Analysis of Cetuximab resistance mechanism in oral cancer and Development of a novel treatment by combining immunotherapy

• Project/Area Number: 16K20592
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Surgical dentistry
• Research Institution: Kumamoto University
• Principal Investigator: Nagata Masashi 熊本大学, 医学部附属病院, 非常勤診療医師 (10635791)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 分子標的薬 / 抗がん剤耐性 / EGFR / ADCC活性 / 口腔扁平上皮がん / 口腔がん / 分子標的薬耐性 / 免疫療法

Outline of Final Research Achievements

In recent years, reduction of therapeutic effect due to acquisition resistance in molecular targeted drugs has become a problem. We succeeded in establishing Cetuximab resistant cell line in oral squamous cell carcinoma. We recognized cells with high expression of target EGFR and downstream signal phosphorylated Akt showed high sensitivity, suggesting a causal relationship between Cetuximab sensitivity and PI3K / Akt pathway . In addition, since it is suggested that ADCC activity by NK cells and cytotoxicity by other immune cells act as important therapeutic effect factors for molecular targeted drugs, changes in immune cells were confirmed using blood samples, but there was no association with the effect of Cetuximab.

Research Products

• [Journal Article] FBXW7 expression affects the response to chemoradiotherapy and overall survival among patients with oral squamous cell carcinoma: A single-center retrospective study. (2017)
  • Author(s): Hidetaka Arita, Masashi Nagata, Ryoji Yoshida, Yuichiro Matsuoka1, Akiyuki Hirosue, Kenta Kawahara, Junki Sakata, Hikaru Nakashima, Taku Kojima, Ryo Toya, Ryuji Murakami, Akimitsu Hiraki, Masanori Shinohara and Hideki Nakayama.
  • Journal Title: Tumour Biology Volume: 39 Issue: 10 Pages: 1-9
  • DOI: 10.1177/1010428317731771
  • Peer Reviewed / Open Access
• [Journal Article] Concurrent chemoradiotherapy with S1 in patients with stage III;IV oral squamous cell carcinoma: A retrospective analysis of nodal classification based on the neck node level. (2017)
  • Author(s): MURAKAMI R, SEMBA A,KAWAHARA K, MATSUYAMA K, HIRAKI A, NAGATA M, TOYA R, YAMASHITA Y, OYA N, NAKAYAMA H.
  • Journal Title: Molecular and clinical oncology. Volume: 2 Issue: 1 Pages: 140-144
  • DOI: 10.3892/mco.2017.1276
  • Peer Reviewed
• [Journal Article] Salivary duct carcinoma treated with cetuximab-based targeted therapy: A case report. (2017)
  • Author(s): Kawahara K, Hiraki A, Yoshida R, Arita H, Matsuoka Y, Yamashita T, Koga K, Nagata M, Hirosue A, Fukuma D, Nakayama H.
  • Journal Title: Molecular and clinical oncology Volume: 6 Issue: 6 Pages: 886-892
  • DOI: 10.3892/mco.2017.1226
  • Peer Reviewed
• [Journal Article] Predictive value of the combination of SMAD4 expression and lymphocyte infiltration in malignant transformation of oral leukoplakia. (2017)
  • Author(s): Sakata J, Yoshida R, Matsuoka Y, Nagata M, Hirosue A, Kawahara K, Nakamura T, Nakamoto M, Hirayama M, Takahashi N, Nakashima H, Arita H, Ogi H, Hiraki A, Shinohara M, Nakayama H
  • Journal Title: Cancer medicine Volume: 6 Issue: 4 Pages: 730-738
  • DOI: 10.1002/cam4.1005
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic impact of the level of nodal involvement: retrospective analysis of patients with advanced oral squamous cell carcinoma (2017)
  • Author(s): Murakami R.、Nakayama H.、Semba A.、Hiraki A.、Nagata M.、Kawahara K.、Shiraishi S.、Hirai T.、Uozumi H.、Yamashita Y.
  • Journal Title: British Journal of Oral and Maxillofacial Surgery Volume: 55 Issue: 1 Pages: 50-55
  • DOI: 10.1016/j.bjoms.2016.08.026
• [Journal Article] Enhancement of active MMP release and invasive activity of lymph node metastatic tongue cancer cells by elevated signaling via the TNF-α-TNFR1-NF-κB pathway and a possible involvement of angiopoietin-like 4 in lung metastasis. (2016)
