Research to construct a novel strategy of identifying for comprehensive acquired resistance to chemotherapy with anti-EGFR antibody.

• Project/Area Number: 17K10634
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Saitama Medical University (2019); Okayama University (2017-2018)
• Principal Investigator: MORI YOSHIKO 埼玉医科大学, 医学部, 講師 (70708081)
• Co-Investigator(Kenkyū-buntansha): 楳田 祐三 岡山大学, 大学病院, 講師 (10573735) ; 豊岡 伸一 岡山大学, 医歯薬学総合研究科, 教授 (30397880) ; 永坂 岳司 川崎医科大学, 医学部, 准教授 (30452569)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 切除不能進行再発大腸癌 / 抗EGFR抗体薬 / 獲得耐性 / Epigenetic変異 / 抗EGFR治療薬 / 癌 / 消化器外科学 / 小腸大腸肛門外科学 / 進行再発大腸癌

Outline of Final Research Achievements

Anti-EGFR antibodies are an essential treatment for RAS wild-type metastatic colorectal cancer. However, the response is transient due to the emergence of acquired resistance. Although it is reported that acquired genetic alteration of the RAS signaling pathway, these genetic alterations are not identified in about half of the patients who had resistance to the anti-EGFR antibodies. To identify the reason for the acquired resistance for anti-EGFR antibodies, we had research of not only genetic but also epigenetic alterations occurring tumor suppressor genes in relation to the RAS signaling pathway. Fifty-five cases of metastatic colorectal cancer have been enrolled and their tissue and peripheral blood were corrected. We are analyzing epigenetic/ genetic status and continuing follow up of prognosis.

Academic Significance and Societal Importance of the Research Achievements

RAS野生型の切除不能進行再発大腸癌治療において、抗EGFR抗体薬は最も有用な治療薬の1つであるが、獲得耐性の為にその効果は一時的である。この獲得耐性の機序を解明することは、大腸癌予後延長につながりうる。

Research Products

• [Journal Article] Upregulation of microRNA?31 is associated with poor prognosis in patients with advanced colorectal cancer (2020)
  • Author(s): Kubota Nobuhito、Taniguchi Fumitaka、Nyuya Akihiro、Umeda Yuzo、Mori Yoshiko、Fujiwara Toshiyoshi、Tanioka Hiroaki、Tsuruta Atsushi、Yamaguchi Yoshiyuki、Nagasaka Takeshi
  • Journal Title: Oncology Letters Volume: 19（４） Pages: 2685-2694
  • DOI: 10.3892/ol.2020.11365
  • Peer Reviewed / Open Access
• [Journal Article] Multicenter phase II study of biweekly XELIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer (JSWOG-C3 study) (2019)
  • Author(s): Suzuki N, Hazama S, Nagasaka T, Tanioka H, Iwamoto Y, Negoro Y, Yamauchi M, Kobayashi M, Okuda H, Fujishima N, Nishimura T, Yamanaka N, Toyota K, Mori Y, Nakagami Y, Shimokawa M, Nagano H, Okajima M
  • Journal Title: Int J Clin Oncol Volume: 24(10) Issue: 10 Pages: 1223-1230
  • DOI: 10.1007/s10147-019-01473-3
  • Peer Reviewed / Open Access
• [Journal Article] Multiple gastrointestinal stromal tumors of the small intestine in a patient with neurofibromatosis type 1: a case report (2019)
  • Author(s): 母里 淑子, 重安 邦俊, 吉岡 貴裕, 永坂 岳司, 原賀 順子, 香川 俊輔, 寺石 文則, 豊岡 伸一, 平沢 晃, 藤原 俊義
  • Journal Title: JOURNAL OF FAMILIAL TUMORS Volume: 19 Issue: 2 Pages: 77-82
  • DOI: 10.18976/jsft.19.2_77
  • NAID: 130007803646
  • ISSN: 1346-1052, 2189-6674
  • Peer Reviewed / Open Access
• [Journal Article] Activation of AZIN1 RNA editing is a novel mechanism that promotes invasive potential of cancer-associated fibroblasts in colorectal cancer (2019)
  • Author(s): Takeda S, Shigeyasu K, Okugawa Y, Yoshida K, Mori Y, Yano S, Noma K, Umeda Y, Kondo Y, Kishimoto H, Teraishi F, Nagasaka T, Tazawa H, Kagawa S, Fujiwara T, Goel A.
