Approaches to predict resistance and elucidate resistance mechanisms of molecularly targeted drugs using "on-time methods''

• Project/Area Number: 17K09641
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Tohoku University
• Principal Investigator: Ishizawa Kota 東北大学, 東北メディカル・メガバンク機構, 非常勤講師 (60400313)
• Co-Investigator(Kenkyū-buntansha): 堀井 明 東北大学, 医学系研究科, 名誉教授 (40249983) ; 三森 隆広 国立研究開発法人理化学研究所, 革新知能統合研究センター, 研究員 (40760161) ; 桜田 晃 東北大学, 加齢医学研究所, 准教授 (60360872)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 肺がん / 胸水 / EGFR / 薬剤耐性 / TKI / 多様性 / ゼノングラフト / FACS / Cell sorting / EGFR mutation / 肺癌 / トランスレーションナルリサーチ / がん性胸水 / がんゲノム / ドライバーニューテーション / ガンゲノム / ビックデータ

Outline of Final Research Achievements

Cancerous pleural fluid specimens from lung cancer patients were collected during the study period.
Using the collected specimens, we established a method to efficiently collect cells from pleural fluid and also established a method to separate normal viable cells from cancer cells by cell sorter.This has enabled us to divide cancer cells into subgroups using the cell surface markers CD326 and CD45.As a result, we found a previously unidentified population of CD45-positive and CD326-positive cells (CD326+/CD45+DPC). These cancer cells were found to have EGFR mutations, confirming that there is a diversity of cancer cells.It was also suggested that the abundance of this novel cell population may affect the therapeutic efficacy and prognosis of lung cancer patients.

Academic Significance and Societal Importance of the Research Achievements

申請者は無血清培養の「オンタイム法」を開発した。がん細胞を不死化する必要がなく、患者の病態を反映するがん細胞を入手できるようになった。NOGマウスを使ったゼノングラフ(PDX)と併用することで約90%近い成功率で患者由来の細胞株を樹立することが可能になった。
トランスレーションナルリサーチとして研究成果を迅速に患者治療にフィードバック可能である。究極的には患者ごとの細胞株(薬剤非耐性株、耐性株)を制作し、安定供給する事で患者本人の癌細胞株を蓄積し、セルバンク化することが可能である。これらの研究資源は患者本人の治療のみならず、さらなる治療薬の開発研究にも有用である。

