2018 Fiscal Year Final Research Report
Screening for alternative transcription initiation of tyrosine kinase genes in bone and soft tissue tumors
| Project/Area Number |
16K15670
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
Orthopaedic surgery
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| Research Institution | Juntendo University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
高阪 真路 国立研究開発法人国立がん研究センター, 研究所, 主任研究員 (00627119)
小林 英介 国立研究開発法人国立がん研究センター, 中央病院, 医長 (40365292)
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| Research Collaborator |
ENDO Makoto
SAITO Tsuyoshi
HAYASHI Takuo
KUBOTA Daisuke
MUKAIHARA Kenta
AKAIKE Keisuke
TANABE Yu
ISHII Midori
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | 骨軟部腫瘍 / 軟部肉腫 / 融合遺伝子 / 遺伝子転写変異体 |
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| Outline of Final Research Achievements |
Soft tissue sarcomas (STSs) are a heterogeneous group of rare malignant tumors. Systemic chemotherapy consisting cytotoxic anticancer agents for STS contributes on improving prognosis of STS treatment. However, advanced STSs have still poor prognosis and effective systemic therapies have not yet been established. Therefore, the identification of novel therapeutic targets and novel effective therapies are required. Receptor tyrosine kinases (RTKs) are being increasingly used as therapeutic targets for a variety of cancers, especially RTK fusion genes. A recent report found that the novel TK transcript initiates from a de novo alternative transcription initiation (ATI) site, especially in ALK. In addition, the TK-ATI has a novel mechanism of oncogene activation in cancer and TK inhibitors could suppress the kinase activity of TK-ATI. Based on these background, we conducted TK screening using NanoString to identify rational therapeutic TK targets including TK-fusions and TK-ATIs in STSs.
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| Free Research Field |
整形外科
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は、難治性かつ「希少がん」である骨軟部腫瘍の生命予後改善の要となる新規分子治療標的の開発を行った。具体的には、他癌種において発見されているdriver-oncogeneである転写変異体について、骨軟部腫瘍の手術検体を用いて全TK遺伝子の探索を進めた。その方法として独自のNanostringの手法に基づいたTK遺伝子転写変異体・融合遺伝子探索システムを用い、それら同定TK遺伝子転写変異体・融合遺伝子については、骨軟部腫瘍における癌化機能の解明とそのターゲットとなるTK阻害剤奏功性の検証を進め、TK阻害剤の適応拡大を含めた新規分子治療標的の開発を行い、骨軟部腫瘍の予後改善へ貢献を目的とした。
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