Local adjuvant therapy on bone and soft tissue sarcoma by combination of telomerase-specific oncolytic adenovirus with radiotherapy

• Project/Area Number: 16K10862
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Okayama University
• Principal Investigator: Kunisada Toshiyuki 岡山大学, 医歯薬学総合研究科, 准教授 (80346428)
• Co-Investigator(Kenkyū-buntansha): 尾崎 敏文 岡山大学, 医歯薬学総合研究科, 教授 (40294459) ; 藤原 智洋 岡山大学, 医歯薬学総合研究科, 助教 (80639211)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 骨軟部腫瘍 / 肉腫 / 悪性腫瘍 / ウイルス治療 / 軟部腫瘍 / 放射線治療 / 軟部肉腫 / 骨肉腫 / 臨床応用 / 放射線治療併用 / 悪性骨軟部腫瘍

Outline of Final Research Achievements

Our study demonstrated that OBP-702 has much stronger anti-tumor effect compared to OBP-301, and sensitizes radiotherapy to various types of osteosarcoma cell lines. We recently identified that OBP-702 induces profound apoptosis through p53-dependent BAX upregulation and E1A- dependent p21 and MDM2 downregulation in epithelial malignant cells. This study revealed further molecular mechanisms of synergistic antitumor effect of OBP-702 with radiation; p53-dependent apoptosis, downregulation of the anti-apoptotic BCL-2 family proteins and interruption of the cellular DNA repair mechanism. Currently, a Phase I/II clinical study of OBP-301 in combination with radiation against esophageal cancer patients is underway in Japan, and preclinically OBP-702 provides more profound therapeutic potentials than OBP-301 in various tumors. Thus, OBP-702 would provide a novel treatment strategy for STS and wide application of radiotherapy for localized as well as advanced musculoskeletal sarcoma.

Academic Significance and Societal Importance of the Research Achievements

テロメラーゼ活性依存性に癌細胞内で増殖して細胞死を誘導する腫瘍選択的融解ウイルスは当大学で開発され、食道癌ですでに臨床試験が開始されている。今年度までに行った基礎研究から、これらのウイルス治療は単独で投与するよりも、放射線治療や化学療法と併用することで、より強力な抗腫瘍効果を認めた。さらに、相乗効果も確認でき、肉腫に対する新規療法となりうる。そこで、これらのウイルス治療を利用した実際の臨床応用では、単独投与ではなく、放射線治療との併用療法を行うことで、肉腫を安全に切除することが可能となる。また、正常組織を安全に温存できれば、術後の機能が改善され、患者のQOL向上につながる。

