Analysis of renin-angiotensin system in the carcinogenesis of prostate cancer

• Project/Area Number: 19K09695
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Yokohama City University
• Principal Investigator: Uemura Hiroji 横浜市立大学, 附属市民総合医療センター, 准教授 (50244439)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 前立腺癌 / レニン-アンジオテンシン系 / prorenin receptor / AT2レセプターリガンド / PD-L1 / PTEN loss / レニン―アンジオテンシン系 / aPKC / IL6 / がん発生

Outline of Research at the Start

この研究では、前立腺の発癌に関わる遺伝子（aPKC）に対して、動物実験で前立腺発癌予防に影響するレニン・アンジオテンシン系薬剤であるARBあるいはAT2RリガンドのC21が、どのように作用して前立腺の発癌を抑制するかをin vitroおよびin vivoの実験系で調べる。
AT1R やAT2R のようなGPCRは体内の多くの細胞に存在し、生理とホメオスタシスで重要な役割を担い、治療薬創製の標的になっている。今後、前立腺癌に関わる新たなGPCRが、この研究から発展して見つかることになれば、前立腺癌の発生や進展に関わる治療薬の創薬につながる可能性がある。

Outline of Final Research Achievements

The Western blot and RT-PCR resulted that PD-L1 expression was decrease by C21 treatment in prostate cancer cells. On the other hand, PD-L1 expression was increased by ARB in LNCaP and PC3 cells. These results suggest that ARB may induce the function of immune check point inhibitors in prostate cancer cells. Next, we examined the influence of prorenin receptor and AT1 receptors on androgen receptor. We performed western blot and RT-PCR to examine the (p)RR expression in prostate cancer cells. Furthermore, we investigated the change of (p)RR by DHT treatment in LNCaP cells, which showed the increasing of (p)RR. Recently, cell membrane AR (mAR) has been recognized in prostate cancer cells. We will investigate the relationship between (p)RR and mAR.

Academic Significance and Societal Importance of the Research Achievements

ARBがPD-L1発現を亢進することは、免疫チェックポイント阻害剤（ICI）の有効性を誘導する可能性がある。前立腺癌はMSI-Hの発現が高くなく、ICIが効きにくいといわれている。したがって、ARBによるPD-L1発現亢進は、抗腫瘍効果を有するICIの適応を高める可能性があり、去勢抵抗性前立腺癌（CRPC）の治療に有用であると考えられる。CRPC治療は、ホルモン剤や化学療法などの併用だけでなく、ICIの併用が考慮されている。今後、ICIとの併用が現実的になる場合、ARB併用の抗腫瘍効果が期待できる。また、(p)RR発現との関係を調べていくことは、新たな前立腺癌治療の開発に繋がる。

