Innovative development of DDS for microRNA therapeutics by an application of anti-PCSK9 antibody

• Project/Area Number: 16K14630
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: INAZAWA Johji 東京医科歯科大学, 難治疾患研究所, 教授 (30193551)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: がん / マイクロRNA / 核酸抗がん薬 / DDS / 脂質ナノ粒子 / PCSK9 / LDLR / LNP

Outline of Final Research Achievements

Tumor-suppressive microRNAs (TS-miRs) target multiple cancer-promoting genes concurrently and may be useful as a therapeutic agent for cancer therapy. The development of drug delivery system (DDS) is critical for the implementation of miR-based therapeutics. miR-X we identified effectively induces apoptosis by concurrently directly targeting multiple genes associated with cytoprotective mechanisms in esophageal cancer cells. In this project, we investigated therapeutic potential of the lipid-nanoparticle (LNP)-mediated DDS for miR-634-based cancer therapy. We confirmed the enforced expression of miR-X to be able to induce the apoptosis in various cancer cell lines. In xenograft tumors of BxPC3 cells, a pancreatic cancer cell line, in mice, the intravenous administration of the LNP incorporated miR-X significantly induced tumor growth inhibition. These results suggest therapeutic utility of LNP-mediated DDS for TS-miR(s) to cancer cells.