Research Products

• [Journal Article] A rare manifestation of extraskeletal myxoid chondrosarcoma with a huge expanding hematoma (2019)
  • Author(s): Omori Toshinori、Fujiwara Tomohiro、Kunisada Toshiyuki、Takeda Ken、Hasei Joe、Yoshida Aki、Yanai Hiroyuki、Ozaki Toshifumi
  • Journal Title: Journal of Orthopaedic Science Volume: 24 Issue: 2 Pages: 377-381
  • DOI: 10.1016/j.jos.2016.12.011
  • NAID: 120007004863
  • Peer Reviewed
• [Journal Article] Mini-open excision of osteoid osteoma using intraoperative O-arm/Stealth navigation (2019)
  • Author(s): Fujiwara Tomohiro、Kunisada Toshiyuki、Takeda Ken、Hasei Joe、Nakata Eiji、Mochizuki Yusuke、Kiyono Masahiro、Yoshida Aki、Ozaki Toshifumi
  • Journal Title: Journal of Orthopaedic Science Volume: 24 Issue: 2 Pages: 337-341
  • DOI: 10.1016/j.jos.2018.09.017
  • NAID: 120007004864
  • Peer Reviewed
• [Journal Article] Intraoperative O-arm-navigated resection in musculoskeletal tumors (2018)
  • Author(s): Fujiwara Tomohiro、Kunisada Toshiyuki、Takeda Ken、Hasei Joe、Nakata Eiji、Nakahara Ryuichi、Yoshida Aki、Ozaki Toshifumi
  • Journal Title: Journal of Orthopaedic Science Volume: 23 Issue: 6 Pages: 1045-1050
  • DOI: 10.1016/j.jos.2018.06.012
  • Peer Reviewed
• [Journal Article] Patients with osteosarcoma and soft tissue sarcoma might become cancer refugees in some Japanese regional cities (2018)
  • Author(s): Yamane Hiromichi、Kunisada Toshiyuki、Ozaki Toshifumi、Ochi Nobuaki、Honda Yoshihiro、Nagasaki Yasunari、Nakagawa Nozomu、Yamagishi Tomoko、Nakanishi Hidekazu、Takigawa Nagio
  • Journal Title: Cancer Management and Research Volume: Volume 10 Pages: 353-359
  • DOI: 10.2147/cmar.s155282
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of zoledronic acid in oncolytic virotherapy: Promotion of antitumor effect and prevention of bone destruction (2017)
  • Author(s): Yamakawa Yasuaki、Tazawa Hiroshi、Hasei Joe、Osaki Shuhei、Omori Toshinori、Sugiu Kazuhisa、Komatsubara Tadashi、Uotani Kouji、Fujiwara Tomohiro、Yoshida Aki、Kunisada Toshiyuki、Urata Yasuo、Kagawa Shunsuke、Ozaki Toshifumi、Fujiwara Toshiyoshi
  • Journal Title: Cancer Science Volume: 108 Issue: 9 Pages: 1870-1880
  • DOI: 10.1111/cas.13316
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Efficacy of Trabectedin in Patients with Advanced Translocation‐Related Sarcomas: Pooled Analysis of Two Phase II Studies (2017)
  • Author(s): Takahashi Mitsuru、Takahashi Shunji、Araki Nobuhito、Sugiura Hideshi、Ueda Takafumi、Yonemoto Tsukasa、Morioka Hideo、Hiraga Hiroaki、Hiruma Toru、Kunisada Toshiyuki、Matsumine Akihiko、Shimura Masashi、Kawai Akira
  • Journal Title: The Oncologist Volume: 22 Issue: 8 Pages: 979-988
  • DOI: 10.1634/theoncologist.2016-0064
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ablation of MCL1 expression by virally induced microRNA-29 reverses chemoresistance in human osteosarcomas. (2016)
  • Author(s): Osaki S, Tazawa H, Hasei J, Yamakawa Y, Omori T, Sugiu K, Komatsubara T, Fujiwara T, Sasaki T, Kunisada T,
  • Journal Title: Sci Rep. Volume: 30(6) Issue: 1 Pages: 28953-28953
  • DOI: 10.1038/srep28953
  • Peer Reviewed / Open Access
• [Journal Article] Results of sub-analysis of a phase 2 study on trabectedin treatment for extraskeletal myxoid chondrosarcoma and mesenchymal chondrosarcoma. (2016)
  • Author(s): Morioka H, Takahashi S, Araki N, Sugiura H, Ueda T, Takahashi M, Yonemoto T, Hiraga H, Hiruma T, Kunisada T, Matsumine A, Susa M, Nakayama R, Nishimoto K, Kikuta K, Horiuchi K, Kawai A
  • Journal Title: BMC Cancer Volume: 16 Issue: 1 Pages: 479-479
  • DOI: 10.1186/s12885-016-2511-y
  • Peer Reviewed / Open Access
• [Journal Article] Retrospective inter- and intra-patient evaluation of trabectedin after best supportive care for patients with advanced translocation-related sarcoma after failure of standard chemotherapy. (2016)
  • Author(s): Araki N, Takahashi S, Sugiura H, Ueda T, Yonemoto T, Takahashi M, Morioka H, Hiraga H, Hiruma T, Kunisada T, Matsumine A, Kawai A.
  • Journal Title: Eur J Cancer. Volume: 56 Pages: 122-130
  • DOI: 10.1016/j.ejca.2015.12.014
  • Peer Reviewed / Open Access
• [Presentation] p53-armed oncolytic virotherapy promotes immunogenic cell death in human osteosarcoma (2019)
  • Author(s): Koji Demiya, Hiroshi Tazawa, Miho Kure, Yusuke Mochizuki, Joe Hasei Toshiyuki Kunisada, Yasuo Urata, Toshiyoshi Fujiwara, Toshifumi Ozaki