Research Products

• [Int'l Joint Research] Toronto University/Princess Margaret Hospital(カナダ)
• [Journal Article] Retrospective study revealed that Zn relate to improvement of swallowing function in the older adults (2021)
  • Author(s): Seki Yumika、Ishizawa Kota、Akaishi Tetsuya、Abe Michiaki、Okamoto Koji、Tanaka Junichi、Arita Ryutaro、Takayama Shin、Kikuchi Akiko、Miyazaki Mariko、Harigae Hideo、Sato Mayumi、Hoshi Masaya、Hatsugai Kazuaki、Ishii Tadashi
  • Journal Title: BMC Geriatrics Volume: 21 Issue: 1 Pages: 1-7
  • DOI: 10.1186/s12877-021-02224-8
• [Journal Article] RET inhibition in novel patient-derived models of RET-fusion positive lung adenocarcinoma reveals a role for MYC upregulation (2020)
  • Author(s): Hayashi T, Odintsov I, Smith RS, Ishizawa K, Liu AJW, Delasos L, Kurzatkowski C, Tai H, Gladstone E, Vojnic M, Kohsaka S, Suzawa K, Liu Z, Kunte S, Mattar MS, Khodos I, Davare MA, Drilon A, Cheng E, Stanchina E, Ladanyi M, Somwar R
  • Journal Title: Dis Model Mech Volume: － Issue: 2 Pages: 1-11
  • DOI: 10.1242/dmm.047779
  • Peer Reviewed / Open Access
• [Journal Article] Genetic and epigenetic aberrations of ABCB1 synergistically boost the acquisition of taxane resistance in esophageal squamous cancer cells (2020)
  • Author(s): Sumarpo Anton、Ito Kazuma、Saiki Yuriko、Ishizawa Kota、Wang Ruobing、Chen Na、Sunamura Makoto、Horii Akira
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 526 Issue: 3 Pages: 586-591
  • DOI: 10.1016/j.bbrc.2020.03.114
  • Peer Reviewed
• [Journal Article] Genome-wide association study identifies new loci for albuminuria in the Japanese population (2020)
  • Author(s): Hiroshi Okuda, Koji Okamoto, Michiaki Abe, Kota Ishizawa, Satoshi Makino, Osamu Tanabe, Junichi Sugawara, Atsushi Hozawa, Kozo Tanno, Makoto Sasaki, Gen Tamiya, Masayuki Yamamoto, Sadayoshi Ito, Tadashi Ishii
  • Journal Title: Clinical and Experimental Nephrology Volume: 印刷中 Issue: 8 Pages: 1-9
  • DOI: 10.1007/s10157-020-01884-x
  • Peer Reviewed / Open Access
• [Journal Article] A 29-year-old Woman with Recurrent Pregnancy-induced Hypertension Based on Vascular Compression of the Medulla Oblongata (2019)
  • Author(s): Akaishi Tetsuya、Kiyomoto Hideyasu、Abe Michiaki、Okuda Hiroshi、Ishizawa Kota、Endo Toshiki、Miyata Masahiro、Nakayama Keisuke、Ito Sadayoshi、Tominaga Teiji、Ishii Tadashi
  • Journal Title: Internal Medicine Volume: 58 Issue: 15 Pages: 2257-2261
  • DOI: 10.2169/internalmedicine.2382-18
  • NAID: 130007686858
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-08-01
  • Peer Reviewed
• [Journal Article] CD45+CD326+ Cells are Predictive of Poor Prognosis in Non?Small Cell Lung Cancer Patients (2019)
  • Author(s): Ishizawa Kota、Yamanaka Mie、Saiki Yuriko、Miyauchi Eisaku、Fukushige Shinichi、Akaishi Tetsuya、Asao Atsuko、Mimori Takahiro、Saito Ryota、Tojo Yutaka、Yamashita Riu、Sakurada Akira、Pham Nhu-An、Okada Yoshinori、Ishii Tadashi、Ishii Naoto、Kobayashi Seiichi、Ichinose Masakazu、Tsao Ming-Sound、Horii Akira
  • Journal Title: Clinical Cancer Research Volume: 25 Issue: 22 Pages: 6756-6763
  • DOI: 10.1158/1078-0432.ccr-19-0545
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MA18.02 S100A10 Upregulation Associates with Poor Prognosis in Lung Squamous Cell Carcinoma (2019)
  • Author(s): Sato K.、Saiki Y.、Arai K.、Ishizawa K.、Fukushige S.、Sakurada A.、Okada Y.、Horii A.
  • Journal Title: Journal of Thoracic Oncology Volume: 14 Issue: 10 Pages: S321-S322
  • DOI: 10.1016/j.jtho.2019.08.647
  • Peer Reviewed
• [Journal Article] Expression of SNAIL in accompanying PanIN is a key prognostic indicator in pancreatic ductal adenocarcinomas (2019)
  • Author(s): Fujiwara Sho、Saiki Yuriko、Ishizawa Kota、Fukushige Shinichi、Yamanaka Mie、Sato Masaki、Ishida Masaharu、Motoi Fuyuhiko、Unno Michiaki、Horii Akira
  • Journal Title: Cancer Medicine Volume: 8 Issue: 4 Pages: 1671-1678
  • DOI: 10.1002/cam4.2016
  • Peer Reviewed
• [Journal Article] High glucose level and angiotensin II type 1 receptor stimulation synergistically amplify oxidative stress in renal mesangial cells (2019)