  • Author(s): Tanaka, T., Imamura, T., Yoneda, M., Irie, A., Ogi, H., Nagata, M., Yoshida, R., Fukuma, D., Kawahara, K., Shinohara, M, & Nakayama, H.
  • Journal Title: Int. J. Oncol. Volume: 49 Issue: 4 Pages: 1377-1384
  • DOI: 10.3892/ijo.2016.3653
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] IL-6 controls resistance to radiation by suppressing oxidative stress via the Nrf2-antioxidant pathway in oral squamous cell carcinoma. (2016)
  • Author(s): Matsuoka Yuichiro
  • Journal Title: Br J Cancer Volume: 115 Issue: 10 Pages: 1234-1244
  • DOI: 10.1038/bjc.2016.327
  • Peer Reviewed
• [Journal Article] Factors affecting volume change of myocutaneous flaps in oral cancer. (2016)
  • Author(s): Hiraki Akimitsu
  • Journal Title: Int J Oral Maxillofac Surg Volume: 45 Issue: 11 Pages: 1395-1399
  • DOI: 10.1016/j.ijom.2016.04.014
  • Peer Reviewed
• [Journal Article] Sentinel lymph node biopsy reduces the incidence of secondary neck metastasis in patients with oral squamous cell carcinoma. (2016)
  • Author(s): Hiraki A, Fukuma D, Nagata M, Shiraishi S, Kawahara K, Matsuoka Y, Nakagawa Y, Yoshida R, Tanaka T, Yohitake Y, Shinohara M, Yamashita Y, Nakayama H.
  • Journal Title: Molecular and Clinical Oncology Volume: 5 Issue: 1 Pages: 57-60
  • DOI: 10.3892/mco.2016.882
  • Peer Reviewed
• [Journal Article] Pre-treatment neutrophil to lymphocyte ratio predicts the chemoradiotherapy outcome and survival in patients with oral squamous cell carcinoma (2016)
  • Author(s): Hikaru Nakashima, Yuichiro Matsuoka, Ryoji Yoshida, Masashi Nagata, Akiyuki Hirosue, Kenta Kawahara, Jyunki Sakata, Hidetaka Arita, Akimitsu Hiraki and Hideki Nakayama
  • Journal Title: BMC Cancer Volume: 26 Issue: 1 Pages: 41-41
  • DOI: 10.1186/s12885-016-2079-6
  • Peer Reviewed / Open Access
• [Presentation] 当科における舌扁平上皮癌T2N0M0症例の臨床的検討 (2016)
  • Author(s): 山名 啓介, 坂田 純基, 吉田 遼司, 廣末 晃之, 永田 将士, 廣田 渓, 福間 大喜, 尾木 秀直, 篠原 正徳, 中山 秀樹
  • Organizer: 第61回（公社）日本口腔外科学会総会・学術大会
  • Place of Presentation: 幕張メッセ
  • Year and Date: 2016-11-25
• [Presentation] Tumor-suppressive microRNA-X regulates cancer cell migration, invasion and metastasis in oral squamous cell carcinoma by targeting metastasis-related molecule. (2016)
  • Author(s): Ryoji Yoshida, Junki Sakata, Yuichiro Matsuoka, Masashi Nagata, Akiyuki Hirosue, Kenta Kawahara, Hikaru Nakashima, Hidetaka Arita, Akimitsu Hiraki, Masanori Shinohara and Hideki Nakayama
  • Organizer: 第27回日本臨床口腔病理学会総会・学術大会
  • Place of Presentation: 広島大学
  • Year and Date: 2016-08-10
• [Presentation] A study of predictive factors for occult cervical lymph node metastasis of clinical T2N0 tongue squamous cell carcinoma (2016)
  • Author(s): Junki Sakat, Akiyuki Hirosue, Ryoji Yoshida, Masashi Nagata, Kenta Kawahara, Yichiro Matsuoka, HidetakaArita, Hikaru Nakashima, Daiki Fukuma, Hidenao Ogi, Masanori Shinohara and Hideki Nakayama
  • Organizer: 第27回日本臨床口腔病理学会総会・学術大会
  • Place of Presentation: 広島大学
  • Year and Date: 2016-08-10
• [Presentation] 口腔扁平上皮癌患者における循環miRNAの発現に関する臨床的検討 (2016)
  • Author(s): 中嶋光, 吉田遼司, 廣末晃之, 有田英生, 坂田純基, 松岡祐一郎, 川原健太, 中川純泰, 永田将士, 中山秀樹
  • Organizer: 第40回日本頭頸部癌学会
  • Place of Presentation: 大宮ソニックシティ
  • Year and Date: 2016-06-09
• [Presentation] IL‐6はNrf2抗酸化経路を介して口腔扁平上皮癌細胞に放射線耐性を賦与する (2016)
  • Author(s): 松岡祐一郎, 吉田遼司, 廣末晃之, 田中拓也, 永田将士, 川原健太, 中川純泰, 有田英生, 坂田純基, 中嶋光, 尾木秀直, 平木昭光, 篠原正徳, 中山秀樹
  • Organizer: 第40回日本頭頸部癌学会
  • Place of Presentation: 大宮ソニックシティ
  • Year and Date: 2016-06-09
• [Presentation] Stage Ⅱ口腔扁平上皮癌根治手術後のS-1補助化学療法の有効性に関する検討 (2016)
  • Author(s): 吉田 遼司、平山 真敏、永田 将士、廣末 晃之、古賀 幹一、高橋 望、中元 雅史、福間 大喜、尾木 秀直、平木 昭光、篠原 正徳、中山 秀樹
  • Organizer: 第54回日本癌治療学会学術総会
  • Place of Presentation: パシフィコ横浜