Non-comprehensive verification research of biomarkers for therapeutic agents in colorectal cancer using preclinical analysis.

• Project/Area Number: 18K07280
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Tokyo Medical and Dental University (2020); Japanese Foundation for Cancer Research (2018-2019)
• Principal Investigator: SUENAGA MITSUKUNI 東京医科歯科大学, 大学院医歯学総合研究科, 講師 (70462223)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 効果予想マーカー / 効果予測マーカー / がん / バイオマーカー / トランスレーショナルリサーチ

Outline of Final Research Achievements

In this study, we attempted to identify biomarkers for novel chemotherapeutic agents by combining preclinical omics analysis into translational validation study. Regarding TAS-102, EGFR-related factors appeared to be candidates for biomarkers of efficacy, and further verification is underway in combination therapy with TAS-102 and antiangiogenic agent.　For regorafenib, we found that the opposite pattern of changes in serum levels of CCR5 ligands CCL3 and CCL4 were recognized as prognostic marker.

Academic Significance and Societal Importance of the Research Achievements

基礎研究により蓄積されたデータベースと方法論を用いて大腸癌の新規薬剤の効果予測マーカーを開発する手法により、候補となるバイオマーカーが確認された。短期間で信頼性の高いバイオマーカーを臨床の場に導入することを目標に研究を継続している。