  • Organizer: Orthopaedic Research Society
  • Int'l Joint Research
• [Presentation] Combination of PD-1 blockade Immunotherapy and Telomerase-Specific Oncolytic Virotherapy in Osteosarcoma (2019)
  • Author(s): Yusuke Mochizuki, Hiroshi Tazawa, Miho Kure, Koji Demiya, Joe Hasei, Toshiyuki Kunisada, Yasuo Urata, Toshiyoshi Fujiwara, Toshifumi Ozaki
  • Organizer: Orthopaedic Research Society
  • Int'l Joint Research
• [Presentation] 骨肉腫に対するp53誘導性腫瘍融解ウイルス療法による免疫原性細胞死の誘導効果 (2018)
  • Author(s): 出宮光二、田澤大、望月雄介、小松原将、長谷井嬢、中田英二、国定 俊之、浦田泰生、藤原俊義、尾﨑敏文
  • Organizer: 第32回日本整形外科学会基礎学術集会
• [Presentation] 軟部肉腫に対するp53発現腫瘍融解アデノウイルスによるアポトーシス抑制遺伝子発現の制御を介した放射線感受性増感作用の検討 (2018)
  • Author(s): 小松原将、出宮光二、田澤大、望月雄介、長谷井嬢、中田英二、国定 俊之、浦田泰生、藤原俊義、尾﨑敏文
  • Organizer: 第32回日本整形外科学会基礎学術集会
• [Presentation] 骨肉腫に対する抗PD-1抗体の効果増強を目指した腫瘍融解アデノウイルスを用いた複合免疫療法 (2018)
  • Author(s): 望月雄介、田澤大、出宮光二、小松原将、長谷井嬢、中田英二、国定 俊之、浦田泰生、藤原俊義、尾﨑敏文
  • Organizer: 第32回日本整形外科学会基礎学術集会
• [Presentation] Programmed Cell Death Ligand 1 Expression and Clinical Prognosis in Human Osteosarcoma (2018)
  • Author(s): Koji Demiya, Joe Hasei, Suguru Yokoo, Yusuke Mochizuki, Masahiro Kiyono, Tadashi Komatsubara, Takuya Morita, Aki Yoshida, Eiji Nakata, Toshiyuki Kunisada, Toshifumi Ozaki
  • Organizer: Orthopaedic Research Society
  • Int'l Joint Research
• [Presentation] Molecular radiosensitizing effect of p53-armed telomerase-specific oncolytic adenovirus in soft tissue sarcoma (2018)
  • Author(s): Tadashi Komatsubara, Hiroshi Tazawa, Kouji Demiya, Yusuke Mochizuki, Kazuhisa Sugiu, Toshinori Omori, Yasuaki Yamakawa, Syuhei Osaki, Joe Hasei, Tomohiro Fujiwara, Eiji Nakata, Toshiyuki Kunisada, Yasuo Urata, Toshiyoshi Fujiwara, Toshifumi Ozaki
  • Organizer: Orthopaedic Research Society
  • Int'l Joint Research
• [Presentation] Resection Of Soft Tissue Sarcoma With Adequate Wide Margin Can Lead To Good Local Control Without Adjuvant Radiation Therapy (2018)
  • Author(s): oshiyuki Kunisada, Tomohiro Fujiwara, Joe Hasei, Toshifumi Ozaki
  • Organizer: American Academy of Orthopedic Surgery
  • Int'l Joint Research
• [Presentation] ドキソルビシン耐性骨肉腫細胞に対するp53発現腫瘍融解アデノウイルスによるMDR1発現抑制を介した薬剤耐性克服機序の検討 (2017)
  • Author(s): 杉生 和久 田澤 大 望月 雄介 小松原 将 大森 敏規 山川 泰明 吉田 晶 長谷井 嬢 藤原 智洋 国定 俊之 浦田 泰生 藤原 俊義 尾崎 敏文
  • Organizer: 日本整形外科学会基礎学術集会
• [Presentation] p53発現腫瘍融解アデノウイルスによる軟部肉腫に対する放射線治療併用効果の検討 (2017)
  • Author(s): 小松原将 望月雄介 杉生和久 大森敏規 長谷井嬢 吉田晶 藤原智洋 国定俊之 浦田泰生 田澤大 藤原俊義 尾崎敏文
  • Organizer: 日本整形外科学会基礎学術集会
• [Presentation] RESECTION OF SOFT TISSUE SARCOMA WITH ADEQUATE WIDE MARGIN CAN LEAD TO GOOD LOCAL CONTROL WITHOUT ADJUVANT RADIATION THERAPY (2017)
  • Author(s): Toshiyuki Kunisada, Tomohiro Fujiwara, Joe Hasei, Toshifumi Ozaki
  • Organizer: Connective Tissue Oncology Society (CTOS)
  • Int'l Joint Research
• [Presentation] RESECTION OF SOFT TISSUE SARCOMA WITH ADEQUATE WIDE MARGIN CAN LEAD TO GOOD LOCAL CONTROL WITHOUT ADJUVANT RADIATION THERAPY (2016)
  • Author(s): T Kunisada, T Fujiwara, J Hasei, H Yanai, T Ozaki
  • Organizer: Connective Tissue Oncology Society
  • Place of Presentation: Lisbon
  • Year and Date: 2016-11-10
  • Int'l Joint Research
• [Presentation] 放射線抵抗性を示す骨・軟部肉腫におけるに対する腫瘍融解アデノウイルスの放射線増感 作用 (2016)
  • Author(s): 大森敏規, 山川泰明, 長谷井嬢, 田澤大, 尾崎修平, 杉生和久, 藤原智洋, 国定俊之, 浦田泰生, 藤原俊義, 尾﨑敏文
  • Organizer: 日本整形外科学会基礎学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2016-10-13
• [Presentation] Radiosensitization of telomerase-targeted oncolytic adenovirus against human soft-tissue sarcoma (2016)
  • Author(s): Tadashi Komatsubara, Toshinori Omori, Hiroshi Tazawa, Kazuhisa Sugiu, Yusuke Mochizuki, Yasuaki Yamakawa,Syuhei Osaki, Joe Hasei, Kouji Uotani, Tomohiro Fujiwara, Toshiyuki Kunisada, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara
  • Organizer: 日本癌学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] Reversal of ABC transporter-mediated chemoresistance in human osteosarcoma by oncolytic virotherapy (2016)
  • Author(s): Kazuhisa Sugiu, Hiroshi Tazawa , Joe Hasei, Shuhei Osaki, Yasuaki Yamakawa, Toshinori Omori, Tadashi Komatsubara, Yusuke Mochizuki, Kouji Uotani, Tomohiro Fujiwara, Toshiyuki Kunisada, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara
  • Organizer: 日本癌学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06