運営および管理 (2014)
  • Author(s): 丸川 活司，畑中 豊，松野 吉宏
  • Journal Title: 病理と臨床 Volume: 32 Pages: 2-7
• [Journal Article] 固形腫瘍治療とコンパニオン診断 (2014)
  • Author(s): 丸川 活司，畑中 豊，松野 吉宏
  • Journal Title: 臨床検査 Volume: 印刷中
• [Journal Article] Validity and reproducibility of Ki-67 assessment in gastrointestinal stromal tumors and leiomyosarcomas. (2013)
  • Author(s): Ogino J, Asanuma H, Hatanaka Y, Matsuno Y, Gotoda H, Muraoka S, Tsuji T, Fukazawa Y, Yamashiro K, Kondo N, Iwaki H, Miyokawa N, Hasegawa T.
  • Journal Title: Pathol Int Volume: 63巻 Issue: 2 Pages: 102-107
  • DOI: 10.1111/pin.12038
  • Peer Reviewed
• [Journal Article] Ultrastaging of para-aortic lymph nodes in stage IIIC1 endometrial cancer: a preliminary report. (2012)
  • Author(s): Todo Y, Suzuki Y, Azuma M, Hatanaka Y, Konno Y, Watari H, Kato H, Matsuno Y, Yamashiro K, Sakuragi N.
  • Journal Title: Gynecol Oncol Volume: 127巻 Issue: 3 Pages: 532-537
  • DOI: 10.1016/j.ygyno.2012.08.026
  • Peer Reviewed
• [Journal Article] Immunohistochemical molecular expression profile of metastatic brain tumor for potent personalized medicine. (2012)
  • Author(s): Kato Y, Nishihara H, Yuzawa S, Mohri H, Kanno H, Hatanaka Y, Kimura T, Tanino M, Tanaka S.
  • Journal Title: Brain Tumor Pathol Volume: 印刷中 Issue: 3 Pages: 167-174
  • DOI: 10.1007/s10014-012-0124-y
  • NAID: 120005460237
  • Peer Reviewed
• [Journal Article] コンパニオン診断と病理 (2012)
  • Author(s): 畑中 豊, 西尾 和人, 松野 吉宏
  • Journal Title: 病理と臨床 Volume: 30巻 Pages: 1300-1308
• [Journal Article] 分子病理学的検索を目的とした新規組織固定法 (2012)
  • Author(s): 鈴木雄太, 畑中豊, 松野吉宏
  • Journal Title: 検査と技術 Volume: 41巻 Pages: 102-106
• [Presentation] ドライバー遺伝子変異検査法の現状と課題：コンパニオン診断薬の開発と臨床応用 (2015)
  • Author(s): 畑中 豊，松野 吉宏
  • Organizer: 第56回 日本肺癌学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2015-11-26
  • Invited
• [Presentation] コンパニオン診断（CoDx）の規制と質保証 (2015)
  • Author(s): 畑中 豊，松野 吉宏
  • Organizer: 第61回 日本病理学会秋期特別総会
  • Place of Presentation: 東京大学安田講堂（東京都文京区）
  • Year and Date: 2015-11-05
  • Invited
• [Presentation] 希少症例のFFPE組織検体から出発した悪性中皮腫の新規分子診断マーカーの探索 (2015)
  • Author(s): 中 智昭，畑中 豊，菅野 宏美，畑中 佳奈子，武島 幸男，井内 康輝，三橋 智子，松野 吉宏．
  • Organizer: 第74回 日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(愛知県名古屋市)
  • Year and Date: 2015-10-08
• [Presentation] 原発不明癌の分子標的治療の開発を目指したドライバー遺伝子変異解析． (2015)
  • Author(s): 木下 一郎，畑中 豊，本間 理央，辻 靖，坂井 和子，西尾 和人，田中 里枝，鈴木 優介，松野 吉宏，秋田 弘俊．
  • Organizer: 第13回 日本臨床腫瘍学会学術集会
  • Place of Presentation: ロイトン札幌（北海道札幌市）
