Periodic Reporting for period 1 - EwiSarc (A novel in vivo platform to study and target undruggable Ewing onco-chimera.)
Okres sprawozdawczy: 2017-05-01 do 2019-04-30
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.
To induce the expression of Ewing oncoproteins in the isolated mesenchymal stem cells, we have transduced the latter with the viral particles described above. However, integration of the viral genome in the host genome, and consequent expression of the oncoproteins, caused the death of the cells. This unpredicted result suggests that the expression of Ewing oncoproteins is itself toxic for the hosting mesenchymal stem cells and not sufficient to transform them in tumor cells, and that other currently unknown mechanisms are required to induce full cell transformation. Therefore, given our results, we temporarily focused our project on the identification of those molecular events/altered pathways that are required to support Ewing oncochimeras promoting the sarcomagenetic process. Given the massive establishment and optimization work required to develop the preclinical models of Ewing sarcoma and the unforeseen obtained results, two years project were unfortunately not sufficient to complete all the estimated objectives. However, I will continue to work with the Host laboratory on the project towards the overall objectives.
Equally important, this fellowship allowed me to resume my scientific career after two maternity leaves, and to acquire technical skills and scientific knowledge in oncology field that will be of fundamental importance to progress towards more independent positions.
Several outreach activities allowed me also to illustrate and explain the project to the non-scientific community. I have indeed participated to “la Notte del Ricercatore” at the Museum of Science of Trento (MUSE), to the TYSC (Trentino Young Scientist Challenge) initiative, organized for middle school students, and an article has been published on the local magazine L’Adige7 on my research activities.
Ewing Sarcoma is an aggressive type of bone cancer with poor prognosis, and current therapeutic protocols only rely on the use of generic chemo-agents. To develop novel and precise therapeutic strategies, preclinical screenings need to be performed on reliable models of the disease, which are currently missing. Therefore, thanks to this project we can develop faithful preclinical models of Ewing Sarcoma which can be used by the scientific community not only to better understand the biology of the disease, but also to identify novel promising therapeutic strategies which could both potentiate the efficacy of current clinical protocols and decrease the morbidity associated with the aggressive chemotherapy regimen currently used.