  • Journal Title: Cancer Lett Volume: 444 Pages: 127-135
  • DOI: 10.1016/j.canlet.2018.12.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Heterogeneity of Epigenetic and Epithelial Mesenchymal Transition Marks in Hepatocellular Carcinoma with Keratin 19 Proficiency (2018)
  • Author(s): Yokomichi Naosuke、Nishida Naoshi、Umeda Yuzo、Taniguchi Fumitaka、Yasui Kazuya、Toshima Toshiaki、Mori Yoshiko、Nyuya Akihiro、Tanaka Takehiro、Yamada Takeshi、Yagi Takahito、Fujiwara Toshiyoshi、Yamaguchi Yoshiyuki、Goel Ajay、Kudo Masatoshi、Nagasaka Takeshi
  • Journal Title: Liver Cancer Volume: none Issue: 4 Pages: 1-16
  • DOI: 10.1159/000490806
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical outcomes of women with ovarian metastases of colorectal cancer treated with oophorectomy with respect to their somatic mutation profiles. (2018)
  • Author(s): Mori Y, Nyuya A, Yasui K, Toshima T, Kawai T, Taniguchi F, Kimura K, Inada R, Nishizaki M, Haraga J, Nakamura K, Umeda Y, Kishimoto H, Fujiwara T, Katata Y, Yamaguchi Y, Nagasaka T.
  • Journal Title: Oncotarget Volume: 27;9(23) Issue: 23 Pages: 16477-16488
  • DOI: 10.18632/oncotarget.24735
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Accuracy of four mononucleotide-repeat markers for the identification of DNA mismatch-repair deficiency in solid tumors (2018)
  • Author(s): Takehara Y, Nagasaka T, Nyuya A, Haruma T, Haraga J, Mori Y, Nakamura K, Fujiwara T, Boland CR, Goel A.
  • Journal Title: J Transl Med. Volume: 16 Issue: 1 Pages: 5-5
  • DOI: 10.1186/s12967-017-1376-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comparison of outcomes between symptomatic and asymptomatic patients with colorectal cancer: a propensity score-matched analysis of surgical invasiveness, medical costs and oncological outcomes. (2018)
  • Author(s): Inada R, Nagasaka T, Watanabe A, Yagi T, Mori Y, Kondo Y, Kishimoto H, Umeda Y, Fujiwara T.
  • Journal Title: BMJ Open Gastroenterol. Volume: 3;4(1) Issue: 1 Pages: e000146-e000146
  • DOI: 10.1136/bmjgast-2017-000146
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Living Donor Liver Transplantation for Acute Liver Failure : Comparing Guidelines on the Prediction of Liver Transplantation. (2017)
  • Author(s): Yoshida K, Umeda Y, Takaki A, Nagasaka T, Yoshida R, Nobuoka D, Kuise T, Takagi K, Yasunaka T, Okada H, Yagi T, Fujiwara T.
