Pediatric Sarcomas
Ewing sarcoma is the second most common malignant bone tumor after osteosarcoma in adolescents and young adults. Ewing sarcoma affects approximately 80 to 100 new patients per year in France. The majority of cases (70%) occur in young people aged 5 to 25 years. However, these tumors can be diagnosed before the age of 5 and after the age of 30.
The majority of Ewing sarcomas develop in bone, but 15% can develop independently of bone.
About the Project
Ewing sarcoma and desmoplastic small round cell tumors are two rare but aggressive tumors mainly affecting children and young adults. The current treatment for these tumors relies on chemotherapy, radiotherapy, and surgery. Unfortunately, relapses are almost systematic when surgery fails to remove the entire tumor, and little therapeutic progress has been made for these two diseases in recent years.
However, the event that triggers these two sarcomas is well known and has been extensively studied: it involves the abnormal joining of two chromosomes, resulting in the formation of an abnormal protein (EWS-FLI1 for Ewing sarcoma and EWS-WT1 for desmoplastic small round cell tumors). The development of the disease is entirely dependent on this abnormal protein: when cancer cells are prevented from producing the protein, either by genetic manipulation, they die or cease to proliferate.
This project aims to identify new therapeutic approaches for Ewing sarcoma and desmoplastic small round cell tumors by seeking drugs that can either prevent the production of the abnormal protein or promote its degradation within the cell. To achieve this, the team proceeded with the following steps:
- Create a “tagged” protein, i.e., fluorescent and whose quantity can be measured through the measurement of its fluorescence intensity.
- Evaluate, among more than 1500 drugs, which ones can reduce the fluorescence of the cells: thus identifying drugs capable of either preventing the production of the abnormal protein or those promoting its degradation by the cell.
- Study the mechanism by which the drug acts on the abnormal protein, and evaluate if this drug is capable of killing cancer cells or preventing them from proliferating.
In addition to this laboratory-based project, additional tools, called “models,” have been generated to study these rare sarcomas. Biopsies taken from patients followed at the Institut Curie or Gustave Roussy will be used to develop new cell lines or mouse tumor models that can be used in the future to test drugs. The creation of such models is crucial and essential for future research because there are currently very few models worldwide for Ewing sarcoma, and only two for desmoplastic small round cell tumors.
The direct collaboration between the research teams involved in this project and the clinical teams of each of the institutions involved (Institut Curie, Institut Gustave Roussy), as well as the medical training of the project leaders, will significantly facilitate this transfer to the clinic.
Project Progress:
Characterization and targeting of the EWSWT1 fusion protein (Dr. Sophie Postel-Vinay)
- Creation of a cellular sarcoma model where a fluorescence gene (GFP) has been integrated into the EWSWT1 fusion gene.
- Study of potential drugs (epigenetic or communication pathways) to reduce the production of fusion proteins.
- Testing of bortezomib and oporozomib (2 proteasome pathway inhibitors): no effect.
- Testing of PARP inhibitors (Wnt pathway inhibitors): no direct effect.
- Establishment of a high-throughput drug screening. Among all the molecules tested, 79 show efficacy signals, including PARP and ATR inhibitors.
- Study of the mechanisms of action and interactions of these inhibitors with the fusion protein.
- Xenograft model in NUDE mice (without an immune system) and efficacy testing of talazoparib.
Characterization and targeting of EWSR1-FLI1 (Dr. Olivier Delattre)
- Through the high-throughput screening previously used, HDAC inhibitors and more particularly Quisinostat, Pracinostat (pan-HDCAi), and Romidepsin (specific inhibitor of HDAC1 and 2) induce a decrease in the EWSR1-FLI1 protein.
- Creation of a cellular model, particularly via the CRISPR-Cas9 system, to target the fusion protein and study its role.
- Publication: Upregulation of the Mevalonate Pathway through EWSR1-FLI1/EGR2 Regulatory Axis Confers Ewing Cells Exquisite Sensitivity to Statins.
- Presentation of the project at the AACR 2022 conference.
Project Summary:
- Promoter: Gustave Roussy & Curie Institute
- Principal Investigators: Dr. Sophie Postel-Vinay and Dr. Olivier Delattre
- Program Duration: July 2020 – May 2023
- Treatments Tested: 85
- Countries Involved: France
- Funding from Imagine for Margo: €90,000.
