Synthetic lethality-based identification of drug-sensitive genome profiles
| Project/Area Number |
16H04716
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Tumor therapeutics
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| Research Institution | Japanese Foundation for Cancer Research |
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Principal Investigator |
Seimiya Hiroyuki 公益財団法人がん研究会, がん化学療法センター 分子生物治療研究部, 部長 (50280623)
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| Research Collaborator |
FUJIWARA chiaki
SUGIMOTO yoshikazu
MASHIMA tetsuo
MIZUTANI anna
OKAMOTO keiji
TANAKA noritaka
MURAMATSU yukiko
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2017: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2016: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
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| Keywords | 合成致死 / 分子標的治療 / shRNAライブラリー / スクリーニング / ポリ(ADP-リボシル)化 / がん / タンキラーゼ / 効果予測バイオマーカー / ポリ(ADP-リボシル)化酵素 |
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| Outline of Final Research Achievements |
Employing a functional genomic screening with DECIPHER barcode short hairpin RNA libraries, we identified a gene X, which exhibited synthetic lethality with inhibitors for the poly(ADP-ribose) polymerase called tankyrase. While tankyrase inhibitors downregulate beta-catenin signaling and block proliferation of APC-mutated colorectal cancer cells, we found that depletion of gene X enhances the anticancer effects of tankyrase inhibitors in a beta-catenin-independent manner.
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| Academic Significance and Societal Importance of the Research Achievements |
我が国では年間37万人以上の人ががんで死亡している。治癒切除不能な再発・転移がんの根治薬物療法は未確立であり、新たな創薬シーズとしてタンキラーゼ阻害剤の開発・提供が切望されている。合成致死の概念は選択的で効果的な薬物療法に有用である。本研究ではじめて同定されたタンキラーゼ阻害剤の合成致死因子は、阻害剤の適用がふさわしいがん患者の予測法や、より効果的な併用薬物療法の開発に役立つものと期待される。
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Report
(4 results)
Research Products
(43 results)
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[Journal Article] RK-287107, a potent and specific tankyrase inhibitor, blocks colorectal cancer cell growth in a preclinical model.2018
Author(s)
Mizutani A, Yashiroda Y, Muramatsu Y, Yoshisa H, Chikada T, Tsumura T, Okue M, Shirai F, Fukami T, Yoshida M, Seimiya H.
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Journal Title
Cancer Science
Volume: 109
Issue: 12
Pages: 4003-4014
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Tankyrase-Binding Protein TNKS1BP1 Regulates Actin Cytoskeleton Rearrangement and Cancer Cell Invasion.2017
Author(s)
Ohishi T, Yoshida H, Katori M, Migita T, Muramatsu Y, Miyake M, Ishikawa Y, Saiura A, Iemura SI, Natsume T, Seimiya H.
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Journal Title
Cancer Res.
Volume: 77
Issue: 9
Pages: 2328-2338
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] APC mutations as a predictive biomarker for sensitivity to tankyrase inhibitors in colorectal cancer.2017
Author(s)
Noritaka Tanaka, Tetsuo Mashima, Anna Mizutani, Ayana Sato, Aki Aoyama, Bo Gong, Haruka Yoshida, Yukiko Muramatsu, Kento Nakata, Masaaki Matsuura, Ryohei Katayama, Satoshi Nagayama, Naoya Fujita, Yoshikazu Sugimoto, Hiroyuki Seimiya
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Journal Title
Mol. Cancer Ther.
Volume: 16
Issue: 4
Pages: 739-751
DOI
Related Report
Peer Reviewed / Open Access
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