Research Products

• [Journal Article] Apalutamide and Overall Survival in Prostate Cancer. (2021)
  • Author(s): Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, De Porre P, Smith AA, Brookman-May SD, Li S, Zhang K, Rooney B, Lopez-Gitlitz A, Small EJ.
  • Journal Title: Eur Urol. Volume: 79 Issue: 1 Pages: 150-158
  • DOI: 10.1016/j.eururo.2020.08.011
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Apalutamide for metastatic, castration-sensitive prostate cancer in the Japanese population: A subgroup analysis of the randomized, double-blind, placebo-controlled phase 3 TITAN study. (2021)
  • Author(s): Uemura H, Arai G, Uemura H, Suzuki H, Iijima K, Nishimura K, Fujii K, Hatayama T, Aoyama J, Deprince K, Lopez-Gitlitz A, McCarthy S, Larsen JS, Li J, Chi KN.
  • Journal Title: Int J Urol. Volume: 28 Issue: 3 Pages: 280-287
  • DOI: 10.1111/iju.14447
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Unmet needs in non-metastatic castration-resistant prostate cancer from the Japanese patient perspective: a discrete choice experiment. (2021)
  • Author(s): Uemura H, Matsushima H, Yokomizo A, Kobayashi K, Arai G, Satoh T, Grillo V, Chen Y, Singh S, Ledesma DA.
  • Journal Title: BMJ Open Volume: 16 Issue: 8 Pages: e052471-e052471
  • DOI: 10.1136/bmjopen-2021-052471
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A novel prediction model for the completion of six cycles of radium-223 treatment and survival in patients with metastatic castration-resistant prostate cancer. (2021)
  • Author(s): Miyoshi Y, Tsutsumi S, Yasui M, Kawahara T, Uemura KI, Hayashi N, Nozawa M, Yoshimura K, Uemura H, Uemura H.
  • Journal Title: World J Urol. Volume: 39 Issue: 9 Pages: 3323-3328
  • DOI: 10.1007/s00345-021-03639-z
  • Peer Reviewed
• [Journal Article] fficacy and safety of darolutamide in Japanese patients with nonmetastatic castration-resistant prostate cancer: a sub-group analysis of the phase III ARAMIS trial. (2021)
  • Author(s): Uemura H, Matsushima H, Kobayashi K, Mizusawa H, Nishimatsu H, Fizazi K, Smith M, Shore N, Tammela T, Tabata KI, Matsubara N, Iinuma M, Uemura H, Oya M, Momma T, Kawakita M, Fukasawa S, Kobayashi T, Kuss I, Le Berre MA, Snapir A, Sarapohja T, Suzuki K.
  • Journal Title: Int J Clin Oncol. Volume: 26 Issue: 3 Pages: 578-590
  • DOI: 10.1007/s10147-020-01824-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The impact of smoking on male lower urinary tract symptoms (LUTS). (2020)
  • Author(s): Kawahara T, Ito H, Uemura H.
  • Journal Title: Sci Rep Volume: 10 Issue: 1 Pages: 20212-20212
  • DOI: 10.1038/s41598-020-77223-7
  • Peer Reviewed / Open Access
• [Journal Article] Skin rash following Administration of Apalutamide in Japanese patients with Advanced Prostate Cancer: an integrated analysis of the phase 3 SPARTAN and TITAN studies and a phase 1 open-label study. (2020)
  • Author(s): Uemura H, Koroki Y, Iwaki Y, Imanaka K, Kambara T, Lopez-Gitlitz A, Smith A, Uemura H.
  • Journal Title: BMC Urol. Volume: 20 Issue: 1 Pages: 139-139
  • DOI: 10.1186/s12894-020-00689-0
  • Peer Reviewed
• [Journal Article] Efficacy and Safety Exposure-Response Relationships of Apalutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer. (2020)
  • Author(s): Perez-Ruixo C, Ackaert O, Ouellet D, Chien C, Uemura H, Olmos D, Mainwaring P, Lee JY, Yu MK, Perez-Ruixo JJ, Smith MR, Small EJ
  • Journal Title: Clin Cancer Res. Volume: 26 Issue: 17 Pages: 4460-4467
  • DOI: 10.1158/1078-0432.ccr-20-1041
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Efficacy and safety of apalutamide in Japanese patients with nonmetastatic castration-resistant prostate cancer: a subgroup analysis of a randomized, double-blind, placebo-controlled, Phase-3 study. (2020)
  • Author(s): Uemura H, Satoh T, Tsumura H, Arai G, Imanaka K, Shibayama K, Fujii K, Rooney B, Lopez-Gitlitz A, Espina B, Perez-Ruixo C, Small EJ, Smith M.
