Curing rhabdomyosarcoma (RMS), the most commonly diagnosed malignant soft tissue tumour in children and adolescents, mainly requires surgery and radiotherapy (RT) in combination or not with chemotherapy (CHT). Despite improvements in treating RMS, patients still have a poor clinical outcome. So, the identification of innovative therapies against advanced RMS represents an urgent clinical need. Global changes in the epigenetic landscape are a hallmark of cancer and specific epigenetic perturbations have been shown in RMS. Thus, recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer including histone acetylation/deacetylation that has led to the emergence of the promising field of epigenetic-related drugs. In this project, we plan to evaluate the antitumour activity in RMS preclinical models of PXD-101 (Belinostat), MS-275 (Entinostat) and FK-228 (Romidepsin) HDACs inhibitors that are recently moved into 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 PXD-101, MS-275 and FK-228 treatments are able to synergize with RT. In vitro collected evidences will be corroborated by in vivo experiments. Moreover, we will analyse the mRNA and protein levels of HDACs in a cohort of RMS tumour biopsies to look for possible correlations with histological subtypes and clinical parameters, such as disease stage and outcome, particularly in relationship with RT treatment. These preclinical findings on HDACs 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.
