The development of the innovative therapeutic drugs which targete crosstalk in the prostate cancer microenvironment

• Project/Area Number: 17H04325
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Urology
• Research Institution: Kanazawa University
• Principal Investigator: MIZOKAMI Atsushi 金沢大学, 医学系, 教授 (50248580)
• Co-Investigator(Kenkyū-buntansha): 後藤 享子 金沢大学, 薬学系, 准教授 (50180245) ; 泉 浩二 金沢大学, 附属病院, 講師 (80646787)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2019: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2017: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
• Keywords: 前立腺癌 / 微小環境 / 癌細胞間作用 / フラボノイド誘導体 / 抗癌剤耐性 / フラボノイド / 薬剤耐性 / 去勢抵抗性前立腺癌 / タキサン耐性 / クロストーク / taxane系耐性前立腺癌 / Taxane系耐性前立腺癌

Outline of Final Research Achievements

The role of the microenvironment within the cancer tissue in the mechanism of hormone-sensitive prostate cancer (HSPC) developing into castration-resistant prostate cancer (CRPC) remains unclear. In this study, the differences in crosstalk between normal and HSPC-derived stromal cells and between CRPC-derived stromal cells and cancer cells were identified. Crosstalk between HSPC cells and CRPC cells was also revealed. In addition, we attempted to establish and characterize a cabazitaxel-resistant CRPC cell line because elucidating and overcoming the mechanism of cabazitaxel resistance is an important topic to improve patient outcomes. We have succeeded in synthesizing flavonoid derivatives with various actions such as inhibition of androgen signaling, inhibition of AR splicing variant (AR-V7), and proliferation inhibition. In the present study, we clarified the mechanism of action of the drug and confirmed its effect by improving the drug.

Academic Significance and Societal Importance of the Research Achievements

進行性前立腺癌（去勢抵抗性前立腺癌）に対する治療はまだ十分とは言えず、新聞で発表されるほど予後は良くないのが現状である。今回の我々の研究はこの前立腺癌の治療抵抗性の機序やその治療戦略を立てる上で極めて重要な成果を上げた。今後さらにこの研究が臨床応用されれば、前立腺癌の予後が改善されることが期待できる。

Research Products

• [Int'l Joint Research] University of Michigan(米国)
• [Int'l Joint Research] Guangxi Medical University(China)
• [Journal Article] Crosstalk Between Androgen-sensitive and Androgen-insensitive Prostate Cancer Cells. (2018)
  • Author(s): Takezawa Y, Izumi K, Machioka K, Iwamoto H, Naito R, Makino T, Kadomoto S, Natsagdorj A, Kadono Y, Keller ET, Zhang J, Mizokami A.
  • Journal Title: Anticancer research Volume: 38 Pages: 2045-2055
  • Peer Reviewed / Open Access
• [Journal Article] Establishment and characterization of two cabazitaxel-resistant prostate cancer cell lines. (2018)
  • Author(s): Machioka K, Izumi K, Kadono Y, Iwamoto H, Naito R, Makino T, Kadomoto S, Natsagdorj A, Keller ET, Zhang J, Mizokami A
  • Journal Title: Oncotarget Volume: 9 Issue: 22 Pages: 16185-16196
  • DOI: 10.18632/oncotarget.24609
  • Peer Reviewed / Open Access
• [Journal Article] Crosstalk Between Androgen-Sensitive and Androgen-Insensitive Prostate Cancer Cells (2018)
  • Author(s): YUTA TAKEZAWA, KOUJI IZUMI, KAZUAKI MACHIOKA, HIROAKI IWAMOTO, RENATO NAITO, TOMOYUKI MAKINO, SUGURU KADOMOTO, ARIUNBOLD NATSAGDORJ, YOSHIFUMI KADONO, EVAN T. KELLER, JIAN ZHANG and ATSUSHI MIZOKAMI
  • Journal Title: Anticancer Research Volume: 38 Pages: 2045-2055
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Establishment and characterization of two cabazitaxel-resistant prostate cancer cell lines (2018)
  • Author(s): Kazuaki Machioka, 1Kouji Izumi, 1Yoshifumi Kadono, 1Hiroaki Iwamoto, 1Renato Naito, 1Tomoyuki Makino, 1Suguru Kadomoto, 1Ariunbold Natsagdorj, 2Evan T. Keller, 3Jian Zhang, and 1Atsushi Mizokami
  • Journal Title: Oncotarget Volume: 9 Pages: 16185-16196
  • Peer Reviewed / Open Access / Int'l Joint Research