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.
Despite the overall cure rate has increased, the 5-year event-free survival for children with non-metastatic ARMS or with ERMS at unfavourable sites is about 65%, and it's less than 30% for children with metastatic or recurrent tumours. Conventional chemotherapy induces cell death by causing DNA damage, but its activity can become inadequate due to the appearance of drug-resistant tumour cell populations. The expression of DNA damage response molecules, such as PARP1/2/3 proteins, has been demonstrated to be associated with tumour drug resistance.
Based on this evidence, we believe that the evaluation of the activity of Olaparib (PARP1/2 inhibitor) and AZD2461 (PARP1/2/3 inhibitor) in ARMS and ERMS cell lines both as single agents or in combination with chemotherapy may contribute to a deeper understanding of the RMS cancer biology, which is an essential step for the development of novel targeted therapies in RMS treatment. Furthermore, conventional cytotoxic chemotherapy is associated with significant acute and chronic toxicity (myelosuppression, nephrotoxicity, infertility, cardiomiopathy, etc) and with an increased risk of life threatening late events such as secondary malignancies. Therefore, the combined administration of Olaparib and/or AZD2461 with cytotoxics in patients with RMS might allow an improvement of the therapeutic index in terms of reducing side effects, increasing quality of life, and potentiating treatment efficacy, especially for those with high-risk tumours.