Drug development targeting metabolic vulnerability associated with SUCLA2 loss

2020 Fiscal Year Final Research Report

• 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
• Keywords: がん / 前立腺がん / 代謝 / RB1 / SUCLA2 / チモキノン

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.

Free Research Field

分子腫瘍学

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。