  • Author(s): Akaishi Tetsuya、Abe Michiaki、Okuda Hiroshi、Ishizawa Kota、Abe Takaaki、Ishii Tadashi、Ito Sadayoshi
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 5214-5220
  • DOI: 10.1038/s41598-019-41536-z
  • Peer Reviewed
• [Journal Article] Influence of renal function and demographic data on intrarenal Doppler ultrasonography (2019)
  • Author(s): Abe Michiaki、Akaishi Tetsuya、Miki Takashi、Miki Mika、Funamizu Yasuharu、Araya Kaori、Ishizawa Kota、Takayama Shin、Takase Kei、Abe Takaaki、Ishii Tadashi、Ito Sadayoshi
  • Journal Title: PLOS ONE Volume: 14 Issue: 8 Pages: 0221244-0221244
  • DOI: 10.1371/journal.pone.0221244
  • Peer Reviewed
• [Journal Article] Protein‐losing gastroenteropathy with severe hypoalbuminemia associated with Sj?gren’s syndrome: A case report and review of the literature (2019)
  • Author(s): Akaishi Tetsuya、Yasaka Ken、Abe Michiaki、Fujii Hiroshi、Watanabe Mika、Shirai Tsuyoshi、Ishizawa Kota、Takayama Shin、Kagaya Yutaka、Harigae Hideo、Ishii Tadashi
  • Journal Title: Journal of General and Family Medicine Volume: 21 Issue: 1 Pages: 24-28
  • DOI: 10.1002/jgf2.281
  • Peer Reviewed / Open Access
• [Journal Article] Sensitivity and specificity of meningeal signs in patients with meningitis (2019)
  • Author(s): Akaishi Tetsuya、Kobayashi Junpei、Abe Michiaki、Ishizawa Kota、Nakashima Ichiro、Aoki Masashi、Ishii Tadashi
  • Journal Title: Journal of General and Family Medicine Volume: 20 Issue: 5 Pages: 193-198
  • DOI: 10.1002/jgf2.268
  • Peer Reviewed
• [Journal Article] The human central nervous system discharges carbon dioxide and lactic acid into the cerebrospinal fluid (2019)
  • Author(s): Akaishi Tetsuya、Onishi Eiko、Abe Michiaki、Toyama Hiroaki、Ishizawa Kota、Kumagai Michio、Kubo Ryosuke、Nakashima Ichiro、Aoki Masashi、Yamauchi Masanori、Ishii Tadashi
  • Journal Title: Fluids and Barriers of the CNS Volume: 16 Issue: 1 Pages: 1-7
  • DOI: 10.1186/s12987-019-0128-7
  • Peer Reviewed
• [Journal Article] S100A10 upregulation associates with poor prognosis in lung squamous cell carcinoma (2018)
  • Author(s): Sato Kimiaki、Saiki Yuriko、Arai Kazumori、Ishizawa Kota、Fukushige Shinichi、Aoki Kenko、Abe Jiro、Takahashi Satomi、Sato Ikuro、Sakurada Akira、Okada Yoshinori、Horii Akira
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 505 Issue: 2 Pages: 466-470
  • DOI: 10.1016/j.bbrc.2018.09.118
  • Peer Reviewed
• [Journal Article] A Novel <i>SDHB </i>IVS2-2A&gt;C Mutation Is Responsible for Hereditary Pheochromocytoma/Paraganglioma Syndrome (2018)
  • Author(s): Yamanaka Mie、Shiga Kiyoto、Fujiwara Sho、Mizuguchi Yasuhiko、Yasuda Sari、Ishizawa Kota、Saiki Yuriko、Higashi Kenjiro、Ogawa Takenori、Kimura Noriko、Horii Akira
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 245 Issue: 2 Pages: 99-105
  • DOI: 10.1620/tjem.245.99
  • NAID: 130007398139
  • ISSN: 0040-8727, 1349-3329
• [Journal Article] Targeting the Differential Addiction to Anti-apoptotic BCL-2 Family for Cancer Therapy (2017)
  • Author(s): Akane Inoue-Yamauchi, Paul Jeng, Kwanghee Kim, Hui-Chen Chen, Kota Ishizawa, Sylvia Jebiwott , Maria Pietanza, Mark Kris, James Hsieh, Emily Cheng.
  • Journal Title: Nature Communication Volume: 8 Issue: 1 Pages: 1-14
  • DOI: 10.1038/ncomms16078
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] S100A10 Upregulation Associates with Poor Prognosis in Lung Squamous Cell Carcinoma. (2019)
  • Author(s): Yuriko Saiki, Kimiaki Sato, Kazumori Arai, Kota Ishizawa, Shinichi Fukushige, Kenko Aoki, Jiro Abe, Satomi Takahashi, Ikuro Sato, Akira Sakurada, Yoshinori Okada, Akira Horii.
  • Organizer: AACR-JCA Joint conference,
  • Int'l Joint Research
• [Presentation] Mutation Analyses of Four Japanese Pedigrees with Hereditary Pheochromocytoma/Paraganlioma Syndrome (HPPS). (2018)
  • Author(s): Yamanaka M, Ishizawa K, Horii A,
  • Organizer: ASHG, 2018 (2814W)
  • Int'l Joint Research
• [Presentation] MDM2 Amplification Mediates Resistance to Cabozantinib in RET-Rearranged Lung Cancers (2017)
  • Author(s): Kota Ishizawa
  • Organizer: The 76th Annual Meeting of the Japanese Cancer Association