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.
Curing RMS conventionally includes RT combined or not with cytotoxics drugs; however, a subgroup of patients undergoes a rapid disease progression or eventually relapses shortly after treatment ends because of the appearance of resistant cancer cells. Furthermore, conventional chemo/radiotherapy 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. Consequently, the identification of novel sensitizing strategies in the treatment of RMS is urgently required. Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals thus, the disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Global changes in the epigenetic landscape are a hallmark of cancer. 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 therapy, which is already making progress with the recent FDA approval of different epigenetic drugs for cancer treatment. Specific epigenetic perturbations have been shown in RMS. Based on this evidence, we believe that the evaluation of the activity of PXD-101 (Belinostat), MS-275 (Entinostat) and FK-228 (Romidepsin), able to block HDACs, in ARMS and ERMS cell lines both as single agents or in combination between them or with RT might provide an additional therapeutic approach in RMS patients and a deeper insight into the molecular mechanisms underlying tumorigenesis of this soft tissue sarcoma. Furthermore, the identification of the molecular targets and signal pathways modulated by these novel epi-drugs might help in finding novel tissue and serum biomarkers for an early diagnosis and a more appropriate stratification into risk classes. Of particular importance will be the information of the effects of PXD-101, MS-275 and FK-228 on the formation of rhabdospheres, associated with cancer stem cell (CSC) proliferation and maintenance, since the reduction in CSC metastatic potential should be a promising approach to improve the efficacy of cancer treatment and, in turn, patient survival. Finally, the assessment of the combined utilization of PXD-101, MS-275 and FK-228, with IR in RMS in vitro and in vivo models will give a rationale to translate experiments in preclinical mouse models in the attempt of designing more effective and less toxic therapeutic protocols for the management of RMS patients.