Development of PSA-conditional PTEN/p53 double knockout mouse prostate cancer model

• Project/Area Number: 26462433
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Kindai University
• Principal Investigator: DE VELASCO Marco 近畿大学, 医学部, 助教 (20449838)
• Co-Investigator(Kenkyū-buntansha): 植村 天受 近畿大学, 医学部, 教授 (90213397)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 前立腺癌 / 遺伝子改変マウス / PTEN / p53 / 前臨床試験 / Cre-LoxPシステム / PTENノックアウトマウス / PTEN/p53 DKO / 動物モデル / PSAコンディショナル

Outline of Final Research Achievements

We have previously developed a PTEN flox/PSA-Cre transgenic mouse prostate cancer model. In the current research, we focused on p53 (Trp53) to establish a more aggressive metastatic prostate cancer model. Using the same gene engineering method, we established a PSA-conditional PTEN/p53 double knockout (PTEN/p53 DKO) mouse prostate cancer model. Mice with DKO homo-deletion develop an aggressive phenotype characterized by a higher incidence of metastasis, including multiple metastases to lungs, liver, lymph nodes and other distant organs, and decreased survival (median overall survival, 55 weeks of the age), enabling us to use the PTEN/p53 DKO mouse model to evaluate the therapeutic efficacy in a ramdomised controlled studies with similar end points of PFS and OS to a human phase-3 trial. These findings demonstrate the usefulness of the PTEN/p53 DKO mouse prostate cancer model for the preclinical development of novel treatment strategies for prostate cancer.

