Drug development targeting metabolic vulnerability associated with SUCLA2 loss

• Project/Area Number: 19K22555
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: Kanazawa University
• Principal Investigator: Takahashi Chiaki 金沢大学, がん進展制御研究所, 教授 (50283619)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2019: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: がん / 前立腺がん / 代謝 / RB1 / SUCLA2 / チモキノン / 治療 / RB / 創薬

Outline of Research at the Start

RBがん抑制遺伝子は、悪性化した前立腺がんの15～20%においてホモ欠失する。我々は、RBの近傍に位置するSUCLA2という遺伝子がこの欠失に高頻度に巻き込まれることを見出した。SUCLA2は重要な代謝酵素をコードしており、この欠失は、がん細胞になんらかの代謝脆弱性を与えるはずである。本研究では、SUCLA2欠失と合成致死性になる遺伝子を探索する。また、SUCLA2欠失細胞を特異的に傷害する化合物を探索する。がんに特異的な代謝遺伝子ゲノム異常を標的とすれば、スペクトルが絞られ、副作用の無いがん治療薬の開発が可能になるかも知れない。

Outline of Final Research Achievements

We discovered that the SUCLA2 gene located in the vicinity of RB1 is collaterally deleted together with RB1 with 10-30% prevalence in advanced prostate cancer. SUCLA2 gene encodes a metabolic enzyme constituting the a-subunit of the succinate CoA ligase heterodimer that reversibly converts succinyl CoA to succinate. We further found that SUCLA2 deficiency generates a certain metabolic vulnerability thus could be an important Achilles tendon in the treatment strategy. We screened chemical libraries to find compounds that specifically kill SUCLA2-deficient cells and obtained several hits. In this research, we focused on one of them thymoquinone. We performed structural development and molecular target identification. We also aimed to develop a diagnostic method for SUCLA2 gene deletion and search for biomarkers.

Academic Significance and Societal Importance of the Research Achievements

進行前立腺がんの治療には抗アンドロゲン薬等が用いられるが、その効果は限定的であり、新しい治療法の開発が待望されている。進行前立腺がん多くにおいてSUCLA2のホモ型ないしヘテロ型欠失が存在し、しかも、これを治療標的にできるという我々の発見は、前立腺がん治療の新しいパラダイムを拓いたとともに、がん特異的な代謝異常を標的としたがん治療が可能であることを示唆した。これは多くの種類のがん治療に応用することのできる概念・方法論である。