  • Journal Title: Acta Med Okayama Volume: 71(5) Pages: 381-390
  • DOI: 10.3892/ol.2017.7553
  • NAID: 120006352357
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 岡山大学病院における大腸癌エキスパートパネル診療 (2019)
  • Author(s): 母里 淑子，矢野 修也，遠西 大輔，田端 雅弘，柳井 広之，豊岡 伸一，平沢 晃，藤原 俊義
  • Organizer: 第119回日本外科学会定期学術集会
• [Presentation] 切除率向上を目指した転移再発大腸癌に対する FOLFOXIRI 療法の治療成績 (2019)
  • Author(s): 寺石 文則、母里 淑子、重安 邦俊、矢野 修也、 近藤 喜太、岸本 浩行、香川 俊輔 、白川 靖博 、 藤原 俊義
  • Organizer: 第119回日本外科学会定期学術集会
• [Presentation] Precision Medicine to Advanced Colorectal Cancer Patients A Retrospective Analysis of the Molecular Tumor Board in Okayama University Hospital (2019)
  • Author(s): Yoshiko Mori, Syuya Yano, Kunitoshi Shigeyasu, Takeshi Nagasaka, Takahiro Yoshioka, Mariko Kouchi, Daisuke Ennishi, Masahiro Tabata, Hiroyuki Yanai, Toshiyoshi Fujiwara, Shinichi Toyooka, Akira Hirasawa
  • Organizer: International Society for Gastrointestinal Hereditary Tumours (InSiGHT) Meeting 2019
  • Int'l Joint Research
• [Presentation] 小腸癌2例の治療経験 (2018)
  • Author(s): 母里淑子 近藤喜太 重安邦俊 小松泰浩 三村直毅 矢野修也 岸本浩行 寺石文則 香川俊輔 藤原俊義
  • Organizer: 第89回大腸癌研究会
• [Presentation] 多発小腸GISTを伴う 神経線維腫症1型の1手術症例 (2018)
  • Author(s): 母里淑子 重安邦俊 吉岡貴裕 永坂岳司 原賀順子 豊岡伸一 藤原俊義
  • Organizer: 第24回日本家族性腫瘍学会学術集会
• [Presentation] A case report of intrahepatic cholangiocarcinoma responded to bevacizumab + mFOLFOX6 (2018)
  • Author(s): Mori Yoshiko, Nagasaka Takeshi, Umeda Yuzo, Shigeyasu Kunitoshi, Yoshida Kazuhiro, Kishimoto Hiroyuki, Kagawa Syunsuke, Fujiwara Toshiyoshi
  • Organizer: 第16回日本臨床腫瘍学会学術集会
• [Presentation] 直腸骨盤領域でのredo surgeryにおけるtaTMEの有用性と意義 (2018)
  • Author(s): 三村 直毅, 近藤 喜太, 小松 泰浩, 戸嶋 俊明, 重安 邦俊, 母里 淑子, 矢野 修也, 岸本 浩行, 寺石 文則, 香川 俊輔, 白川 靖博, 藤原 俊義
  • Organizer: 第31回日本内視鏡外科学会総会
• [Presentation] 直腸癌に対する術前化学療法後の腹腔鏡下手術の治療成績 (2018)
  • Author(s): 寺石 文則, 三村 直毅, 小松 泰浩, 戸嶋 俊明, 重安 邦俊, 矢野 修也, 母里 淑子, 近藤 喜太, 岸本 浩行, 香川 俊輔, 白川 靖博, 藤原 俊義
  • Organizer: 第31回日本内視鏡外科学会総会
• [Presentation] NCCNガイドラインにおける消化管神経内分泌腫瘍の内視鏡切除・手術適応の妥当性の検討 (2018)
  • Author(s): 重安 邦俊, 母里 淑子, 戸嶋 俊明, 矢野 修也, 近藤 喜太, 浅野 博昭, 岸本 浩行, 寺石 文則, 香川 俊輔, 藤原 俊義
  • Organizer: 第73回日本消化器外科学会総会
• [Presentation] がんの早期診断に向けて がん特異的蛍光ウイルス製剤を用いた簡便な循環がん細胞(CTC)の遺伝子プロファイリング技術の開発 (2018)
  • Author(s): 重安 邦俊, 田澤 大, 橋本 悠里, 母里 淑子, 西崎 正彦, 岸本 浩行, 永坂 岳司, 黒田 新士, 香川 俊輔, 藤原 俊義
  • Organizer: 第118回日本外科学会定期学術集会
• [Presentation] Lynch症候群 子宮体癌におけるMMR statusとLynch症候群関連腫瘍家族歴との相関 (2018)
