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 novel therapeutic agents against RMS represents an urgent clinical need. Aberrant expression of polyadenosine diphosphate-ribose polymerase (PARP) genes has been implicated in the malignant progression of different cancer types, including RMS. This observation suggests that targeted therapies against PARP proteins may have a therapeutic role in RMS, although antitumour activity of the new PARP inhibitor molecules in this malignancy has not yet been studied. In this project, we intend to evaluate the efficacy of Olaparib and AZD2461, two potent and selective PARP inhibitors, in RMS preclinical in vitro models. We will analyse the biological effects in RMS cell lines of the two PARP1/2/(3) inhibitors on proliferation, apoptosis, migration and DNA repair by cellular and molecular techniques. Finally, we will assess in vitro whether the combination of Olaparib or AZD2461 with doxorubicin or 4-hydroxycyclophosphamide, two antitumour agents widely used in RMS treatment, might have a synergistic effect. These findings might be useful in order to enhance selective cytotoxicity against RMS cells and to overcome possible chemoresistance. The results of our project will shed further light on RMS development and could represent a further step towards more efficient and less toxic treatments for RMS patients.