Research Products

• [Journal Article] Associations among plasma concentrations of regorafenib and its metabolites, adverse events, and ABCG2 polymorphisms in patients with metastatic colorectal cancers (2021)
  • Author(s): Kobayashi Kazuo、Sugiyama Erika、Shinozaki Eiji、Wakatsuki Takeru、Tajima Masataka、Kidokoro Hiyori、Aoyama Takeshi、Nakano Yasuhiro、Kawakami Kazuyoshi、Hashimoto Koki、Suenaga Mitsukuni、et al.
  • Journal Title: Cancer Chemotherapy and Pharmacology Volume: － Issue: 6 Pages: 767-777
  • DOI: 10.1007/s00280-021-04237-x
  • Peer Reviewed
• [Journal Article] Clinical significance of enterocyte-specific gene polymorphisms as candidate markers of oxaliplatin-based treatment for metastatic colorectal cancer (2021)
  • Author(s): Suenaga Mitsukuni、Schirripa Marta、Cao Shu、Zhang Wu、Cremolini Chiara、Lonardi Sara、Okazaki Satoshi、Berger Martin D.、Miyamoto Yuji、Soni Shivani、Barzi Afsaneh、Yamaguchi Toshiharu、Loupakis Fotios、Falcone Alfredo、Lenz Heinz-Josef
  • Journal Title: The Pharmacogenomics Journal Volume: 印刷中 Issue: 3 Pages: 285-295
  • DOI: 10.1038/s41397-021-00207-x
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Serum IL-8 level as a candidate prognostic marker of response to anti-angiogenic therapy for metastatic colorectal cancer (2020)
  • Author(s): Suenaga Mitsukuni、Mashima Tetsuo、Kawata Naomi、Wakatsuki Takeru、Dan Shingo、Seimiya Hiroyuki、Yamaguchi Kensei
  • Journal Title: International Journal of Colorectal Disease Volume: 36 Issue: 1 Pages: 131-139
  • DOI: 10.1007/s00384-020-03748-y
  • Peer Reviewed
• [Journal Article] Role of enterocyte-specific gene polymorphisms in response to adjuvant treatment for stage III colorectal cancer (2020)
  • Author(s): Suenaga Mitsukuni、Cao Shu、Zhang Wu、Matsusaka Satoshi、Okazaki Satoshi、Berger Martin D.、Miyamoto Yuji、Schirripa Marta、Barzi Afsaneh、Yamamoto Noriko、Yamaguchi Toshiharu、Lenz Heinz-Josef
  • Journal Title: Pharmacogenetics and Genomics Volume: 31 Issue: 1 Pages: 10-16
  • DOI: 10.1097/fpc.0000000000000416
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A polymorphism in the cachexia-associated gene INHBA predicts efficacy of regorafenib in patients with refractory metastatic colorectal cancer (2020)
  • Author(s): Miyamoto Yuji、Schirripa Marta、Suenaga Mitsukuni、Cao Shu、Zhang Wu、Okazaki Satoshi、Berger Martin D.、Matsusaka Satoshi、Yang Dongyun、Ning Yan、Baba Hideo、Loupakis Fotios、Lonardi Sara、Pietrantonio Filippo、Borelli Beatrice、Cremolini Chiara、Yamaguchi Toshiharu、Lenz Heinz-Josef
  • Journal Title: PLOS ONE Volume: 15 Issue: 9 Pages: e0239439-e0239439
  • DOI: 10.1371/journal.pone.0239439
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Single Nucleotide Polymorphisms in MiRNA Binding Sites of Nucleotide Excision Repair-Related Genes Predict Clinical Benefit of Oxaliplatin in FOLFOXIRI Plus Bevacizumab: Analysis of the TRIBE Trial (2020)
  • Author(s): Suenaga Mitsukuni、Schirripa Marta、Cao Shu、Zhang Wu、Yang Dongyun、Cremolini Chiara、Murgioni Sabina、Lonardi Sara、Ning Yan、Okazaki Satoshi、Berger Martin D.、Miyamoto Yuji、Barzi Afsaneh、Loupakis Fotios、Falcone Alfredo、Lenz Heinz-Josef
  • Journal Title: Cancers Volume: 12 Issue: 7 Pages: 1742-1742
  • DOI: 10.3390/cancers12071742
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epidermal growth factor receptor mRNA expression: A potential molecular escape mechanism from regorafenib (2020)
  • Author(s): Matsusaka Satoshi、Hanna Diana L.、Ning Yan、Yang Dongyun、Cao Shu、Berger Martin D.、Miyamoto Yuji、Suenaga Mitsukuni、Dan Shingo、Mashima Tetsuo、Seimiya Hiroyuki、Zhang Wu、Lenz Heinz‐Josef
  • Journal Title: Cancer Science Volume: 111 Issue: 2 Pages: 441-450
  • DOI: 10.1111/cas.14273
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A phase I study to determine the maximum tolerated dose of trifluridine/tipiracil and oxaliplatin in patients with refractory metastatic colorectal cancer: LUPIN study (2019)
  • Author(s): Suenaga Mitsukuni、Wakatsuki Takeru、Mashima Tetsuo、Ogura Mariko、Ichimura Takashi、Shinozaki Eiji、Nakayama Izuma、Osumi Hiroki、Ota Yumiko、Takahari Daisuke、Chin Keisho、Seimiya Hiroyuki、Yamaguchi Kensei
  • Journal Title: Investigational New Drugs Volume: 印刷中 Issue: 1 Pages: 2567-2575
  • DOI: 10.1007/s10637-019-00749-9
  • Peer Reviewed / Open Access
• [Journal Article] Factors Associated With Regorafenib Adherence With Metastatic Colorectal Cancer. (2019)
  • Author(s): Kawakami K, Wakatsuki T, Soejima A, Kobayashi K, Yokokawa T, Aoyama T, Suzuki K, Suenaga M, Yamaguchi K, Inoue A, Machida Y, Hama T.