  • Author(s): 原賀 順子, 永坂 岳司, 春間 朋子, 西田 傑, 入谷 大洋, 母里 淑子, 小川 千加子, 中村 圭一郎, 藤原 俊義, 増山 寿
  • Organizer: 第43回日本外科系連合学会学術集会
• [Presentation] A Novel Circulating Cell Free DNA-Based Assay Can Predict Tumor Response to Systematic Chemotherapy (2017)
  • Author(s): T. Toshima, T. Nagasaka, Y. Mori, T. Kawai, K. Yasui, T. Fuji, F. Taniguchi, K. Kimura, H. Kishimoto, Y. Umeda, A. Goel, T. Fujiwara
  • Organizer: ESMO 2017 Congress
  • Int'l Joint Research
• [Presentation] Heterogenity of epigenetic and EMT marks observed in hepatocellular carcinoma with keratin 19 proficiency (2017)
  • Author(s): Nagasaka T, Okada T, Yokomichi N, Taniguchi F, Toshima T, Yasui K, Fuji T, Mori Y, Kawai T, Umeda Y, Yagi T, Fujiwara T, Goel A
  • Organizer: ESMO 2017 Congress
  • Int'l Joint Research
• [Presentation] Multicenter phase II study of biweekly XELIRI plus Bevacizumab as a second-line therapy in patients with metastatic colorectal cancer (JSWOG-C3 study) (2017)
  • Author(s): Y. Mori, N. Suzuki, T. Nagasaka, H. Tanioka, Y. Iwamoto, Y. Neki, T. Yamatsuji, M. Kobayashi, M. Nakajima, Y. Ojima, S. Ikeda, K. Kawamoto, K. Shinozaki, A. Tsuji, T. Hinoi, Y. Yamaguchi, K. Yamashita, M. Shimokawa, M. Okajima, S. Hazama
  • Organizer: ESMO 2017 Congress
  • Int'l Joint Research
• [Presentation] Gene expression signatures in BRAF V600E mutant colorectal cancer in relation to WNT signaling cascade (2017)
  • Author(s): Yasui K, Nagasaka T, Nyuya A, Toshima T, Kawai T, Shigeyasu K, Yano S, Mori Y, Haraga J, Nakamura K, Umeda Y, Goel A, Fujiwara T
  • Organizer: ESMO GI 2017 Congress
  • Int'l Joint Research
• [Presentation] The clinical predictor of antitumor efficacy of cetuximab retreatment in patients with metastatic colorectal cancer who had a clinical benefit in response to prior cetuximab based regimen. (2017)
  • Author(s): Tanioka H, Asano M, Yoshida R, Waki N, Ishizaki M, Yamashita K, Mori Y, Nagasaka T.
  • Organizer: ESMO GI 2017 Congress
  • Int'l Joint Research
• [Presentation] Ovarian metastasectomy in colorectal cancer may improve the clinical outcomes of patients with metastatic colorectal cancer regardless of BRAF or KRAS mutational profiles. (2017)
  • Author(s): Mori Y, Nagasaka T, Tanioka H, Nyuya A, Kawai T, Toshima T, Yasui K, Shigeyasu K, Kishimoto H, Umeda Y, Fujiwara T.
