2021 Fiscal Year Final Research Report
Molecular mechanism of resistance to tyrosine kinase receptor in soft tissue sarcoma
Project/Area Number |
17K08730
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Human pathology
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Research Institution | Juntendo University |
Principal Investigator |
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Co-Investigator(Kenkyū-buntansha) |
末原 義之 順天堂大学, 医学部, 客員教授 (70509405)
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Project Period (FY) |
2017-04-01 – 2022-03-31
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Keywords | sarcoma / fusion gene / molecular target therapy |
Outline of Final Research Achievements |
We found a leiomyosarcoma of soft tissue with ROS1 fusion and a leiomyosarcoma of bone with NTRK3 fusion by the combination of immunohistochemistry and imbalanced gene expression assay using RNA. Gene expression profiles were compared between sarcoma samples treated by multi-kinase inhibitor, pazopanib. Pazopanib targets including PDGFRA, PDGFRB, vascular endothelial growth factor receptor (VEGFR)1-3, and stem cell factor receptor (KIT). The mRNA expression of GLI1 and CDK4 was significantly higher in patient's sarcoma sample showing complete response (CR) to pazopanib. Furthermore, the amplification of receptor tyrosine kinase genes such as PDGFRA and VEGFRs was not observed in a patient with CR and the presence of amplification of these genes was closely associated with poor response.
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Free Research Field |
病理学
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Academic Significance and Societal Importance of the Research Achievements |
骨軟部肉腫ではこれまでに融合遺伝子腫瘍が存在することはわかっていたが、肺腺癌のような直接の分子治療標的となるようなものはなく、それゆえこれまで治療に難渋していたが、今回の研究成果により骨軟部肉腫においても有効な治療標的となりうる新規の融合遺伝子が発見され、今後も探索の方法を工夫することにより、これまで思っていた以上の頻度で肉腫においても同様の遺伝子異常が発見される可能性があるという意味で大きな成果である。また、これらの治療には治療抵抗性・耐性の問題が切り離せないが、それらに影響を与える遺伝子異常を見つけられたことで、臨床的な治療戦略にも貢献すると考えらえる。
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