Research Products

• [Journal Article] Ovarian cancer therapeutic potential of glutamine depletion based on GS expression. (2018)
  • Author(s): Furusawa A, Miyamoto M, Takano M, Tsuda H, Song YS, Aoki D, Miyasaka N, Inazawa J, Inoue J.
  • Journal Title: Carcinogenesis Volume: 印刷中 Issue: 6 Pages: 758-766
  • DOI: 10.1093/carcin/bgy033
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] miR-3140 suppresses tumor cell growth by targeting BRD4 via its coding sequence and downregulates the BRD4-NUT fusion oncoprotein (2018)
  • Author(s): Tonouchi Erina、Gen Yasuyuki、Muramatsu Tomoki、Hiramoto Hidekazu、Tanimoto Kousuke、Inoue Jun、Inazawa Johji
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 4482-4482
  • DOI: 10.1038/s41598-018-22767-y
  • Peer Reviewed / Open Access
• [Journal Article] GWAS Identifies Two Novel Colorectal Cancer Loci at 16q24.1 and 20q13.12. (2018)
  • Author(s): Tanikawa C, Kamatani Y, Takahashi A, Momozawa Y, Leveque K, Nagayama , Mimori K, Mori M, Ishii H, Inazawa J, Yasuda J, Tsuboi A, Shimizu A, Sasaki M, Yamaji T, Sawada N, Iwasaki M, Tsugane S, Naito M, Wakai K, Koyama T, Takezaki T, Yuji K, Murakami Y, Nakamura Y, Kubo M, Matsuda K
  • Journal Title: Carcinogenesis Volume: Epub Issue: 5 Pages: 652-660
  • DOI: 10.1093/carcin/bgy026
  • Peer Reviewed / Open Access
• [Journal Article] The Japanese Society of Pathology Guidelines on the handling of pathological tissue samples for genomic research: Standard operating procedures based on empirical analyses. (2018)
  • Author(s): Kanai Y, Nishihara H, Miyagi Y, Tsuruyama T, Taguchi K, Katoh H, Takeuchi T, Gotoh M, Kuramoto J, Arai E, Ojima H, Shibuya A, Yoshida T, Akahane T, Kasajima R, Morita KI, Inazawa J, Sasaki T, Fukayama M, Oda Y.
  • Journal Title: Pathology International Volume: 68 Issue: 2 Pages: 63-90
  • DOI: 10.1111/pin.12631
  • NAID: 120007134466
  • Peer Reviewed / Open Access
• [Journal Article] Regional evaluation of childhood acute lymphoblastic leukemia genetic susceptibility loci among Japanese (2018)
  • Author(s): Urayama Kevin Y.、Takagi Masatoshi、Kawaguchi Takahisa、Matsuo Keitaro、Tanaka Yoichi、Ayukawa Yoko、Arakawa Yuki、Hasegawa Daisuke、Yuza Yuki、Kaneko Takashi、Noguchi Yasushi、Taneyama Yuichi、Ota Setsuo、Inukai Takeshi、Yanagimachi Masakatsu、Keino Dai、Koike Kazutoshi、Toyama Daisuke、Inazawa Johji 他16名
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 789-789
  • DOI: 10.1038/s41598-017-19127-7
  • Peer Reviewed / Open Access
• [Journal Article] miR-432 Induces NRF2 Stabilization by Directly Targeting KEAP1 (2017)
  • Author(s): Akdemir Burak、Nakajima Yasuaki、Inazawa Johji、Inoue Jun
  • Journal Title: Molecular Cancer Research Volume: 15 Issue: 11 Pages: 1570-1578
  • DOI: 10.1158/1541-7786.mcr-17-0232
  • Peer Reviewed
• [Journal Article] miR-509-5p and miR-1243 increase the sensitivity to gemcitabine by inhibiting epithelial-mesenchymal transition in pancreatic cancer (2017)
  • Author(s): Hiramoto Hidekazu、Muramatsu Tomoki、Ichikawa Daisuke、Tanimoto Kousuke、Yasukawa Satoru、Otsuji Eigo、Inazawa Johji
  • Journal Title: Scientific Reports Volume: 7 Issue: 1
  • DOI: 10.1038/s41598-017-04191-w
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide screening of DNA methylation associated with lymph node metastasis in esophageal squamous cell carcinoma (2017)
  • Author(s): Nagata Hiroaki、Kozaki Ken-Ichi、Muramatsu Tomoki、Hiramoto Hidekazu、Tanimoto Kousuke、Fujiwara Naoto、Imoto Seiya、Ichikawa Daisuke、Otsuji Eigo、Miyano Satoru、Kawano Tatsuyuki、Inazawa Johji
  • Journal Title: Oncotarget Volume: 8 Issue: 23 Pages: 37740-37750
  • DOI: 10.18632/oncotarget.17147
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Subcloning and characterization of highly metastatic cells derived from human esophageal squamous cell carcinoma KYSE150 cells by <i>in vivo</i> selection (2017)
  • Author(s): Okuda Masafumi、Inoue Jun、Fujiwara Naoto、Kawano Tatsuyuki、Inazawa Johji
  • Journal Title: Oncotarget Volume: 8 Issue: 21 Pages: 34670-34677
  • DOI: 10.18632/oncotarget.16668
  • Peer Reviewed / Open Access
• [Journal Article] Autophagy is required for cell survival under L-asparaginase induced metabolic stress in acute lymphoblastic leukemia cells (2017)
  • Author(s): akahashi H, Inoue J, Sakaguchi K, Tanakagi M, Mizutani S, and Inazawa J
  • Journal Title: Oncogene Volume: 印刷中 Issue: 30 Pages: 4267-4276
  • DOI: 10.1038/onc.2017.59
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Exosomal microRNA miR-1246 induces cell motility and invasion through the regulation of DENND2D in oral squamous cell carcinoma. (2016)
  • Author(s): Sakha S, Muramatsu T, Ueda K, Inazawa J:
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 38750-38750