  • Year and Date: 2015-07-16
• [Presentation] ホルマリン固定の核酸品質への影響; 次世代シークエンスを用いた解析 (2015)
  • Author(s): 的場亮、畑中豊、喜久川真悟、沼田興治、山本伸子、松野吉宏、中江裕樹
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋国際会議場（名古屋市）
  • Year and Date: 2015-04-30 – 2015-05-02
• [Presentation] PHGDH and TRIM29 as novel diagnostic markers for malignant pleural mesothelioma: An exploring approach from FFPE tissue-based gene expression profiling of a synchronous thoracic tumor. (2015)
  • Author(s): Naka T, Hatanaka Y, Kanno H, Hatanaka K, Mitsuhashi T, Matsuno Y
  • Organizer: 104th Annual Meeting, United States and Canadian Academy of Pathology
  • Place of Presentation: Hynes Convention Center (Boston, USA)
  • Year and Date: 2015-03-21 – 2015-03-27
• [Presentation] 体外診断用医薬品承認EGFR変異検出キットのホルマリン固定パラフィン包埋検体における検出感度に関する検討 (2014)
  • Author(s): 丸川 活司，畑中 豊，藤井 恭子，平野 裕子，恩田 千景，畑中 佳奈子，三橋 智子，松野 吉宏
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: 広島国際会議場（広島市）
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 体外診断用医薬品承認EGFR変異検出キットのホルマリン固定パラフィン包埋検体における検出感度に関する検討 (2014)
  • Author(s): 丸川 活司，畑中 豊，藤井 恭子，平野 裕子，恩田 千景，畑中 佳奈子，三橋 智子，松野 吉宏
  • Organizer: 第103回 日本病理学会総会
  • Place of Presentation: 広島国際会議場（広島市）
• [Presentation] コンパニオン診断の現状と今後の課題 (2013)
  • Author(s): 畑中 豊，西尾 和人，松野 吉宏
  • Organizer: 第52回 日本臨床細胞学会秋期大会
  • Place of Presentation: 大阪国際会議場（大阪市）
  • Invited
• [Presentation] 治療戦略を見据えた細胞診－免疫細胞化学検索－ (2013)
  • Author(s): 森谷 純，畑中 豊，松野吉宏
  • Organizer: 第52回 日本臨床細胞学会秋期大会
  • Place of Presentation: 大阪国際会議場（大阪市）
• [Presentation] 分子病理診断の標準化と精度管理における課題と取り組み (2012)
  • Author(s): 畑中豊, 松野吉宏
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 京王プラザホテル（東京都）
• [Presentation] Ki-67標識率の画像解析評価におけるプレアナリシスおよびアナリシス因子に関する研究 (2012)
  • Author(s): 森谷純, 畑中豊, 鈴木雄太, 野澤あさひ, 丸川活司, 久保田佳奈子, 三橋智子, 松野吉宏
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 京王プラザホテル（東京都）
• [Presentation] 分子病理学的検索を目的とした新規組織固定法PAXgene Tissue Systemの有用性に関する検討 (2012)
  • Author(s): 鈴木雄太, 畑中豊, 久保田佳奈子, 野澤あさひ, 丸川活司, 森谷純, 三橋智子, 松野吉宏
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 京王プラザホテル（東京都）
• [Presentation] MET遺伝子コピー数および遺伝子発現解析に基づくFFPEサンプルにおけるMETタンパク質免疫組織化学的検索法の妥当性評価 (2012)
  • Author(s): 齋藤辰朗, 西脇森衛, 畑中 豊, 吉木 敬
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌（北海道）
• [Presentation] Tissue microarrayを用いた胆管癌発現蛋白の解析と細胞診断への応用に関する検討 (2012)
  • Author(s): 田畑佑希子, 宮本正樹, 真木健裕, 畑中豊, 久保田佳奈子, 松野吉宏, 平野聡
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌（北海道）