Preclinical study of tumor-specific p53 gene therapy against refractory pancreatic cancer

• Project/Area Number: 16K10596
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Okayama University
• Principal Investigator: TAZAWA HIROSHI 岡山大学, 大学病院, 准教授 (90415513)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 膵臓癌 / p53 / KRAS / 腫瘍融解 / アデノウイルス / オートファジー / 免疫原性細胞死 / 神経関連因子 / マイクロRNA

Outline of Final Research Achievements

Pancreatic ductal adenocarcinoma (PDAC) frequently shows invasion and metastasis, leading to treatment resistance and poor prognosis. The development of novel antitumor strategy for PDAC is an urgent issue. Here, we show that a tumor-specific replication-competent oncolytic adenovirus expressing tumor suppressor p53, OBP-702, inhibits the migration and invasion abilities and tumor growth and induces the immunogenic cell death in human PDAC cells. In the future, the clinical application of a multiplidisciplinary therapy with OBP-702 is important.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は、高率にKRAS癌遺伝子やp53癌抑制遺伝子の異常を伴う膵臓癌に対して癌特異的増殖型ウイルスを用いたp53遺伝子治療がp53シグナルの活性化とKRAS-ERKシグナルの抑制を介して抗腫瘍効果を発揮する新たな治療戦略となる可能性を示唆している。予後不良な膵臓癌は有効な治療法の確立に未だ至っておらず、新規治療法の開発研究は膵臓癌患者の生命予後の改善につながるため社会的意義は大きい。

Research Products

• [Journal Article] 膵癌に対するウイルス療法の実用化に向けて (2018)
  • Author(s): 國府島 健、田澤 大、杭瀬 崇、吉田龍一、楳田祐三、藤原俊義
  • Journal Title: 消化器外科 Volume: 41 Pages: 931-938
  • Peer Reviewed
• [Journal Article] Impact of Autophagy in Oncolytic Adenoviral Therapy for Cancer (2017)
  • Author(s): Tazawa Hiroshi、Kuroda Shinji、Hasei Joe、Kagawa Shunsuke、Fujiwara Toshiyoshi
  • Journal Title: International Journal of Molecular Sciences Volume: 18 Issue: 7 Pages: 1479-1479
  • DOI: 10.3390/ijms18071479
  • Peer Reviewed / Open Access
• [Presentation] Overexpression of tumor suppressor p53 gene by oncolytic adenovirus boosts immune responses in human pancreatic ductal adenocarcinoma cells. (2018)
  • Author(s): Araki H, Tazawa H, Ieda T, Fushimi T, Kuroda S, Yoshida R, Kishimoto H, Nishizaki M, Urata Y, Kagawa S, Fujiwara T.
  • Organizer: 109th Annual Meeting of the American Association for Cancer Research
  • Int'l Joint Research
• [Presentation] Oncolytic adenovirus-mediated p53 overexpression induces profound immunogenic cell death in human pancreatic ductal adenocarcinoma cells. (2018)
  • Author(s): Araki H, Tazawa H, Ieda T, Fushimi T, Kuroda S, Yoshida R, Kishimoto H, Nishizaki M, Urata Y, Kagawa S, Fujiwara T.
  • Organizer: 第24回日本遺伝子細胞治療学会
• [Presentation] 膵癌に対するp53誘導性腫瘍融解ウイルスによる免疫原性細胞死の誘導効果 (2018)
  • Author(s): 荒木宏之、田澤 大、金谷信彦、菊地覚次、黒田新士、吉田龍一、岸本浩行、西崎正彦、浦田泰生、香川俊輔、藤原俊義
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Impairment of KRAS-driven pancreatic cancer growth and invasion by tumor-specific oncolytic adenoviruses (2016)
  • Author(s): Koujima T, Tazawa H、Kuwada K、Tanimoto T、Kuroda S、Kishimoto H、Nishizaki M、Urata Y、Kagawa S、Fujiwara T
  • Organizer: 第22回日本遺伝子治療学会
  • Place of Presentation: 東京
  • Year and Date: 2016-07-28
• [Presentation] Virally enhanced p53 reactivation impairs KRAS-driven pancreatic cancer invasion (2016)
  • Author(s): Koujima T, Tazawa H, Ieda T, Kuwada K, Tanimoto T, Kuroda S, Kishimoto H, Nishizaki M, Urata Y, Kagawa S, Fujiwara T
  • Organizer: 107th Annual Meeting of the American Association for Cancer Research
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-04-16
  • Int'l Joint Research
• [Book] 次世代がん治療 （第3章第1節） (2017)
  • Author(s): 田澤 大、田辺俊介、香川俊輔、白川靖博、藤原俊義
  • Total Pages: 347
  • Publisher: エヌ・ティー・エス
  • ISBN: 4860435036
• [Book] Advances in Medicine and Biology. Volume 110 (2017)
  • Author(s): Tazawa H, Kagawa S, Shigeyasu K, Fujiwara T
  • Total Pages: 226
  • Publisher: Nova Science Publishers
• [Book] Recent Results in Cancer Research (Current Strategies in Cancer Gene Therapy) (2016)
  • Author(s): Tazawa H, Kagawa S, Fujiwara T
  • Total Pages: 121
  • Publisher: Springer International Publishing