Cancer represents the second major cause of death and morbidity after cardiovascular diseases, with more than 3 Million new cases and 1.7 Million deaths each year (WHO data). While most of the new cancer diagnosis is made in adults, childhood cancers make up less than 1% of all cases diagnosed every year, but the rate has been rising slightly for the past few decades (American Cancer Society). Cancer in children is relatively rare, yet it is the leading cause of death by disease in developed countries. About 3% of childhood cancers are represented by primary bone tumors, of which 2 main types have been described: Osteosarcoma and Ewing sarcoma. While osteosarcoma is the most common type in teens, Ewing sarcoma represents 1% of all childhood cancers (incidence approximately 3 cases/million/year). However, given its aggressiveness, while the current 5-years survival rate for young patients with localized ES is about 70%, this prognosis value drops to 15-30% for patients with metastatic tumors at diagnosis. Chemotherapy and radiotherapy have drastically reduced the lethality of leukemia and lymphoma, however, they have only slightly improved sarcomas outcome in the past 30 years, and Ewing sarcoma treatment is still only based on the use of generic chemo agents such as doxorubicin, vincristine, cyclophosphamide, and dactinomycin.
In many different forms of sarcoma, the initial oncogenic event is a balanced chromosomal translocation originating a chimeric oncoprotein. Even though much is known regarding the oncogenic functions of different chimeras, the success rate at which this advanced knowledge has been translated into effective therapies is pitifully low. Chimeric oncoproteins are exclusive hallmarks of tumor cells and should represent the most valuable therapeutic target to identify novel precision's medicine approaches to flank and support the current chemotherapy protocols against Ewing sarcoma.
The identification of novel drugs through preclinical studies is however heavily influenced by the model enrolled in the studies. Faithfull preclinical models able to recapitulate most of the biological characteristics of the human disease should always be employed to improve the efficiency of the preclinical study and to decrease the percentage of subsequently failing clinical tests. Currently, however, no faithful preclinical models of Ewing Sarcoma are available. Therefore, main objectives of this study will be the development of reliable preclinical models able to faithfully recapitulate Ewing sarcomagenetic process to study the pathobiology basis of the disease (Work Package 1) and the identification of molecular mechanisms whose pharmacological tuning will tear down Ewing sarcoma lethality (Work Package 2).
Thanks to the work carried out in this project, our understanding of Ewing sarcoma’s pathobiology has further improved. Indeed, while previous scientific knowledge suggested that Ewing sarcoma development is driven uniquely by specific chromosomal translocations, results from this projects strongly support the idea that Ewing oncochimeras are not sufficient to induce cell transformation, and other currently unknown events are required to unleash their full transforming potential.
