「persister」がん細胞マウスモデルによる肺癌の根治的薬物療法の開発

2021 Fiscal Year Annual Research Report

• Project/Area Number: 19K08625
• Research Institution: Okayama University
• Principal Investigator: 大橋 圭明 岡山大学, 大学病院, 研究准教授 (60729193)
• Co-Investigator(Kenkyū-buntansha): 木浦 勝行 岡山大学, 大学病院, 教授 (10243502)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 非小細胞肺癌 / EGFR変異 / 腫瘍免疫 / PD-1 / VEGR2

Outline of Annual Research Achievements

上皮成長因子受容体（EGFR）変異を有する肺癌（EGFR肺癌）は、日本人の非喫煙者に発生する肺癌の半数以上を占める重要な疾患である。EGFRチロシンキナーゼ阻害薬（TKI）は、EGFR肺癌に一過性に奏効するが、耐性化し治癒には至らない。EGFR-TKI投与後に残存するpersister癌細胞と呼ばれる細胞集団が、根治の障壁として注目されている。しかし、in　vitroモデルではpersister癌細胞が腫瘍微小環境とどのように協調して生き延びるのか？について評価が困難であった。申請者らは、persister癌細胞と腫瘍微小環境の相互関係を評価するため独自にマウス2型肺胞上皮を起源としEGFRに依存した肺癌が自然発生するEgfr遺伝子改変肺癌マウスを樹立し、またそのモデルを用いin vivo persister癌細胞シンジェニックマウスモデルを作製した。本研究では、in vivo persister癌細胞マウスモデルを用い、(1) persister癌細胞およびその腫瘍微小環境の包括的な遺伝子発現解析、(2) 臨床応用可能な治療標的の同定、および(3) in vivoでの抗腫瘍効果、腫瘍免疫活性化効果を検証した。(1)- (3)を通して、EGFR-TKIの治療効果にはCD8陽性細胞が介在した腫瘍免疫が介在していることがわかった。また、EGFR-TKIが誘導する腫瘍免疫を最大化するため、抗PD-1抗体、抗VEGFR2抗体の併用効果を検証した。EGFR-TKIの治療効果が最大化するまで前治療を行い、逐次的に抗PD-1抗体、抗VEGFR2抗体の２剤併用治療を行うことにより、より持続的な抗腫瘍免疫を誘導することができた 。

