Development of a next-generation viral agent targeting immunosuppression by crosstalk in the pancreatic cancer microenvironment

• Project/Area Number: 19H03731
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Okayama University
• Principal Investigator: Fujiwara Toshiyoshi 岡山大学, 医歯薬学域, 教授 (00304303)
• Co-Investigator(Kenkyū-buntansha): 黒田 新士 岡山大学, 大学病院, 助教 (60633758) ; 吉田 龍一 岡山大学, 大学病院, 講師 (80534768) ; 田澤 大 岡山大学, 大学病院, 准教授 (90415513)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2021: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2019: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
• Keywords: 癌 / 遺伝子 / 細胞・組織 / 医療・福祉 / トランスレーショナルリサーチ / トランスレーショナル・リサーチ

Outline of Research at the Start

本研究では、テロメラーゼ依存性アデノウイルスOBP-301（Telomelysin）に多機能がん抑制遺伝子であるp53を搭載した次世代型武装化ウイルス製剤 OBP-702（Pfifteloxin）の膵癌間質細胞による免疫抑制機構への効果を検証し、臨床試験用ロットの大量製造が進む本製剤の難治性膵癌を対象とした実用化を目指す。特に、がん関連線維芽細胞（cancer-associated fibroblast; CAF）の免疫抑制分子であるTGF-β発現調節や免疫活性化に繋がるPTENがん抑制遺伝子の膵癌細胞での発現調節に着目してin vitroおよびin vivoでの解析を進める。

Outline of Final Research Achievements

We examined the effect of OBP-702, a next-generation armed adenovirus OBP-702, which carries the multifunctional tumor suppressor p53 gene, on the immunosuppressive pancreatic cancer microenvironment. Pancreatic cancer stromal cells (human pancreatic stellate cells: hPSC) promoted tumor growth by coexisting with pancreatic cancer cells in the pancreatic cancer microenvironment, and OBP-702 produced strong p53 gene expression in hPSC. By inducing selective apoptosis, in addition to the antitumor effect on the pancreatic cancer cells, OBP-702 exhibited a profound antitumor activity through the control of the pancreatic cancer microenvironment.

Academic Significance and Societal Importance of the Research Achievements

膵癌微小環境において、膵癌間質細胞hPSCは膵癌細胞と共存することで腫瘍増殖を促進しており、OBP-702は膵癌細胞自体への抗腫瘍効果に加えて膵癌微小環境の制御を介した統合的な抗腫瘍活性を発揮した。間質細胞を標的とすることで他の種々の細胞とのクロストークに関わる様々な分子を制御することができ、がん細胞のみを狙った既存のコンセプトとは異なる革新的な治療法の開発につながる可能性がある。