Research Products

• [Int'l Joint Research] 南オーストラリア大学(オーストラリア)
• [Int'l Joint Research] 南オーストラリア大学(オーストラリア)
• [Int'l Joint Research] サンクトペテルブルグ医科大学(ロシア連邦)
• [Int'l Joint Research] ダナファーバーがん研究所(米国)
• [Journal Article] Essential role of autophagy in protecting neonatal haematopoietic stem cells from oxidative stress in a p62-independent manner (2021)
  • Author(s): Nomura Naho、Ito Chiaki、Ooshio Takako、Tadokoro Yuko、Kohno Susumu、Ueno Masaya、Kobayashi Masahiko、Kasahara Atsuko、Takase Yusuke、Kurayoshi Kenta、Si Sha、Takahashi Chiaki、Komatsu Masaaki、Yanagawa Toru、Hirao Atsushi
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 1666-1679
  • DOI: 10.1038/s41598-021-81076-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Synthetic inhibitors of CDK4/6 activities and tumor suppression: a preface to the special issue. (2021)
  • Author(s): Takahashi C and Kato J.
  • Journal Title: Onco Volume: 1 Issue: 1 Pages: 1-2
  • DOI: 10.3390/onco1010001
  • Peer Reviewed
• [Journal Article] Peripubertal high‐fat diet promotes c‐Myc stabilization in mammary gland epithelium (2020)
  • Author(s): Kulathunga Nilakshi、Kohno Susumu、Linn Paing、Nishimoto Yuuki、Horike Shin‐ichi、Zaraiskii Mikhail I.、Kumar Sharad、Muranaka Hayato、Takahashi Chiaki
  • Journal Title: Cancer Science Volume: 111 Issue: 7 Pages: 2336-2348
  • DOI: 10.1111/cas.14492
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pharmacologically targetable vulnerability in prostate cancer carrying RB1-SUCLA2 deletion (2020)
  • Author(s): Kohno Susumu、Linn Paing、Nagatani Naoko、Watanabe Yoshihiro、Kumar Sharad、Soga Tomoyoshi、Takahashi Chiaki
  • Journal Title: Oncogene Volume: 39 Issue: 34 Pages: 5690-5707
  • DOI: 10.1038/s41388-020-1381-6
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] mDia1/3-dependent actin polymerization spatiotemporally controls LAT phosphorylation by Zap70 at the immune synapse. (2020)
  • Author(s): Thumkeo, D., Katsura, Y., Nishimura, Y., Kanchanawong, P., Tohyama, K., Ishizaki, T., Kitajima, S., Takahashi, C., Hirata, T., Watanabe, N., Krummel, M. F., and Narumiya, S.
  • Journal Title: Sci. Adv. Volume: 6 Issue: 1 Pages: 2432-2432
  • DOI: 10.1126/sciadv.aay2432
  • NAID: 120006777011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regucalcin enhances adipocyte differentiation and attenuates inflammation in 3T3‐L1 cells (2020)
  • Author(s): Murata Tomiyasu、Yamaguchi Masayoshi、Kohno Susumu、Takahashi Chiaki、Risa Watanabe、Hatori Kanna、Hikita Kiyomi、Kaneda Norio
  • Journal Title: FEBS Open Bio Volume: 10 Issue: 10 Pages: 1967-1984
  • DOI: 10.1002/2211-5463.12947
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Retinoblastoma Inactivation Induces a Protumoral Microenvironment via Enhanced CCL2 Secretion (2019)
  • Author(s): Li Fengkai、Kitajima Shunsuke、Kohno Susumu、Yoshida Akiyo、Tange Shoichiro、Sasaki Soichiro、Okada Nobuhiro、Nishimoto Yuuki、Muranaka Hayato、Nagatani Naoko、Suzuki Misa、Masuda Sayuri、Thai Tran C.、Nishiuchi Takumi、Tanaka Tomoaki、Barbie David A.、Mukaida Naofumi、Takahashi Chiaki
  • Journal Title: Cancer Research Volume: 79 Issue: 15 Pages: 3903-3915
  • DOI: 10.1158/0008-5472.can-18-3604
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cancer stem-like properties and gefitinib resistance are dependent on purine synthetic metabolism mediated by the mitochondrial enzyme MTHFD2 (2018)
  • Author(s): Nishimura Tatsunori、Nakata Asuka、Chen Xiaoxi、Nishi Kurumi、Meguro-Horike Makiko、Sasaki Soichiro、Kita Kenji、Horike Shin-ichi、Saitoh Kaori、Kato Keiko、Igarashi Kaori、Murayama Takahiko、Kohno Susumu、Takahashi Chiaki、Mukaida Naofumi、Yano Seiji、Soga Tomoyoshi、Tojo Arinobu、Gotoh Noriko
  • Journal Title: Oncogene Volume: 38 Issue: 14 Pages: 2464-2481
  • DOI: 10.1038/s41388-018-0589-1
  • Peer Reviewed / Open Access
• [Presentation] RB1-SUCLA2欠損による代謝脆弱性を標的とした前立腺がん治療法の探索 (2020)
  • Author(s): 河野晋, Paing Linn, 曽我朋義, 高橋智聡
  • Organizer: 第79回日本癌学会学術総会
  • Int'l Joint Research
• [Presentation] 進行前立腺がんにおけるRB1-SUCLA2遺伝子欠失を標的とする新規治療 (2020)
  • Author(s): 高橋智聡, Paing Linn, 曽我朋義, 河野晋
  • Organizer: 第58回日本癌治療学会学術総会
  • Int'l Joint Research
• [Presentation] RB欠損に付随する代謝遺伝子欠損を標的とした治療法の探索 (2019)
  • Author(s): 河野晋, Paing Linn, 曽我朋義, 髙橋智聡
  • Organizer: 第7回がんと代謝研究会
• [Presentation] Therapeutic Vulnerability of RB1-SUCLA2 co-deleted Prostate Cancer (2019)
  • Author(s): Linn P, Kohno S and Takahashi C
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Pharmacologically targetable vulnerability in prostate adenocarcinoma carrying RB1-SUCLA2 deletion (2019)
  • Author(s): Linn P, Kohno S and Takahashi C
  • Organizer: 第42回日本分子生物学会年会
• [Remarks] 高橋智聡研究室HP
  • URL: https://omb.w3.kanazawa-u.ac.jp
• [Remarks] 金沢大学がん進展制御研究所HP
  • URL: http://ganken.cri.kanazawa-u.ac.jp
• [Remarks] 高橋智聡研究室ホームページ
  • URL: https://omb.w3.kanazawa-u.ac.jp/index.html
• [Remarks] 金沢大学がん進展制御研究所ホームページ
  • URL: http://ganken.cri.kanazawa-u.ac.jp
• [Patent(Industrial Property Rights)] ＲＢ１陽性癌の治療用医薬組成物及びキット (2020)
  • Inventor(s): 高橋智聡、河野晋、盛金丹
  • Industrial Property Rights Holder: 高橋智聡、河野晋、盛金丹
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2020-180429
  • Filing Date: 2020
• [Patent(Industrial Property Rights)] SUCLA2遺伝子欠失前立腺がんを特異的に死滅させる化合物 (2019)
  • Inventor(s): 高橋智聡、河野晋、Paing Linn
  • Industrial Property Rights Holder: 高橋智聡、河野晋、Paing Linn
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-228526
  • Filing Date: 2019