Combination therapies for chondrosarcoma

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K07765
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Okinawa Institute of Science and Technology Graduate University
• 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)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: chondrosarcoma / radiation therapy / particle therapy / cancer stem cells / cancer / micro-RNA

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.

Free Research Field

Radiation oncology

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.