Research Products

• [Journal Article] Efficacy of targeted AKT inhibition in genetically engineered mouse models of PTEN-deficient prostate cancer. (2015)
  • Author(s): De Velasco MA, Kura Y, Yoshikawa K, Nishio K, Davies BR, Uemura H.
  • Journal Title: Oncotarget. Volume: 7 Issue: 13 Pages: 15959-15976
  • DOI: 10.18632/oncotarget.7557
  • Peer Reviewed / Open Access
• [Journal Article] Conditional PTEN-deficient mice as a prostate cancer chemoprevention model. (2015)
  • Author(s): Koike H1, Nozawa M, De Velasco MA, Kura Y, Ando N, Fukushima E, Yamamoto Y, Hatanaka Y, Yoshikawa K, Nishio K, Uemura H.
  • Journal Title: Asian Pac J Cancer Prev. Volume: 16 Pages: 1827-1831
  • Peer Reviewed
• [Journal Article] Androgen deprivation induces phenotypic plasticity and promotes resistance to molecular targeted therapy in a PTEN-deficient mouse model of prostate cancer (2014)
  • Author(s): M.A. De Velasco, M. Tanaka, Y. Yamamoto, Y. Hatanaka, H. Koike, K. Nishio, K. Yoshikawa and H. Uemura
  • Journal Title: Carcinogenesis Volume: 35 Issue: 9 Pages: 2142-2153
  • DOI: 10.1093/carcin/bgu143
  • Peer Reviewed
• [Presentation] Co-targeting of AKT and Pim kinases in mouse PTEN-deficient prostate cance (2017)
  • Author(s): 倉由吏恵、デベラスコ マルコ、安藤直美、佐古紀子、杉本公一、坂井和子、Barry R. Davies、Dennis Huszay、野澤昌弘、吉村一宏、吉川和宏、西尾和人、植村天受
  • Organizer: AACR
  • Place of Presentation: ワシントンDC, USA
  • Year and Date: 2017-04-02
• [Presentation] Therapeutic potential of combination therapy using a next-generation antisense oligonucleotide targeting the androgen receptor and AKT inhibition with AZD5363 in genetically engineered mouse models of prostate cancer (2017)
  • Author(s): デベラスコ マルコ、倉由吏恵、安藤直美、杉本公一、坂井和子、Barry R. Davies、Youngsoo Kim、A. Robert Macleod、野澤昌弘、吉村一宏、吉川和宏、西尾和人、植村天受
  • Organizer: AACR
  • Place of Presentation: ワシントンDC, USA
  • Year and Date: 2017-04-02
• [Presentation] PD-L1 blockade in preclinical models of PTEN-deficient prostate cancer (2017)
  • Author(s): デベラスコ マルコ、倉由吏恵、安藤直美、佐古紀子、Barry R. Devies、杉本公一、野澤昌弘、吉村一宏、吉川和宏、西尾和人、植村天受
  • Organizer: AACR
  • Place of Presentation: ワシントンDC, USA
  • Year and Date: 2017-04-02
• [Presentation] 遺伝子改変と前立腺癌マウスモデルにおける高脂肪食摂取による腫瘍増殖 (2016)
  • Author(s): 森康範、デベラスコ マルコ、倉由吏恵、畑中祐二、沖貴士、杉本公一、吉村一宏、野澤昌弘、吉川和宏、西尾和人、植村天受
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜、神奈川県横浜市
  • Year and Date: 2016-10-06
• [Presentation] PTENノックアウトマウス前立腺癌におけるノンコーディングRNAの (2016)
  • Author(s): 倉由吏恵、デベラスコ マルコ、坂井和子、藤田至彦、冨樫庸介、寺嶋雅人、吉川和宏、西尾和人、植村天受
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜、神奈川県横浜市
  • Year and Date: 2016-10-06
• [Presentation] PTENノックアウトマウス前立腺癌におけて選択的スプライシング (2016)
  • Author(s): デベラスコ マルコ、倉由吏恵、坂井和子、藤田至彦、冨樫庸介、寺嶋雅人、吉川和宏、西尾和人、植村天受
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜、神奈川県横浜市
  • Year and Date: 2016-10-06
• [Presentation] PTENノックアウト前立腺癌マウスモデルにおけるJAK1/2阻害によ (2016)
  • Author(s): 植村天受、倉由吏恵、森康範、畑中祐二、沖貴士、杉本公一、吉村一宏、野澤昌弘、吉川和宏、西尾和人、デベラスコ マルコ
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜、神奈川県横浜市
  • Year and Date: 2016-10-06
• [Presentation] PTEN/p53ダブルノックアウト前立腺癌マウスモデルにおけるクロ (2016)
  • Author(s): 杉本公一、デベラスコ マルコ、倉由吏恵、森康範、畑中祐二、沖貴士、吉村一宏、野澤昌弘、吉川和宏、西尾和人、植村天受
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜、神奈川県横浜市
  • Year and Date: 2016-10-06
• [Presentation] マウス前立腺癌モデルを用いたAKT阻害薬 AZD 5356の抗腫瘍効果 (2015)
  • Author(s): Uemura H., Kura Y., De Velasco MA. et al.,
  • Organizer: 第74回 日本癌学会学術総会
  • Place of Presentation: 名古屋コングレスセンター
  • Year and Date: 2015-10-09
• [Presentation] Chloroquine demonstrates limited effectiveness in an autochthonous preclinical model of prostate cancer (2015)
  • Author(s): Kura Y., De Velasco MA., Uemura H. et al.
  • Organizer: AACR
  • Place of Presentation: フィラデルフィア, アメリカ
  • Year and Date: 2015-04-20
  • Int'l Joint Research
• [Presentation] Preclinical effects of dual AKT/MAPK inhibition in PTEN-deficient prostate cancer (2015)
  • Author(s): De Velasco MA., Yamamot Y., Uemura H, et al.
  • Organizer: AACR
  • Place of Presentation: フィラデルフィア, アメリカ
  • Year and Date: 2015-04-20
  • Int'l Joint Research
• [Presentation] Effects of long-term chloroquine chemotherapy in a preclinical model of PTEN-deficier (2015)
  • Author(s): Yoshikawa K., De Velasco MA., Uemura H. et al
  • Organizer: AACR
  • Place of Presentation: フィラデルフィア, アメリカ
  • Year and Date: 2015-04-20
  • Int'l Joint Research
• [Presentation] Development of a lethal genetically engineered mouse model of prostate cancer for surivival studies and end-stage cancer (2014)
  • Author(s): 植村天受、倉由吏恵、畑中祐二、山本 豊、清水信貴、吉村一宏、野澤昌弘、吉川和宏、西尾和人、デベラスコ マルコ
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜市（パシフィコ横浜）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Functional evaluation of synchronous inactivation of PTEN and P53 in a murine model of prostate cancer. (2014)
  • Author(s): H. Uemura, Y. Kura, N. Ando, E. Fukushima, Y. Hatanaka, Y. Yamamoto, N. Shimizu, K. Yoshimura, M. Nozawa, K. Yoshikawa, K. Nishio and M.A. De Velasco
  • Organizer: AACR
  • Place of Presentation: San Diego
  • Year and Date: 2014-04-05 – 2014-04-09