Basic study on combined modality therapy for advanced lung cancer harboring activated EGFR gene mutation

• Project/Area Number: 25670399
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Respiratory organ internal medicine
• Research Institution: Okayama University
• Principal Investigator: KIURA Katsuyuki 岡山大学, 大学病院, 教授 (10243502)
• Co-Investigator(Kenkyū-buntansha): KONDO Eisei 岡山大学, 医歯(薬)学総合研究科, 講師 (30379747)
• Research Collaborator: KUDO Kenichiro 岡山大学, 医歯(薬)学総合研究科
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 上皮成長因子受容体 / PD-L1 / EGFR遺伝子変異 / Egfr遺伝子改変マウス / 免疫染色 / EGFR阻害薬 / 手術検体 / 相関 / EGFR / EGFR遺伝子改変マウス / 抗PD-１抗体 / 抗PD-L1抗体 / EGFR遺伝子変異陽性肺癌 / PNA LNA PCR-Clamp法 / PD-1抗体 / PD-L1抗体 / gefetinib / everolimus / afatinib / vandetanib

Outline of Final Research Achievements

It has been suggested that expression of epidermal growth factor receptor (EGFR) gene mutation induces PD-L1 on the tumor cells, and that PD-L1 expression can be reduced by EGFR inhibitors in EGFR gene positive lung cancer; however, adenocarcinoma of the lungs in del exon19 Egfr transgenic mouse we established in our lab did not express PD-L1 by the immunostaining，but did express 1.2-fold when compared to controls by flow cytometry.
In the study of human tissue specimen from 2004 to 2008 in resected 25 cases of adenocarcinoma of the lung in Okayama University Hospital, EGFR gene mutation-positive cases in 9/12 (75%), EGFR gene mutations in negative cases 4/13 (31%) were PD-L1 positive. Significant association has been suggested to EGFR gene mutation positive and PD-L1 expression (P = 0.047).

Research Products

• [Journal Article] Vaccination With NY-ESO-1 Overlapping Peptides Mixed With Picibanil OK-432 and Montanide ISA-51 in Patients With Cancers Expressing the NY-ESO-1 Antigen (2014)
  • Author(s): Wada H, Isobe M, Kakimi K, Mizote Y, Eikawa S, Sato E, Takigawa N, Kiura K, Tsuji K, Iwatsuki K, Yamasaki M, Miyata H, Matsushita H, Udono H, Seto Y, Yamada K, Nishikawa H, Pan L, Venhaus R, Oka M, Doki Y, Nakayama E.
  • Journal Title: J Immunother Volume: 37(2) Issue: 2 Pages: 84-92
  • DOI: 10.1097/cji.0000000000000017
  • Peer Reviewed
• [Journal Article] Novel germline mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas. (2014)
  • Author(s): Yamamoto H, Higasa K, Sakaguchi M, Shien K, Soh J, Ichimura K, Furukawa M, Hashida S, Tsukuda K, Takigawa N, Matsuo K, Kiura K, Miyoshi S, Matsuda F, Toyooka S.
  • Journal Title: J Natl Cancer Inst Volume: 106 Issue: 1
  • DOI: 10.1093/jnci/djt338
  • Peer Reviewed
• [Journal Article] Effect of AZD1480 in an epidermal growth factor receptor-driven lung cancer model (2014)
  • Author(s): Murakami Toshi, Takigawa Nagio, Ninomiya Takashi, Ochi Nobuaki, Yasugi Masaaki, Honda Yoshihiro, Kubo Toshio, Ichihara Eiki, Hotta Katsuyuki, Tanimoto Mitsune, Kiura Katsuyuki
  • Journal Title: Lung Cancer Volume: 83 Issue: 1 Pages: 30-36
  • DOI: 10.1016/j.lungcan.2013.10.011
  • NAID: 120005473065
  • Peer Reviewed
• [Journal Article] Everolimus prolonged survival in transgenic mice with EGFR-driven lung tumors. (2014)
  • Author(s): Yasugi M, Takigawa N, Ochi N, Ohashi K, Harada D, Ninomiya T, Murakami T, Honda Y, Ichihara E, Tanimoto M, Kiura K.
  • Journal Title: Exp Cell Res. Volume: 326 Issue: 2 Pages: 201-209
  • DOI: 10.1016/j.yexcr.2014.04.012
  • NAID: 120005526613
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Src mediates ERK reactivation in gefitinib resistance in non-small cell lung cancer. (2014)
  • Author(s): Ochi N, Takigawa N, Harada D, Yasugi M, Ichihara E, Hotta K, Tabata M, Tanimoto M, Kiura K.
  • Journal Title: Exp Cell Res. Volume: 322 Issue: 1 Pages: 168-177
  • DOI: 10.1016/j.yexcr.2014.01.007
  • NAID: 120005517858
  • Peer Reviewed
• [Journal Article] Afatinib prolongs survival compared with gefitinib in an epidermal growth factor receptor-driven lung cancer model. (2013)
  • Author(s): Ninomiya T, Takigawa N, Ichihara E, Ochi N, Murakami T, Honda Y, Kubo T, Minami D, Kudo K, Tanimoto M, Kiura K.
  • Journal Title: Mol Cancer Ther. Volume: 12 Issue: 5 Pages: 589-597
  • DOI: 10.1158/1535-7163.mct-12-0885
  • NAID: 120005359109
  • Peer Reviewed
• [Journal Article] Vandetanib is effective in EGFR-mutant lung cancer cells with PTEN deficiency. (2013)
  • Author(s): Takeda H, Takigawa N, Ohashi K, Minami D, Kataoka I, Ichihara E, Ochi N, Tanimoto M, Kiura K.
  • Journal Title: Exp Cell Res Volume: 319 Issue: 4 Pages: 417-427
  • DOI: 10.1016/j.yexcr.2012.12.018
  • NAID: 120005359097
  • Peer Reviewed
• [Journal Article] 抗PD-1抗体 (2013)
  • Author(s): 近藤英生, 木浦勝行
  • Journal Title: 呼吸 Volume: 32 Pages: 1141-1147
• [Book] Annual Review呼吸器2014 (2014)
  • Author(s): 木浦勝行
  • Publisher: 中外医学社