  • Organizer: ESMO GI 2017 Congress
  • Int'l Joint Research
• [Presentation] 遺伝子変異情報に基づいた大腸癌肝転移の治療戦略―原発巣の左右局在とRAS/RAF 変異の意義― (2017)
  • Author(s): 楳田祐三, 永坂岳司, 母里淑子, 吉田龍一, 信岡大輔, 杭瀬 崇, 藤 智和, 河合 毅, 荒木宏之, 八木孝仁, 藤原俊義
  • Organizer: 第117回日本外科学会定期学術集会
• [Presentation] StageIV大腸癌に対するPrecision Medicineの構築 (2017)
  • Author(s): 河合 毅, 永坂岳司, 母里淑子, 楳田祐三, 稲田 涼, 谷口文崇, 安井和也, 戸嶋俊明, 岸本浩行, 藤原俊義
  • Organizer: 第117回日本外科学会定期学術集会築
• [Presentation] Outcome of locally advanced rectal cancer with or without preoperative treatments (2017)
  • Author(s): 母里淑子, 永坂岳司, 稲田 涼, 河合 毅, 近藤喜太, 浅野博昭, 佃 和憲, 木村圭佑, 楳田祐三, 岸本浩行, 藤原俊義
  • Organizer: 第117回日本外科学会定期学術集会築
• [Presentation] MSH2欠損StageⅣ大腸癌 (2017)
  • Author(s): 母里淑子
  • Organizer: 第5回岡山大腸腫瘍研究会
• [Presentation] 便中メチル化CpG検出による非侵襲的大腸癌スクリーニング技術の実用化を目指して (2017)
  • Author(s): 永坂岳司, 母里淑子, 入谷光洋, 安井和也, 戸嶋俊明, 河合 毅, 重安邦俊, 谷口文崇, 藤 智和, 楳田祐三, 岸本浩行, 藤原俊義
  • Organizer: 第87回大腸癌研究会
• [Presentation] PVT1 は癌遺伝子MYC を駆動するエンハンサーでありStage II, III 大腸癌の予後予測マーカーになりうる (2017)
  • Author(s): 重安邦俊, 小澤穀士, 松山貴俊, 河合 毅, 矢野修也, 母里淑子, 岸本浩行, 永坂岳司, Goel A, 藤原俊義
  • Organizer: 第72回日本消化器外科学会総会
• [Presentation] 大腸癌多発肝転移におけるRAS/RAF変異の意義～生物学的悪性度から術前化学療法適応を見極める～ (2017)
  • Author(s): 楳田祐三, 八木孝仁, 永坂岳司, 吉田龍一, 信岡大輔, 母里淑子, 杭瀬 崇, 高木弘誠, 河合 毅, 藤原俊義
  • Organizer: 第72回日本消化器外科学会総会
• [Presentation] 局所進行直腸癌に対する術前化学療法の有用性 (2017)
  • Author(s): 母里淑子, 永坂岳司, 河合 毅, 重安邦俊, 矢野修也, 近藤喜太, 楳田祐三, 岸本浩行, 藤原俊義
  • Organizer: 第72回日本消化器外科学会総会
• [Presentation] Lynch Syndrome に対する化学療法 (2017)
  • Author(s): 母里淑子, 永坂岳司, 角田美穂, 山口達郎, 田中屋宏爾, 山下健太郎, 野水整, 檜井孝夫, 石田秀行, 赤木究
  • Organizer: 第15回日本臨床腫瘍学会学術集会
• [Presentation] Clinical prevalence of microsatellite instability colorectal cancer and lynch syndrome cancer (2017)
  • Author(s): 永坂岳司, 母里淑子, 重安邦俊, 原賀順子, 谷口文崇, 藤原俊義
  • Organizer: 第23回家族性腫瘍学会学術集会
• [Presentation] ミスマッチ修復の観点からみた、大腸癌におけるExportin-5 の臨床的意義 (2017)
  • Author(s): 重安邦俊, 奥川喜永, 母里淑子, 安井和也, 入谷光洋, 河合 毅, 矢野修也, 岸本浩行, 永坂岳司, 香川俊輔, Goel A, 藤原俊義
  • Organizer: 第23回家族性腫瘍学会学術集会
• [Presentation] 切除不能進行再発大腸がんの２次治療以降における Ramcirumab + FOLFIRI 療法の治療成績 (2017)
  • Author(s): 永坂岳司, 母里淑子, 重安邦俊, 河合 毅, 矢野修也, 岸本浩行, 楳田祐三, 山口佳之, 藤原俊義
  • Organizer: 第55回日本癌治療学会学術集会
• [Presentation] 遅発性に肝転移・骨盤内リンパ節転移をきたした直腸神経内分泌腫瘍の1例 (2017)
  • Author(s): 重安邦俊, 杭瀬 崇, 母里淑子, 河合 毅, 矢野修也, 戸嶋俊明, 浅野博昭, 近藤喜太, 佃 和憲, 永坂岳司, 八木孝仁, 藤原俊義
  • Organizer: 第72回日本大腸肛門病学会学術集会