Research Products

• [Journal Article] Targeting neutrophil extracellular traps with thrombomodulin prevents pancreatic cancer metastasis (2021)
  • Author(s): Kajioka Hiroki、Kagawa Shunsuke、Ito Atene、Yoshimoto Masashi、Sakamoto Shuichi、Kikuchi Satoru、Kuroda Shinji、Yoshida Ryuichi、Umeda Yuzo、Noma Kazuhiro、Tazawa Hiroshi、Fujiwara Toshiyoshi
  • Journal Title: Cancer Letters Volume: 497 Pages: 1-13
  • DOI: 10.1016/j.canlet.2020.10.015
  • NAID: 120007188794
  • Peer Reviewed
• [Journal Article] Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer (2021)
  • Author(s): Katsube Ryoichi、Noma Kazuhiro、Ohara Toshiaki、Nishiwaki Noriyuki、Kobayashi Teruki、Komoto Satoshi、Sato Hiroaki、Kashima Hajime、Kato Takuya、Kikuchi Satoru、Tazawa Hiroshi、Kagawa Shunsuke、Shirakawa Yasuhiro、Kobayashi Hisataka、Fujiwara Toshiyoshi
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 1693-1693
  • DOI: 10.1038/s41598-021-81465-4
  • NAID: 120006961122
  • Peer Reviewed / Open Access
• [Journal Article] Extracellular vesicles shed from gastric cancer mediate protumor macrophage differentiation (2021)
  • Author(s): Ito Atene、Kagawa Shunsuke、Sakamoto Shuichi、Kuwada Kazuya、Kajioka Hiroki、Yoshimoto Masashi、Kikuchi Satoru、Kuroda Shinji、Yoshida Ryuichi、Tazawa Hiroshi、Fujiwara Toshiyoshi
  • Journal Title: BMC Cancer Volume: 21 Issue: 1 Pages: 102-114
  • DOI: 10.1186/s12885-021-07816-6
  • NAID: 120006980466
  • Peer Reviewed / Open Access
• [Journal Article] Nanog is a promising chemoresistant stemness marker and therapeutic target by iron chelators for esophageal cancer (2021)
  • Author(s): Toru Narusaka, Toshiaki Ohara, Kazuhiro Noma, Noriyuki Nishiwaki, Yuki Katsura, Takuya Kato, Hiroaki Sato, Yasuko Tomono, Satoru Kikuchi, Hiroshi Tazawa, Yasuhiro Shirakawa, Akihiro Matsukawa, Toshiyoshi Fujiwara
  • Journal Title: International Journal of Cancer Volume: - Issue: 2 Pages: 347-357
  • DOI: 10.1002/ijc.33544
  • Peer Reviewed
• [Journal Article] Oncolytic virotherapy promotes radiosensitivity in soft tissue sarcoma by suppressing anti-apoptotic MCL1 expression (2021)
  • Author(s): Omori Toshinori、Tazawa Hiroshi、Yamakawa Yasuaki、Osaki Shuhei、Hasei Joe、Sugiu Kazuhisa、Komatsubara Tadashi、Fujiwara Tomohiro、Yoshida Aki、Kunisada Toshiyuki、Urata Yasuo、Kagawa Shunsuke、Ozaki Toshifumi、Fujiwara Toshiyoshi
  • Journal Title: PLOS ONE Volume: 16 Issue: 4 Pages: e0250643-e0250643
  • DOI: 10.1371/journal.pone.0250643
  • NAID: 120007045007
  • Peer Reviewed / Open Access
• [Journal Article] Local oncolytic adenovirotherapy produces an abscopal effect via tumor-derived extracellular vesicles (2021)
  • Author(s): Yoshihiko Kakiuchi, Shinji Kuroda, Nobuhiko Kanaya, Kento Kumon, Tomoko Tsumura, Masashi Hashimoto, Chiaki Yagi, Ryoma Sugimoto, Yuki Hamada, Satoru Kikuchi, Masahiko Nishizaki, Shunsuke Kagawa, Hiroshi Tazawa, Yasuo Urata, Toshiyoshi Fujiwara
  • Journal Title: Molecular Therapy Volume: 29 Issue: 10 Pages: 2925-2930
  • DOI: 10.1016/j.ymthe.2021.05.015
  • Peer Reviewed / Open Access
• [Journal Article] Hyperthermia generated by magnetic nanoparticles for effective treatment of disseminated peritoneal cancer in an orthotopic nude-mouse model. (2021)
  • Author(s): Matsumi Y, Kagawa T, Yano S, Tazawa H, Shigeyasu K, Takeda S, Ohara T, Aono H, Hoffman RM, Fujiwara T, Kishimoto H.
  • Journal Title: Cell Cycle Volume: 20(12) Issue: 12 Pages: 1122-1133
  • DOI: 10.1080/15384101.2021.1919441
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Oncolytic virotherapy reverses chemoresistance in osteosarcoma by suppressing MDR1 expression (2021)
  • Author(s): Sugiu Kazuhisa、Tazawa Hiroshi、Hasei Joe、Yamakawa Yasuaki、Omori Toshinori、Komatsubara Tadashi、Mochizuki Yusuke、Kondo Hiroya、Osaki Shuhei、Fujiwara Tomohiro、Yoshida Aki、Kunisada Toshiyuki、Ueda Koji、Urata Yasuo、Kagawa Shunsuke、Ozaki Toshifumi、Fujiwara Toshiyoshi
  • Journal Title: Cancer Chemotherapy and Pharmacology Volume: 88 Issue: 3 Pages: 513-524
  • DOI: 10.1007/s00280-021-04310-5
  • Peer Reviewed
• [Journal Article] Immuno-hyperthermia effected by antibody-conjugated nanoparticles selectively targets and eradicates individual cancer cells. (2021)
  • Author(s): Kagawa T, Matsumi Y, Aono H, Ohara T, Tazawa H, Shigeyasu K, Yano S, Takeda S, Komatsu Y, Hoffman RM, Fujiwara T, Kishimoto H.
  • Journal Title: Cell Cycle Volume: 20(13) Issue: 13 Pages: 1221-1230