  • Journal Title: Patient Prefer Adherence Volume: 13 Pages: 1745-1750
  • DOI: 10.2147/ppa.s217835
  • Peer Reviewed / Open Access
• [Journal Article] Association of Hand-Foot Skin Reaction with Regorafenib Efficacy in the Treatment of Metastatic Colorectal Cancer (2019)
  • Author(s): Kobayashi Kazuo、Kawakami Kazuyoshi、Yokokawa Takashi、Aoyama Takeshi、Suzuki Kenichi、Wakatsuki Takeru、Suenaga Mitsukuni、Sato Hitoshi、Sugiyama Erika、Yamaguchi Kensei、Hama Toshihiro
  • Journal Title: Oncology Volume: 96 Issue: 4 Pages: 200-206
  • DOI: 10.1159/000495989
  • Peer Reviewed
• [Journal Article] Genetic variants in CCL5 and CCR5 genes and serum VEGF‐A levels predict efficacy of bevacizumab in metastatic colorectal cancer patients (2019)
  • Author(s): Suenaga Mitsukuni、Cao Shu、Zhang Wu、Yang Dongyun、Ning Yan、Okazaki Satoshi、Berger Martin D.、Miyamoto Yuji、Schirripa Marta、Soni Shivani、Barzi Afsaneh、Yamaguchi Toshiharu、Lenz Heinz‐Josef
  • Journal Title: International Journal of Cancer Volume: 144 Issue: 10 Pages: 2567-2577
  • DOI: 10.1002/ijc.31968
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Regorafenib-Induced Hand-Foot Skin Reaction is More Severe on the Feet than on the Hands (2018)
  • Author(s): Nonomiya Yuma、Yokokawa Takashi、Kawakami Kazuyoshi、Kobayashi Kazuo、Aoyama Takeshi、Takiguchi Tomomi、Sugisaki Takahito、Suzuki Kenichi、Suenaga Mitsukuni、Wakatsuki Takeru、Yamaguchi Kensei、Sugimoto Yoshikazu、Hama Toshihiro
  • Journal Title: Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics Volume: 印刷中 Issue: 5 Pages: 551-556
  • DOI: 10.3727/096504018x15291727589740
  • Peer Reviewed
• [Journal Article] Gene Polymorphisms in the CCL5/CCR5 Pathway as a Genetic Biomarker for Outcome and Hand-Foot Skin Reaction in Metastatic Colorectal Cancer Patients Treated With Regorafenib. (2018)
  • Author(s): Suenaga M, Schirripa M, Cao S, Zhang W, Yang D, Ning Y, Cremolini C, Antoniotti C, Borelli B, Mashima T, Okazaki S, Berger MD, Miyamoto Y, Gopez R Jr., Barzi A, Lonardi S, Yamaguchi T, Falcone A, Loupakis F, Lenz HJ
  • Journal Title: Clin Colorectal Cancer Volume: 印刷中 Issue: 2 Pages: e395-e414
  • DOI: 10.1016/j.clcc.2018.02.010
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Serum IL-8 level as a candidate prognostic marker of response to anti-angiogenic therapy for metastatic colorectal cancer. (2021)
  • Author(s): 末永光邦、馬島哲夫、若槻尊、清宮啓之
  • Organizer: 第18回日本臨床腫瘍学会学術総会
• [Presentation] Circulating IL-8 levels as candidate marker of antiangiogenic therapy for metastatic colorectal cancer. (2020)
  • Author(s): Suenaga, M., Mashima, T., Kawata, N., Wakatsuki, T., Seimiya, H., Yamaguchi, K
  • Organizer: ASCO 2020 Gastrointestinal Cancer Symposium
  • Int'l Joint Research
• [Presentation] Gene polymorphisms of CCL3, CCL4, CCL5, and CCR5 network in metastatic colorectal cancer patients treated with regorafenib. (2020)
  • Author(s): Suenaga, M., Zhang, W., Mashima, T., Schirripa, M., Cao, S., Okazaki, S., Berger, M. D., Miyamoto, Y., Barzi, A., Lenz, H. J.
  • Organizer: ASCO 2020 Gastrointestinal Cancer Symposium（国際学会）
  • Int'l Joint Research
• [Presentation] Role of enterocyte-specific gene polymorphisms in adjuvant treatment for stage III colorectal cancer (2019)
  • Author(s): Suenaga, M., Cao, S., Zhang, W., Matsusaka, S., Okazaki, S., Berger, M.D., Miyamoto, Y., Schirripa, M., Barzi, A., Ueno, M., Lenz, H.J. Role of enterocyte-specific gene polymorphisms in adjuvant treatment for stage III colorectal cancer.
  • Organizer: ASCO 2019 Gastrointestinal Cancer Symposium
  • Int'l Joint Research
• [Presentation] A phase I study to determine the maximum tolerated dose of trifluridine/tipiracil and oxaliplatin in patients with refractory metastatic colorectal cancer: LUPIN study. (2018)
  • Author(s): Suenaga, M., Wakatsuki, T., Ogura, M., Ichimura, T., Shinozaki, E., Nakayama, I., Osumi, H., Ota, Y., Chin, K., Mashima, T., Seimiya, H., Takahari, D., Yamaguchi, K.
  • Organizer: ESMO 2018 Congress
  • Int'l Joint Research
• [Presentation] Clinical significance of enterocyte-specific gene polymorphisms as candidate marker of oxaliplatin-based treatment for metastatic colorectal cancer. (2018)
  • Author(s): Suenaga, M., Schirripa, M., Loupakis, F., Cao, S., Zhang, W., Cremolini, C., Lonardi, S., Okazaki, S., Berger, M. D., Miyamoto, Y., Soni, S., Barzi, A., Yamaguchi, T., Falcone, A., Lenz, H. J.
  • Organizer: 54th ASCO Annual Meeting
  • Int'l Joint Research