Ricerc@Sapienza

Rhabdomyosarcoma (RMS) is the most commonly diagnosed malignant soft tissue tumour in children and adolescents. Patients with metastatic or recurrent disease have a poor clinical outcome with a 5-year overall survival of about 30%. So, the identification of innovative therapies against advanced RMS represents an urgent clinical need. Aberrant epigenetic landscape is a hallmark of different malignancies due to alterations in the enzymes that modify DNA methylation and histone marks (acetylation/methylation). As a result, a number of therapeutic compounds against proteins involved in epigenetic modifications are regarded as promising anticancer epi-drugs. In this project, we plan to evaluate the antitumour activity in RMS preclinical models of OTX015, a bromodomain and extra terminal (BET) inhibitor, as well as of CPI-1205, targeting the histone methyltransferases EZH2, both of which have recently moved into phase I clinical trials for different haematological and solid tumours. Firstly, we will analyse the biological effects of these two drugs, as single agents or in combination, in alveolar and embryonal RMS cell lines, focusing on proliferation, survival, migration, DNA damage and cancer stem cell formation. We will also assess in vitro whether OTX015 and/or CPI-1205 treatments are able to synergize with ionizing radiations, a conventional therapeutic tool widely used in RMS patients, in order to understand if epigenetic reprogramming might be a useful approach to enhance selective cytotoxicity against RMS cells and to overcome possible radioresistance mechanisms. These preclinical findings on BET and EZH2 inhibitors should shed further light on RMS development and could have the potential to be translated into a more efficient and less toxic treatment for RMS patients.