Development of novel treatment for prostate cancer with the specific peptide which target to prostate cancer tissue

• Project/Area Number: 16K11001
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Kawauchi Akihiro 滋賀医科大学, 医学部, 教授 (90240952)
• Co-Investigator(Kenkyū-buntansha): 小島 秀人 滋賀医科大学, 医学部, 教授 (00225434) ; 寺島 智也 滋賀医科大学, 医学部, 准教授 (40378485) ; 影山 進 滋賀医科大学, 医学部, 講師 (50378452) ; 和田 晃典 滋賀医科大学, 医学部, 医員 (90750539)
• Research Collaborator: Narita Mitsuhiro ; Yoshida Tetsuya
• 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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 前立腺癌 / 標的治療 / ファージディスプレイ / 組織標的ペプチド / 標的ペプチド

Outline of Final Research Achievements

We performed an in vivo phage display to identify peptides that specifically target xenografted prostate cancer cells. This yielded three peptide candidates, each of these peptides was synthesized and evaluated for binding and biological activity. We could identify peptide which showed the highest avidity for LNCaP prostate cancer cells in vitro, and the peptide was thus administered to tumor-bearing mice to evaluate in vivo binding. it specifically bound to the tumor tissue and exhibited very low reactivity with normal liver and kidney tissues.
To demonstrate that peptide could specifically deliver drugs to prostate cancer tissue, a therapeutic peptide was prepared, and was used to treat LNCaP cells in vitro and was also administered to tumor-bearing mice. The therapeutic peptide significantly suppressed tumor growth both in vitro and in vivo. We could identify specific peptide which bind to prostate cancer tissue. Our study showed the possibility of developing new therapeutic methods.

Academic Significance and Societal Importance of the Research Achievements

我々の手法により、前立腺癌組織に特異的に結合する組織標的ペプチドを同定することができ、同ペプチドを用いたペプチド治療の効果が示された。このことにより、前立腺癌に対する新たな治療法としての可能性が見出され、また既存の治療効果を高めることができる可能性が示唆された。
さらに我々が本研究で行った既存の方法から発展させたファージディスプレイ法は治療薬物の輸送を担う特異的な担体としてのペプチドを同定することができることが確認できた。この手法を用いることで、標的とする疾患は前立腺癌に限らず、様々な疾患に対して応用が可能であり、本手法は特異的組織標的ペプチドを同定するための非常に有用な方法であると考えられた。

Research Products

• [Journal Article] Efficient Prostate Cancer Therapy with Tissue-Specific Homing Peptides Identified by Advanced Phage Display Technology (2019)
  • Author(s): Wada Akinori、Terashima Tomoya、Kageyama Susumu、Yoshida Tetsuya、Narita Mitsuhiro、Kawauchi Akihiro、Kojima Hideto
  • Journal Title: Molecular Therapy - Oncolytics Volume: 12 Pages: 138-146
  • DOI: 10.1016/j.omto.2019.01.001
  • Peer Reviewed / Open Access
• [Journal Article] Prohibitin-2 is a novel regulator of p21WAF1/CIP1 induced by depletion of γ-glutamylcyclotransferase. (2018)
  • Author(s): Taniguchi K, Matsumura K, Kageyama S, Ii H, Ashihara E, Chano T, Kawauchi A, Yoshiki T, Nakata S.
  • Journal Title: Biochem Biophys Res Commun. Volume: 496 Issue: 1 Pages: 218-224
  • DOI: 10.1016/j.bbrc.2018.01.029
  • Peer Reviewed / Open Access
• [Journal Article] Depletion of gamma-glutamylcyclotransferase in cancer cells induces autophagy followed by cellular senescence (2018)
  • Author(s): Taniguchi K, Matsumura K, Ii H, Kageyama S, Ashihara E, Chano T, Kawauchi A, Yoshiki T, Nakata S.
  • Journal Title: Am J Cancer Res Volume: 8 Pages: 650-661
  • Peer Reviewed
• [Journal Article] Periostin suppresses in vitro invasiveness via PDK1/Akt/mTOR signaling pathway in a orthotopic model of bladder cancer. (2017)
  • Author(s): Kim, C. J., Tambe, Y., Mukaisho, K., Sugihara, H., Kageyama, S., Kawauchi, A., Inoue, H.
  • Journal Title: Oncology Letters Volume: 13 Issue: 6 Pages: 4276-4284
  • DOI: 10.3892/ol.2017.6004
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Depletion of γ-glutamylcyclotransferase inhibits breast cancer cell growth via cellular senescence induction mediated by CDK inhibitor upregulation (2016)
  • Author(s): Matsumura K, Nakata S, Taniguchi K, Ii H, Ashihara E, Kageyama S, Kawauchi A, Yoshiki T
  • Journal Title: BMC Cancer Volume: 16 Pages: 748-748
  • Open Access
• [Journal Article] Hydroxyl-HIF2-alpha is potential therapeutic target for renal cell carcinomas (2016)
  • Author(s): Isono T, Chano T, Yoshida T, Kageyama S, Kawauchi A, Suzaki M, Yuasa T
  • Journal Title: Am J Cancer Res Volume: 6 Pages: 2263-2276
  • Peer Reviewed / Open Access
• [Journal Article] Akt-dependent activation of Erk by cyclin D1b contributes to cell invasiveness and tumorigenicity. (2016)
  • Author(s): Kim CJ, Tambe Y, Mukaisho KI, Sugihara H, Kawauchi A, Inoue H.
  • Journal Title: Oncology Letters Volume: 12 Issue: 6 Pages: 4850-4856
  • DOI: 10.3892/ol.2016.5286
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] In vivo phage displayを用いた前立腺癌特異的組織標的ペプチドによる新規治療法の開発 (2019)
  • Author(s): 和田晃典、小島秀人、寺島智也、影山進、成田充弘、河内明宏
  • Organizer: 第107回日本泌尿器科学会総会
• [Presentation] Identification of novel cell-specific DDS peptide in prostate cancer by in vivo phage display (2019)
  • Author(s): Akinori Wada*, Hideto kojima, Tomoya Terashima, Susumu Kageyama, Akihiro Kawauchi
  • Organizer: AUA 2019
  • Int'l Joint Research
• [Presentation] Identification of novel cell specific DDS peptides for prostate cancer by in vivo phage biopanning. (2018)
  • Author(s): Akinori Wada, Hideto Kojima, Tomoya Terashima, Susumu Kageyama, Akihiro Kawauchi
  • Organizer: 第77回日本癌学会