| Project/Area Number |
19K07765
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 50020:Tumor diagnostics and therapeutics-related
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| Research Institution | Okinawa Institute of Science and Technology Graduate University |
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Principal Investigator |
Vares Guillaume 沖縄科学技術大学院大学, 細胞シグナルユニット, 客員研究員 (10415432)
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| Project Period (FY) |
2019-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | chondrosarcoma / radiation therapy / particle therapy / cancer stem cells / cancer / micro-RNA / radiotherapy / PARP inhibitors / microRNA / carbon-ion therapy |
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| Outline of Research at the Start |
Chondrosarcomas (CS) are chemo- and radiation-resistant tumors with no established molecular therapy. I will evaluate the ability of combination therapies to efficiently target CS, using in vitro human 3D culture models of CS and mouse xenografts. Several molecular strategies will be investigated: HR-modulating micro-RNA mimics and PARP inhibitors, micro-RNA mimics targeting radioresistance and CSC maintenance, mTOR pathway inhibitors, in combination with carbon-ion therapy at the HIMAC medical accelerator.
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| Outline of Final Research Achievements |
High-grade chondrosarcomas are chemo- and radio-resistant cartilage-forming tumors of bone that often relapse and metastase. Thus, new therapeutic strategies are urgently needed. In this study, we showed that high-grade chondrosarcoma cells contain a population of radioresistant cancer stem cells that can be targeted by a combination of carbon-ion therapy, miR-34 mimic administration and/or rapamycin treatment that triggers FOXO3 and miR-34 over-expression. mTOR inhibition by rapamycin triggered FOXO3 and miR-34, leading to KLF4 repression. Altogether, our results suggest that mTOR inhibition by rapamycin supplemented with miR-34 mimic treatment may be able to overcome CSC-associated radioresistance in chondrosarcoma during carbon-ion therapy. Combination treatments might also improve the effectiveness of carbon-ion therapies at lower doses, decrease risks of relapse and metastasis, and better preserve surrounding normal tissues against non-targeted effects.
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| Academic Significance and Societal Importance of the Research Achievements |
Our results suggest that combination approaches might be effective for hard-to-treat, resistant tumors, by targeting treatment-resistant subpopulations of cancer stem cells. This might lead to better outcomes with lower risks of relapse and metastasis.
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