  • DOI: 10.1080/15384101.2021.1915604
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Induction chemoradiotherapy including docetaxel, cisplatin, and 5-fluorouracil for locally advanced esophageal cancer (2020)
  • Author(s): Hashimoto Masashi、Shirakawa Yasuhiro、Maeda Naoaki、Tanabe Shunsuke、Noma Kazuhiro、Sakurama Kazufumi、Katsui Kuniaki、Nishizaki Masahiko、Fujiwara Toshiyoshi
  • Journal Title: Esophagus Volume: 17 Issue: 2 Pages: 127-134
  • DOI: 10.1007/s10388-019-00709-5
  • NAID: 40022193284
  • Peer Reviewed / Open Access
• [Journal Article] Immune Modulation by Telomerase-Specific Oncolytic Adenovirus Synergistically Enhances Antitumor Efficacy with Anti-PD1 Antibody. (2020)
  • Author(s): Kanaya N., Kuroda S., Kakiuchi Y., Kumon K., Tsumura T., Hashimoto M., Morihiro T., Kubota T., Aoyama K., Kikuchi S., Nishizaki M., Kagawa S., Tazawa H., Mizuguchi H., Urata Y., Fujiwara T.
  • Journal Title: Mol. Ther. Volume: 28 Issue: 3 Pages: 794-804
  • DOI: 10.1016/j.ymthe.2020.01.003
  • NAID: 120006952300
  • Peer Reviewed
• [Journal Article] Oncolytic Virus-Mediated Targeting of the ERK Signaling Pathway Inhibits Invasive Propensity in Human Pancreatic Cancer. (2020)
  • Author(s): Koujima T., Tazawa H., Ieda T., Araki H., Fushimi T., Shoji R., Kuroda S., Kikuchi S., Yoshida R., Umeda Y., Teraishi F., Urata Y., Mizuguchi H., Fujiwara T.
  • Journal Title: Mol. Ther. Oncolysis. Volume: 17 Pages: 107-117
  • DOI: 10.1016/j.omto.2020.03.016
  • NAID: 120006869596
  • Peer Reviewed / Open Access
• [Journal Article] Elimination of MYCN-Amplified Neuroblastoma Cells by Telomerase-Targeted Oncolytic Virus via MYCN Suppression. (2020)
  • Author(s): Tanimoto T, Tazawa H, Ieda T, Nouso H, Tani M, Oyama T, Urata Y, Kagawa S, Noda T, Fujiwara T.
  • Journal Title: Molecular Therapy-Oncolytics Volume: 18 Pages: 14-23
  • DOI: 10.1016/j.omto.2020.05.015
  • NAID: 120006892941
  • Peer Reviewed / Open Access
• [Journal Article] Boosting Replication and Penetration of Oncolytic Adenovirus by Paclitaxel Eradicate Peritoneal Metastasis of Gastric Cancer. (2020)
  • Author(s): Ishikawa W, Kikuchi S, Ogawa T, Tabuchi M, Tazawa H, Kuroda S, Noma K, Nishizaki M, Kagawa S, Urata Y, Fujiwara T.
  • Journal Title: Molecular Therapy-Oncolytics Volume: 18 Pages: 262-271
  • DOI: 10.1016/j.omto.2020.06.021
  • NAID: 120006892937
  • Peer Reviewed / Open Access
• [Journal Article] High incidence of tracheobronchial diverticulum in esophageal cancer patients: a retrospective survey alerting pitfall during thoracoscopic esophagectomy. (2020)
  • Author(s): Nishiwaki N, Noma K, Maeda N, Tanabe S, Sakurama K, Shirakawa Y, Fujiwara T.
  • Journal Title: General Thoracic and Cardiovascular Surgery Volume: 68 Issue: 9 Pages: 1018-1023
  • DOI: 10.1007/s11748-020-01421-3
  • Peer Reviewed / Open Access
• [Journal Article] Activation of AZIN1 RNA editing is a novel mechanism that promotes invasive potential of cancer-associated fibroblasts in colorectal cancer (2019)
  • Author(s): Takeda S, Shigeyasu K, Okugawa Y, Yoshida K, Mori Y, Yano S, Noma K, Umeda Y, Kondo Y, Kishimoto H, Teraishi F, Nagasaka T, Tazawa H, Kagawa S, Fujiwara T, Goel A.
  • Journal Title: Cancer Lett Volume: 444 Pages: 127-135
  • DOI: 10.1016/j.canlet.2018.12.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PD-L1 expression combined with microsatellite instability/CD8+ tumor infiltrating lymphocytes as a useful prognostic biomarker in gastric cancer. (2019)
  • Author(s): Morihiro T, Kuroda S, Kanaya N, Kakiuchi Y, Kubota T, Aoyama K, Tanaka T, Kikuchi S, Nagasaka T, Nishizaki M, Kagawa S, Tazawa H, Fujiwara T.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 4633-4633
  • DOI: 10.1038/s41598-019-41177-2
  • NAID: 120006777516
  • Peer Reviewed / Open Access
• [Journal Article] Visualization of epithelial-mesenchymal transition in an inflammatory microenvironment?colorectal cancer network (2019)
  • Author(s): Ieda Takeshi、Tazawa Hiroshi、Okabayashi Hiroki、Yano Shuya、Shigeyasu Kunitoshi、Kuroda Shinji、Ohara Toshiaki、Noma Kazuhiro、Kishimoto Hiroyuki、Nishizaki Masahiko、Kagawa Shunsuke、Shirakawa Yasuhiro、Saitou Takashi、Imamura Takeshi、Fujiwara Toshiyoshi
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 16378-16378
  • DOI: 10.1038/s41598-019-52816-z
  • Peer Reviewed / Open Access