Establishment of the new modalities for diagnosis and treatment of prostate cancer by focusing on amino acid metabolism reprogramming mechanism

• Project/Area Number: 17K11163
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Fujita Health University (2018-2020); Aichi Medical University (2017)
• Principal Investigator: Sumitomo Makoto 藤田医科大学, 医学部, 教授 (50255535)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 前立腺癌 / 腎細胞癌 / アミノ酸リプログラミング / キヌレニン / TDO / AMACR / アミノ酸トランスポーター / ASCT2 / トリプトファン / IDO-1 / 去勢抵抗性前立腺癌 / オートファジー / 去勢抵抗性 / 予後 / アミノ酸代謝リプログラミング

Outline of Final Research Achievements

In this study, We elucidated special amino acid metabolism reprogramming mechanism in the microenvironment of urologic cancers. We showed that TDO expression in RCC tumor tissues is associated with progression and survival, confirming its potential as a predictive biomarker of primary resistance to immunotherapy in patients with mRCC. In castration-resistant prostate cancer (CRPC) we demonstrated that AMACR inhibition and docetaxel treatment, under androgen deprivation conditions, significantly reduced the proliferation of ARV7 positive cancer cells and decreased the levels of AR and ARV7 expression, possibly via downregulation of heat shock protein 27.

Academic Significance and Societal Importance of the Research Achievements

泌尿器系がん組織内では特異的なアミノ酸の吸収増加や特有のアミノ酸供給のリサイクリング現象が認められ、これらの代謝産物が浸潤・転移に直接関与していることが報告されている。組織内で増加の認められるアミノ酸のプロファイリングによって、それらのアミノ酸を優先的に輸送するトランスポーター候補を比較的容易に選び出すことが可能である。これらの代謝産物や代謝経路を修飾するための方法論を確立することは、特異的な抗腫瘍効果を誘導する理想的な分子標的治療、ひいては個別化治療のストラテジーを提唱することにつながるものと考える。

Research Products

• [Journal Article] Tryptophan 2,3-dioxygenase in tumor cells is associated with resistance to immunotherapy in renal cell carcinoma (2021)
  • Author(s): Sumitomo M, Takahara K, Zennami K, Nagakawa T, Maeda Y, Shiogama K, Yamamoto Y, Muto Y, Nukaya T, Takenaka M, Fukaya K, Ichino M, Sasaki H, Saito K, Shiroki R.
  • Journal Title: Cancer Sci Volume: 112 Issue: 3 Pages: 1038-1047
  • DOI: 10.1111/cas.14797
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Combined α-methylacyl-CoA racemase inhibition and docetaxel treatment reduce cell proliferation and decrease expression of heat shock protein 27 in androgen receptor-variant-7?positive prostate cancer cells (2021)
  • Author(s): Yoshizawa Atsuhiko、Takahara Kiyoshi、Saruta Masanobu、Zennami Kenji、Nukaya Takuhisa、Fukaya Kosuke、Ichino Manabu、Fukami Naohiko、Niimi Atsuko、Sasaki Hitomi、Kusaka Mamoru、Suzuki Motoshi、Sumitomo Makoto、Shiroki Ryoichi
  • Journal Title: Prostate International Volume: 9 Issue: 1 Pages: 18-24
  • DOI: 10.1016/j.prnil.2020.07.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Targeting lactate dehydrogenase-A promotes docetaxe-induced cytotoxicity predominantly in castration-resistant prostate cancer cells. (2019)
  • Author(s): Muramatsu H, Sumitomo M, Morinaga S, Kajikawa K, Kobayashi I, Nishikawa G, Kato Y, Watanabe M, Zennami K, Kanao K, Nakamura K, Suzuki S, Yoshikawa K.
  • Journal Title: Oncol Rep. Volume: 42(1) Pages: 224-230
  • DOI: 10.3892/or.2019.7171
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Increased infiltration of CCR4-positive regulatory T cells in prostate cancer tissue is associated with a poor prognosis. (2019)
  • Author(s): Watanabe M, Kanao K, Suzuki S, Muramatsu H, Morinaga S, Kajikawa K, Kobayashi I, Nishikawa G, Kato Y, Zennami K, Nakamura K, Tsuzuki T, Yoshikawa K, Ueda R, Sumitomo M.
  • Journal Title: Prostate Volume: 79(14) Issue: 14 Pages: 1658-1665
  • DOI: 10.1002/pros.23890
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 前立腺癌細胞株に対するdocetaxelとLDH阻害薬による抗腫瘍効果の検討 (2018)
  • Author(s): 村松洋行, 住友 誠, 杉江美穂, 森永慎吾, 小林郁生, 梶川圭史, 西川源也, 加藤義晴, 渡邊將人, 全並賢二, 金尾健人, 中村小源太, 吉川和宏
  • Organizer: 第27回泌尿器科分子・細胞研究会
• [Presentation] Warburg effect in chemosensitivity: Targeting lactate dehydrogenase-A promotes docetacel-induced cytotoxicity in prostate cancer cells (2018)
  • Author(s): Hiroyuki Muramatsu, Makoto Sumitomo, Shingo Morinaga, Masanobu Saito, Miho Sugie, Keishi Kajikawa, Ikuo Kobayashi, Genya Nishikawa, Yoshiharu Kato, Masahito Watanabe, Kent Kanao, Kogenta Nakamura, Kazuhiro Yoshikawa
  • Organizer: EAU annal meeting 2018
• [Presentation] 前立腺癌細胞株に対するLDH阻害薬とdocetaxelによる抗腫瘍効果の検討 (2017)
  • Author(s): 村松洋行, 住友 誠, 斎藤政信, 杉江美穂, 森永慎吾, 小林郁生, 梶川圭史, 西川源也, 加藤義晴, 渡邊將人, 金尾健人, 中村小源太, 吉川和宏
  • Organizer: 第105回日本泌尿器科学会総会
• [Presentation] Warburg effect in chemosensitivity: Targeting lactate dehydrogenase-A promotes docetacel-induced cytotoxicity in prostate cancer cells (2017)
  • Author(s): Hiroyuki Muramatsu, Makoto Sumitomo, Shingo Morinaga, Masanobu Saito, Miho Sugie, Keishi Kajikawa, Ikuo Kobayashi, Genya Nishikawa, Yoshiharu Kato, Masahito Watanabe, Kent Kanao, Kogenta Nakamura, Kazuhiro Yoshikawa
  • Organizer: AACR annual meeting 2017