  • Journal Title: Prostate Int. Volume: 8 Issue: 4 Pages: 190-197
  • DOI: 10.1016/j.prnil.2020.05.002
  • Peer Reviewed
• [Journal Article] Matching-Adjusted Indirect Comparison of Health-Related Quality of Life and Adverse Events of Apalutamide Versus Enzalutamide in Non-Metastatic Castration-Resistant Prostate Cancer. (2020)
  • Author(s): Chowdhury S, Oudard S, Uemura H, Joniau S, Pilon D, Lefebvre P, McQuarrie K, Liu J, Dearden L, Sermon J, Van Sanden S, Diels J, Hadaschik BA.
  • Journal Title: Adv Ther. Volume: 37 Issue: 1 Pages: 512-526
  • DOI: 10.1007/s12325-019-01157-4
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Matching-Adjusted Indirect Comparison of the Efficacy of Apalutamide and Enzalutamide with ADT in the Treatment of Non-Metastatic Castration-Resistant Prostate Cancer. (2020)
  • Author(s): Chowdhury S, Oudard S, Uemura H, Joniau S, Pilon D, Ladouceur M, Behl AS, Liu J, Dearden L, Sermon J, Van Sanden S, Diels J, Hadaschik BA.
  • Journal Title: Adv Ther. Volume: 37 Issue: 1 Pages: 501-511
  • DOI: 10.1007/s12325-019-01156-5
  • Peer Reviewed
• [Journal Article] Matching-Adjusted Indirect Comparison of Health-Related Quality of Life and Adverse Events of Apalutamide Versus Enzalutamide in Non-Metastatic Castration-Resistant Prostate Cancer. (2020)
  • Author(s): （4）Chowdhury S, Oudard S, Uemura H, Joniau S, Pilon D, Lefebvre P, McQuarrie K, Liu J, Dearden L, Sermon J, Van Sanden S, Diels J, Hadaschik BA.
  • Journal Title: Adv Ther Volume: 37 Pages: 512-526
  • Peer Reviewed
• [Journal Article] Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer. (2019)
  • Author(s): （8）Small EJ, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, De Porre P, Smith AA, Zhang K, Lopez-Gitlitz A, Smith MR
  • Journal Title: Ann Onco Volume: 30 Pages: 1813-1820
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Enazlutamide plus androrogen deprivation therapy versus flutamide plus androgen deprivation therapy in men with castration-resistant prostate cancer: AFTERCAB (2021)
  • Author(s): Hiroji Uemura
  • Organizer: ASCO-GU 2021
  • Int'l Joint Research
• [Presentation] 降圧剤のアンジオテンシン受容体ブロッカー（ARB)による前立腺がんの化学予防の可能性． (2021)
  • Author(s): 上村博司
  • Organizer: 日本がん予防学術大会
  • Invited
• [Presentation] 降圧剤のアンジオテンシン受容体ブロッカーによる前立腺がん発生予防の可能性を探る (2021)
  • Author(s): 上村博司
  • Organizer: 第80回日本癌学会学術総会
  • Invited
• [Presentation] 非転移性去勢抵抗性前立腺癌に対するアパルタミドの有効性及び安全性：国際共同第III相ランダム化二重盲検比較SPARTAN試験日本人サブグループ解析最終報告 (2021)
  • Author(s): 上村博司
  • Organizer: 第109回日本泌尿器科学会総会
• [Presentation] リアルワールドにおける転移性去勢抵抗性前立腺癌患者の相同組換え修復遺伝子変異保有率及び予後に関する国内多施設共同観察研究：ZENSHIN Study (2021)
  • Author(s): 上村博司
  • Organizer: 第109回日本泌尿器科学会総会
• [Presentation] Efficacy and problem of abiraterone acetate for metastatic hormone naive; prostate cancer (mHNPC) (2020)
  • Author(s): Hiroji Uemura
  • Organizer: 第58回日本癌治療学会学術集会
  • Invited
• [Presentation] Final survival results from SPARTAN, a Phase 3 study of apalutamide vs placebo in patients with non-metastatic prostate cancer (2020)
  • Author(s): Hiroji Uemura
  • Organizer: 第58回日本癌治療学会学術集会
  • Invited
• [Presentation] 非転移性去勢抵抗性前立腺癌における日本人患者のアンメットニーズに関する研究 (2020)
  • Author(s): 上村博司
  • Organizer: 第108回日本泌尿器科学会総会
• [Presentation] 前立腺癌薬物療法のパラダイムシフト (2020)
  • Author(s): 上村博司
  • Organizer: 第32回日本内分泌外科学会総会
  • Invited
• [Presentation] 日本人の進行性前立腺癌患者においてアパルタミド投与後に見られた皮疹：SPARTAN, TITAN, PCR1008からの考察 (2020)
  • Author(s): 上村博司
  • Organizer: 第108回日本泌尿器科学会総会
• [Presentation] 骨転移を有する去勢抵抗性前立腺癌を対象とした多施設共同前向き観察研究 (2020)
  • Author(s): 上村博司
  • Organizer: 第108回日本泌尿器科学会総会
• [Presentation] A phase 2, open label, multi-arm study of TAS-115 for castration-resistant prostate cancer patients with bone metastases (2019)
  • Author(s): Uemura Hiroji
  • Organizer: ASCO-GU2019
  • Int'l Joint Research
• [Presentation] 泌尿器癌のプレシジョンメディシン (2019)
  • Author(s): 上村博司
  • Organizer: 第107回日本泌尿器科学会総会
  • Invited
• [Presentation] 転移性ホルモン感受性前立腺がんの治療戦略 (2019)
  • Author(s): 上村博司
  • Organizer: 第57回日本癌治療学会