  • DOI: 10.1038/srep38750
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The hypusine cascade promotes cancer progression and metastasis through the regulation of RhoA in squamous cell carcinoma. (2016)
  • Author(s): Muramatsu T, Kozaki KI, Imoto S, Yamaguchi R, Tsuda H, Kawano T, Fujiwara N, Morishita M, Miyano S, Inazawa J.
  • Journal Title: Oncogene Volume: - Issue: 40 Pages: 5304-5316
  • DOI: 10.1038/onc.2016.71
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Down-regulation of LAPTM5 in human cancer cells (2016)
  • Author(s): Nuylan M, Kawano T, Inazawa J, Inoue J
  • Journal Title: Oncitarget Volume: 7 Issue: 19 Pages: 28320-8
  • DOI: 10.18632/oncotarget.8614
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] がんの増殖を抑える小さな分子、マイクロRNA (2018)
  • Author(s): 稲澤譲治
  • Organizer: 第7回山梨医学フォーラム
  • Invited
• [Presentation] Exploring novel cancer-related microRNAs and their diagnostic and therapeutic potentials in Precision Cancer Medicine (PCM) (2018)
  • Author(s): Inazawa J.
  • Organizer: The 2nd International Symposium of Internaional Society of Precision Cancer Medicine
  • Int'l Joint Research / Invited
• [Presentation] Exploring novel cancer-related microRNAs and their diagnostic and therapeutic potentials in Precision Cancer Medicine (PCM) (2018)
  • Author(s): Inazawa J.
  • Organizer: TMU-TMDU Joint Symposium 2018
  • Int'l Joint Research / Invited
• [Presentation] High expression of MiR-432-3p is associated with the chemoresistance by NRF2 stabilization via directly targeting KEAP1 (2017)
  • Author(s): Akdemir B, Inoue J, Kawano T, Inazawa J
  • Organizer: 108th annual meeting of American Association for Cancer Research 2017
  • Int'l Joint Research
• [Presentation] Differential requirement of amino acids on cell survival of ovarian cancer cells (2017)
  • Author(s): Furusawa A, Inoue J, Tsuda H, Miyasaka N, Inazawa J
  • Organizer: 108th annual meeting of American Association for Cancer Research 2017
  • Int'l Joint Research
• [Presentation] Autophagy is required for cell survival under L-asparaginase-induced metabolic stress in acute lymphoblastic leukemia cells (2017)
  • Author(s): Inoue J, Takahashi H, Sakaguchi K, Takagi M, Mizutani S, Inazawa J
  • Organizer: 108th annual meeting of American Association for Cancer Research 2017
  • Int'l Joint Research
• [Presentation] ヒストンアセチル基転移酵素阻害剤C646 はG2/M 細胞周期停止を介し膵臓癌細胞株における細胞増殖を抑制する (2017)
  • Author(s): 小野宏晃、Basson Marc、稲澤譲治、田邉稔、伊藤寛倫
  • Organizer: 第117 回日本外科学会定期学術集会
• [Presentation] がんの特性を制御するマイクロRNA の探索と核酸抗がん薬への応用 (2017)
  • Author(s): 稲澤譲治
  • Organizer: 第49 回日本臨床分子形態 学会総会・学術集会
  • Invited
• [Presentation] 卵巣癌細胞の生存におけるアミノ酸要求性 (2017)
  • Author(s): 古澤啓子、井上純、津田均、宮坂尚幸、稲澤譲治
  • Organizer: 第76 回日本 癌学会学術総会
• [Presentation] オートファジーを指標とした癌治療戦略の分子基盤 (2017)
  • Author(s): 井上純、稲澤譲治
  • Organizer: 第76 回日本 癌学会学術総会
• [Presentation] miR-509-5p とmiR-1243 は膵癌においてEMT を抑 制する (2017)
  • Author(s): 平本秀一、村松智輝、市川大輔、大辻英吾、稲澤譲治
  • Organizer: 第76 回日本 癌学会学術総会
• [Presentation] 機能的miRNA スクリーニングを用いた、p53 不活性型癌に細胞死を誘導する miRNA の探索 (2017)
  • Author(s): 玄泰行、井上純、稲澤譲治
  • Organizer: 第76 回日本 癌学会学術総会
• [Presentation] 機能的miRNA ライブラリースクリーニングを用い た、BET family 遺伝子を制御するがん抑制型miRNA の同定 (2017)
  • Author(s): 外内えり奈、村松智輝、玄泰行、平本秀一、稲澤譲治
  • Organizer: 第76 回日本 癌学会学術総会
• [Presentation] High expression of miR-432-3p is involved in NRF2 stabilization by directly targeting KEAP1 (2017)
  • Author(s): Burak Akdemir、中島康晃、稲澤譲治、井上純
  • Organizer: 第76 回日本 癌学会学術総会
• [Presentation] ゲノム医療に必要な遺伝子異常の基礎知識 (2017)
  • Author(s): 稲澤譲治
  • Organizer: 第76 回日本 癌学会学術総会
  • Invited
• [Presentation] Exploring novel cancer-related microRNAs and their diagnostic and therapeutic potentialsin precision cancer medicine (PCM) (2017)
  • Author(s): Inazawa J.
  • Organizer: 8th International Conference on Nutrition and Physical Activity
  • Int'l Joint Research / Invited
• [Book] 次世代がん治療 「ハイプシン経路によるがん浸潤・転移メカニズム」 (2017)
  • Author(s): （分担）村松智輝, 稲澤譲治
  • Total Pages: 386
  • Publisher: エヌ・ティー・エス
  • ISBN: 9784860435035
• [Book] 日本臨床増刊号 がん転移学上「In vivo 選択法による高転移がん細胞亜株の分離 (2017)
  • Author(s): （分担）村松智輝, 稲澤譲治
  • Total Pages: 305
  • Publisher: 株式会社 日本臨床社
• [Remarks] 東京医科歯科大学難治疾患研究所ゲノム応用医学研究部門分子細胞遺伝ホームページ （MCG HP）
  • URL: http://www.tmd.ac.jp/mri/cgen/framepage.htm
• [Remarks] がんCGHデータベース （CGH Data Base）
  • URL: http://www.cghtmd.jp/CGHDatabase/
• [Remarks] 日本人CNVデータベース （MCG CNV database）
  • URL: http://www.cghtmd.jp/CNVDatabase/
• [Patent(Industrial Property Rights)] マイクロRNA及びその誘導体を有効成分とするがん治療剤 (2017)
  • Inventor(s): 稲澤譲治、玄泰行、村松智輝、外内えり奈
  • Industrial Property Rights Holder: 国立大学法人東京医科歯科大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-229046
  • Filing Date: 2017