Development of novel molecular targeted therapy against small-cell lung cancer

• Project/Area Number: 26860606
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Respiratory organ internal medicine
• Research Institution: Osaka University
• Principal Investigator: MINAMI TOSHIYUKI 大阪大学, 医学(系)研究科(研究院), 助教 (00705113)
• Co-Investigator(Kenkyū-buntansha): MORIMURA OSAMU 大阪大学, 大学院医学系研究科, 院生 (80743765)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 小細胞肺癌 / 抗癌剤耐性 / 分子標的治療 / HER2 / EphA2 / trastuzumab / T-DM1 / dasatinib / Dasatinib / ADCC

Outline of Final Research Achievements

Therapeutic strategy against small-cell lung cancer (SCLC) has not improved over the last two decades. We examined the potential of HER2 and EphA2 as therapeutic targets in SCLC. We first evaluated HER2 expression by immunohistochemistry. HER2 expression was detected in 28% of diagnostic biopsy SCLC specimens. Then, we performed trastuzumab plus irinotecan combination therapy in two patients with HER2-positive SCLC. This combination therapy resulted in successful disease control in both patients. We next validated the antitumor activity of trastuzumab emtansine (T-DM1) in SCLC. T-DM1 induced apoptosis and suppressed the growth of HER2-positive irinotecan resistant SCLC xenografts in mice. We further evaluated the biological effects of EphA2 inhibition. EphA2 knockdown and functional inhibition by dasatinib brought about senescence in EphA2-positive SCLC cells, and inhibited their proliferation.
These results indicate that HER2 and EphA2 could be novel therapeutic candidates in SCLC.

Research Products

• [Journal Article] Weight Loss Associated with Platinum-Based Chemotherapy in Patients with Advanced Lung Cancer (2016)
  • Author(s): Kayoko Morio, Toshiyuki Minami, Takashi Sozu, Kazuyuki Niki, Takashi Kijima, Etsuko Uejima
  • Journal Title: Chemotherapy Volume: 61 Issue: 5 Pages: 256-261
  • DOI: 10.1159/000443983
  • Peer Reviewed
• [Journal Article] Favorable response to trastuzumab plus irinotecan combination therapy in two patients with HER2-positive relapsed small-cell lung cancer. (2015)
  • Author(s): Kinehara Y, Minami T, Kijima T, Hoshino S, Morimura O, Otsuka T, Hayama Y, Fukushima K, Takeuchi Y, Higashiguchi M, Miyake K, Hirata H, Nagatomo I, Inoue K, Takeda Y, Kida H, Kumanogoh A.
  • Journal Title: Lung Cancer. Volume: 87 Issue: 3 Pages: 321-325
  • DOI: 10.1016/j.lungcan.2015.01.003
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] トラスツズマブ-エムタンシン（T-DM1）は抗癌剤およびトラスツズマブ耐性HER2陽性小細胞肺癌の増殖を抑制する (2016)
  • Author(s): 森村 治、木島貴志、南 俊行、小山正平、甲原雄平、長 彰翁、大塚倫之、熊ノ郷 淳
  • Organizer: 第56回日本呼吸器学会
  • Place of Presentation: 国立京都国際会館（京都府・京都市）
  • Year and Date: 2016-04-08
• [Presentation] HER2陽性再発小細胞肺癌に対するirinotecan + trastuzumab併用療法（基礎研究から臨床応用まで） (2014)
  • Author(s): 南 俊行、甲原雄平、木島貴志、星野茂則、森村 治、東口将佳、三宅浩太郎、竹内美子、葉山善友、福島清春、長 彰翁、石島里佳子、仲谷健史、松木隆典、大塚倫之、平田陽彦、井上幸治、長友 泉、武田吉人、木田 博、熊ノ郷 淳1
  • Organizer: 第55回日本肺癌学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-11-14 – 2014-11-16
• [Presentation] EphA2 receptor inhibition suppresses proliferation of small cell lung cancer (SCLC) cells via cell senescenece. (2014)
  • Author(s): 森村 治、南 俊行、木島 貴志、武田 吉人、長友 泉、熊ノ郷 淳
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Trastuzumab-based Chemotherapy for HER2-positive Refractory Relapsed Small-Cell Lung Cancer (from Bench to Bed Side) (2014)
  • Author(s): 甲原雄平、南 俊行、木島貴志，福島清春，葉山善友，竹内美子，平田陽彦，井上幸治，熊ノ郷 淳
  • Organizer: 第12回日本臨床腫瘍学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2014-07-17 – 2014-07-19
• [Presentation] Targeting stepwise HER2 and VEGF can overcome multidrug resistance in small cell lung cancer (2014)
  • Author(s): Toshiyuki Minami, Takashi Kijima, Osamu Morimura, Yuhei Kinehara, Masayoshi Higashiguchi, Kotaro Miyake, Haruhiko Hirata, Yoshiko Takeuchi, Kiyoharu Fukushima, Yoshitomo Hayama, Koji Inoue, Izumi Nagatomo, Yoshito Takeda, Hiroshi Kida, Atsushi Kumanogoh
  • Organizer: AACR (American Association for Cancer Research) 105th Annual Meeting
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2014-04-05 – 2014-04-09