Research Products

• [Int'l Joint Research] University of Cologne(ドイツ)
  • Country Name: GERMANY
  • Counterpart Institution: University of Cologne
• [Journal Article] MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I (2021)
  • Author(s): Bragelmann J, Lorenz C, Borchmann S, Nishii K, Wegner J, Meder L, Ostendorp J, Ast DF, Heimsoeth A, Nakasuka T, Hirabae A, Okawa S, et al, and Ohashi K, Schlee M, Sos ML.
  • Journal Title: Nat Commun. Volume: 12 Pages: 5505
  • DOI: 10.1038/s41467-021-25728-8.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Triple therapy with osimertinib, bevacizumab and cetuximab in EGFR-mutant lung cancer with HIF-1α/TGF-α expression (2021)
  • Author(s): Nishii K, Ohashi K, Watanabe H, Makimoto G, Nakasuka T, Higo H, Ninomiya K, Kato Y, Kubo T, Rai K, Ichihara E, Hotta K, Tabata M, Maeda Y, Kiura K.
  • Journal Title: Oncol Lett . Volume: 22(3) Pages: 639
  • DOI: 10.3892/ol.2021.12900.
  • Peer Reviewed / Open Access
• [Journal Article] A novel osimertinib-resistant human lung adenocarcinoma cell line harbouring mutant EGFR and activated IGF1R (2021)
  • Author(s): Makimoto G, Ninomiya K, Kubo T, Sunami R, Kato Y, Ichihara E, Ohashi K, Rai K, Hotta K, Tabata M, Maeda Y, Kiura K.
  • Journal Title: Jpn J Clin Oncol. Volume: 51 Pages: 956-965.
  • DOI: 10.1093/jjco/hyab048.
  • Peer Reviewed
• [Journal Article] A case of dramatic reduction in cancer-associated thrombus following initiation of pembrolizumab in patient with a poor performance status and PD-L1+ lung adenocarcinoma harboring CCDC6-RET fusion gene and NF1/TP53 mutations. (2021)
  • Author(s): Nakasuka T, Ohashi K, Watanabe H, Kubo T, Matsumoto S, Goto K, Hotta K, Maeda Y, Kiura K.
  • Journal Title: Lung Cancer. Volume: 156 Pages: 1-4.
  • DOI: 10.1016/j.lungcan.2021.03.022.
  • Peer Reviewed / Open Access
• [Journal Article] Survival of chemo-naive patients with EGFR mutation-positive advanced non-small cell lung cancer after treatment with afatinib and bevacizumab: updates from the Okayama Lung Cancer Study Group Trial 1404 (2021)
  • Author(s): Ninomiya T, Nogami N, Kozuki T, Harada D, Kubo T, Ohashi K, Ichihara E, Kuyama S, Kudo K, Bessho A, Sakugawa M, Fujimoto N, Aoe K, Minami D, Sugimoto K, Ochi N, Takigawa N, Hotta K, Maeda Y, Kiura K.
  • Journal Title: Jpn J Clin Oncol . Volume: 51(8) Pages: 1269-1276.
  • DOI: 10.1093/jjco/hyab084.
  • Peer Reviewed
• [Journal Article] Phase 1/2 study of alectinib in RET-rearranged previously-treated non-small cell lung cancer (ALL-RET) (2021)
  • Author(s): Takeuchi S, Yanagitani N, Seto T, Hattori Y, Ohashi K, Morise M, Matsumoto S, Yoh K, Goto K, Nishio M, Takahara S, Kawakami T, Imai Y, Yoshimura K, Tanimoto A, Nishiyama A, Murayama T, Yano S.
  • Journal Title: Transl Lung Cancer Res. Volume: 10(1) Pages: 314-325.
  • DOI: 10.21037/tlcr-20-549.
  • Peer Reviewed / Open Access
• [Journal Article] Capmatinib in Japanese patients with MET exon 14 skipping-mutated or MET-amplified advanced NSCLC: GEOMETRY mono-1 study (2021)
  • Author(s): Seto T, Ohashi K, Sugawara S, Nishio M, Takeda M, Aoe K, Moizumi S, Nomura S, Tajima T, Hida T.
  • Journal Title: Cancer Sci. Volume: 112(4) Pages: 1556-1566.
  • DOI: 10.1111/cas.14826.
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of bronchoscopy and computed tomography-guided needle biopsy for re-biopsy in non-small cell lung cancer patients (2021)
  • Author(s): Kano H, Kubo T, Ninomiya K, Ichihara E, Ohashi K, Rai K, Hotta K, Tabata M, Hiraki T, Kanazawa S, Maeda Y, Kiura K.
  • Journal Title: Respir Investig . Volume: 59(2) Pages: 240-246.
  • DOI: 10.1016/j.resinv.2020.12.001.
  • Peer Reviewed
• [Presentation] Therapeutic stimulation of nucleic acid receptor RIG-I enhances efficacy of kinase inhibitor treatment in oncogene-driven tumors (2021)
  • Author(s): Johannes Bragelmann; Carina Lorenz; Sven Borchmann; Kazuya Nishii; Julia Wegner; Jenny Ostendorp; David Ast; Alena Heimsoeth; Philipp Lohneis; Thomas Zillinger; Roland Ullrich; Kadoaki Ohashi; Martin Schlee; Martin Sos
  • Organizer: AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics
  • Int'l Joint Research
• [Presentation] Novel combined immunotherapy with EGFR-TKI follow by dual blockade of PD-1 and VGFR2 in lung cancer harboring Egfr mutation. (2021)
  • Author(s): Kazuya Nishii,, Kadoaki Ohashi, Shuta Tomida, Takamasa Nakasuka, Atsuko Hirabae, Sachi Okawa, Hisao Higo, Hiromi Watanabe, Hirohisa Kano, Chihiro Ando, Go Makimoto, Kiichiro Ninomiya,et al and Heiichiro Udono, Yoshinobu Maeda, Katsuyuki Kiura
  • Organizer: 1st JCA-AACR Precision Cancer Medicine International Conference
  • Int'l Joint Research
• [Presentation] Increased expression of amphiregulin may contribute to crizotinib resistance in lung cancer cells harboring ROS1 fusion genes (2021)
  • Author(s): Hiromi Watanabe, Yuka Kato, Kadoaki Ohashi, Shuta Tomida, Kenji Takada, Kazuya Nishii, Go Makimoto, Kiichiro Ninomiya, Masanori Fujii, Toshio Kubo, Eiki Ichihara, Yoshinobu Maeda, Katsuyuki Kiura
  • Organizer: 1st JCA-AACR Precision Cancer Medicine International Conference
  • Int'l Joint Research
• [Presentation] Combined efect of Lorlatinib and Bcl-2 inhibitors in intrinsic Alectinib resistant Lung Adenocarcinoma Harboring the EML4-ALK Fusion Gene (2021)
  • Author(s): Go Makimoto, Kadoaki Ohashi, Shuta Tomida, Kenji Takada, Hiromi Watanabe, Kazuya Nishii, Kiichiro Ninomiya, Yuka Kato, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda and Katsuyuki Kiura
  • Organizer: 1st JCA-AACR Precision Cancer Medicine International Conference
  • Int'l Joint Research