Background of the Project
Osteosarcoma is the most common primary bone tumor affecting children and young adults (incidence peak between 15 and 19 years old). The current treatment for this cancer involves tumor removal, combined with polychemotherapy. Unfortunately, a lack of response to antitumor drugs is often observed, promoting the development of metastases and leading to patient death. Apart from a few classical mechanisms, very little is known about the chemoresistance of osteosarcomas.
Objective of the Study
To improve therapeutic management, Professor Ory’s team has chosen to explore the possible epigenetic origin of therapeutic resistance to chemotherapy agents used in osteosarcoma treatment.
About the Project
Professor Ory’s team has previously demonstrated the involvement of bromodomain proteins (epigenetic factors regulating the expression of many genes) in the survival of osteosarcomas. These proteins are capable of activating certain genes that may play a role in tumor progression and chemotherapy resistance. Recent studies indicate that these proteins bind to regulatory regions of DNA (called “Super-Enhancers”), which in turn activate genes responsible for relapses.
To identify genes involved in the development of chemoresistance, Professor Ory’s team studied in detail, at the cellular level, the activation of specific regions of our DNA (Super-Enhancers) between osteosarcoma cells sensitive to doxorubicin and others resistant to this commonly used chemotherapy treatment. The “Single-Cell” approach, which allows the study of all genes expressed in a single cell, was indispensable for evaluating the tumor’s innate and acquired potential for resistance to doxorubicin. The ultimate goal was to identify new therapeutic targets in the hope of developing adapted protocols to improve patient prognosis.
Key Findings
- Many genetic (epigenetic and transcriptomic) modifications have been identified in doxorubicin-resistant cells.
- “Super-Enhancer” regions have been identified as highly active in doxorubicin-resistant osteosarcoma cells and notably enable the expression of ABCB1 and ABCB4. ABCB1 is strongly present in resistant cells exposed to high doses of chemotherapy. These proteins are located on the membranes of tumor cells and prevent the entry of many chemotherapy agents, including doxorubicin. Unfortunately, these proteins are frequently found in the mechanisms employed by cancer cells to evade treatments.
- Deactivating these “Super Enhancer” regions, abolishing the expression of ABCB1 and 4, once again renders tumor cells more sensitive to doxorubicin.
- An article is in preparation and will soon be submitted to an international journal.
Conclusion: Professor Ory’s team demonstrates that targeting Super-Enhancer genetic regions is a very promising avenue to restore the effectiveness of chemotherapy for osteosarcoma treatment and possibly other cancers.
Project Summary
- Promoter: University of Nantes
- Principal Investigator: Professor Benjamin Ory
- Program Duration: 2020-2024
- Funding from Imagine for Margo: €45,000
This project was funded through donations collected during the Rallye du Cœur, organized in Nantes in 2021, and was selected by the SFCE as part of its 2020 call for projects.
