Development of novel cancer vaccine therapy using oncolytic Ad-REIC

2016 Fiscal Year Annual Research Report

• Project/Area Number: 15K20093
• Research Institution: Okayama University
• Principal Investigator: 黄 鵬 岡山大学, 医歯薬学総合研究科, 助教 (00610841)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Keywords: REIC/DKK-3 / 制限増殖型アデノウイルスベクター / 抗癌免疫制御 / 免疫活性

Outline of Annual Research Achievements

平成28年度は、昨年度に引き続き、REIC遺伝子発現制限増殖型アデノウイルスベクターを用いた治療法の抗腫瘍免疫学的解析をした。さらに、REICによるMDSCの分化抑制に基づく抗癌免疫活性化作用の機序を解明する為の研究を実施した。我々の確立したREIC/Dkk-3ノックアウト（KO）マウスを用いた実験系では、生体内の内在性・機能的REIC/Dkk-3タンパク質の影響を回避することが可能と考え、以下の研究を行った。a) REIC/Dkk-3 KOマウスでのベンゾピレン等を用いた自家発癌モデルを用いて、REIC遺伝子発現制限増殖型アデノウイルスベクターや精製REICタンパク質を腫瘍内局所または全身投与した場合の、腫瘍内・骨髄・全身でのMDSCを含む種々の癌免疫担当細胞の出現動態を解析した。
b)上記a)の実験系において、腫瘍局所での癌細胞選択的アポトーシスの誘導や癌細胞増殖、腫瘍血管新生抑制効果、また癌転移抑制効果について解析を行った。さらに、治療効果としての腫瘍増大抑制作用と抗癌免疫活性化作用との相関、ならびに、当該KOマウスの通常と担癌状態、および発癌過程でのMDSCの出現と癌免疫抑制作用との相関性を解析及び検証を行った。
本申請研究では、我々が新たに開発したREIC遺伝子発現制限増殖型アデノウイルスベクター（腫瘍融解性Ad-REIC）が、従来のアデノウイルスベクターより強く抗腫瘍効果を認めることを確認し、REIC/Dkk-3タンパク質の機能として抗癌免疫の制御と活性化の面からKey分子を同定することができた。

Research Products

• [Journal Article] Lycorine induces apoptosis of bladder cancer T24 cells by inhibiting phospho-Akt and activating the intrinsic apoptotic cascade (2017)
  • Author(s): Wang C, Wang Q, Li X, Jin Z, Xu P, Xu N, Xu A, Xu Y, Zheng S, Zheng J, Liu C, Huang P.
  • Journal Title: Biochem Biophys Res Commun Volume: 483 Pages: 197-202
  • DOI: doi: 10.1016/j.bbrc.2016.12.168.
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Synergistic effects of the immune checkpoint inhibitor CTLA-4 combined with the growth inhibitor lycorine in a mouse model of renal cell carcinoma (2017)
  • Author(s): Li X, Xu P, Xu N, Guo K, Xu A, Takenaka F, Matsuura E, Liu C, Kumon H, Huang P.
  • Journal Title: Oncotarget. Volume: 未定 Pages: 印刷中
• [Journal Article] MCAM, as a novel receptor for S100A8/A9, mediates progression of malignant melanoma through prominent activation of NF-κB and ROS formation upon ligand binding. (2016)
  • Author(s): Ruma IM, Putranto EW, Kondo E, Murata H, Watanabe M, Huang P, Kinoshita R, Futami J, Inoue Y, Yamauchi A, Sumardika IW, Youyi C, Yamamoto K, Nasu Y, Nishibori M, Hibino T, Sakaguchi M.
  • Journal Title: Clin Exp Metastasis. Volume: 33 Pages: 609-627
  • DOI: doi: 10.1007/s10585-016-9801-2.
  • Peer Reviewed / Open Access
• [Journal Article] Real-time monitoring of tumor progression and drug responses in a preclinical mouse model of prostate cancer. (2016)
  • Author(s): Xu P, Xu N, Guo K, Xu A, Takenaka F, Matsuura E, Liu C, Kumon H, Huang P.
  • Journal Title: Oncotarget. Volume: 7 Pages: 33025-33034
  • DOI: doi: 10.18632/oncotarget.8846.
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Influence of a single-nucleotide polymorphism of the DNA mismatch repair-related gene exonuclease-1 (rs9350) with prostate cancer risk among Chinese people. (2016)
  • Author(s): Zhang Y, Li P, Xu A, Chen J, Ma C, Sakai A, Xie L, Wang L, Na Y, Kaku H, Xu P, Jin Z, Li X, Guo K, Shen H, Zheng S, Kumon H, Liu C, Huang P.
  • Journal Title: Tumour Biol. Volume: 37 Pages: 6653-6659
  • DOI: doi: 10.1007/s13277-015-4298-x
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Real-time monitoring of tumor progression and drug responses in a preclinical mouse model of prostate cancer (2016)
  • Author(s): Peng Huang , Naijin Xu, Eiji Matsuura, Chunxiao Liu , Masami Watanabe, Hiromi Kumon and Yasutomo Nasu
  • Organizer: International Society for Cell and Gene Therapy of Cancer 2016
  • Place of Presentation: seoul, Korea
  • Year and Date: 2016-11-14 – 2016-11-16
  • Int'l Joint Research
• [Presentation] Monitoring and imaging tumor progression and tracking drug response in a preclinical mouse model (2016)
  • Author(s): Peng Huang , Naijin Xu, Eiji Matsuura, Chunxiao Liu , Masami Watanabe, Hiromi Kumon and Yasutomo Nasu
  • Organizer: 22nd Annual Meeting of Japan Society of Gene and Cell Therapy
  • Place of Presentation: Tokyo
  • Year and Date: 2016-07-28 – 2016-07-30
• [Presentation] Real-time monitoring of tumor progression and drug responses in a preclinical mouse model of prostate cancer (2016)
  • Author(s): Naijin Xu, Peng Huang , Eiji Matsuura, Chunxiao Liu , Masami Watanabe, Hiromi Kumon and Yasutomo Nasu
  • Organizer: Best ofASCO (The Singapore Scoiety of Oncology 2016)
  • Place of Presentation: Singapore
  • Year and Date: 2016-07-08 – 2016-07-10
  • Int'l Joint Research