Rhabdomyosarcoma (RMS) is the most commonly diagnosed malignant soft tissue tumor in children and adolescents. Standard therapeutic approaches for RMS treatment involve surgery, chemotherapy and radiotherapy (RT). In particular, the indications and techniques for pediatric RT evolved considerably over the years, resulting in improved cure rates together with the potential for decreased treatment-related morbidity and mortality. Anyway, despite the initial efficacy, 5-year survival rates of RMS patients remain unfavorable. Individuals with metastatic or recurrent disease have a poor clinical outcome, with a 5-year overall survival of about 30%. RMS relapsing is mainly due to the expansion of cancer stem cells (CSCs), which are able to self-renew and possess a high capability to efficiently repair DNA damage. These features render CSCs resistant to conventional therapies, including RT, and the eradication of all CSCs is a requirement for a more effective antineoplastic treatment and an improvement of patient prognosis. So, a deep understanding of the molecular and cellular pathways that comprise the radio-resistance is an urgent clinical need. In the present project, we aim to extend current knowledge on the mechanisms of radio-resistance in parental and highly radio-resistant RMS cells as well as CSCs by performing gene expression analysis of a large number of coding and non-coding genes. A bioinformatic approach will be used to select drivers of important molecular networks to be addressed for experimental validation. Our final aim is to identify new molecules useful both as biomarkers and targets for setting up new treatment approaches or to improve current therapies, mainly in the context of RT. In particular, our in vitro and in vivo studies are committed to continuing research to refine and modernize the use of RT in current and future protocols, with the goal of further improving the cure rates and quality of life of children stricken with RMS cancer.
Despite the overall cure rate has increased, the 5-year event-free survival for children with non-metastatic ARMS or with ERMS at unfavorable sites is about 65%, and less than 30% for children with metastatic or recurrent tumors. Conventional therapies, including chemo- and radiotherapy, induce massive cell death by causing DNA damage, but their activity may become inadequate due to the appearance of tumor cell populations that are resistant and represent the bulk for new and more aggressive cancer stem cells (CSCs).
So, resistance to radiotherapy represents an important limiting factor, with cancer cells often able to escape from RT-induced cell death damaging programs, this contributing to therapeutic failures and poor survival in patient care. Characterizing the response of RMS cells, highly resistant and isogenic parental, to RT seems to be essential to understand the mechanisms through which RMS tumors can develop intrinsic and acquired radio-resistance that finally determine local recurrence and dissemination. Based on this evidence, we believe that a deeper understanding of the RMS cancer biology involved in radio-resistance mechanisms is an essential step for the development of more appropriate RT-based treatments, in order to find new factors that might represent potential biomarkers and targets for new advanced treatment. Moreover, we will also characterize the biological role of CSCs in RMS and identify the molecular mechanisms through which they influence radioresistance. The identification of new molecular targets and signal pathways governing RMS stemness properties, which have a critical role in tumor maintenance and metastasis as well as in resistance phenomena to radiation treatments, might represent a key finding that will positively impact RMS clinical management, fostering the development of novel therapies combining RT with drugs directly acting on the CSC population. Indeed, radiosensitizers represent compounds that, when combined with radiation, achieve greater tumor inactivation than would have been expected from the additive effect of each modality. No radiosensitizers have been yet identified for RMA and we think that the contribution of the present project to the understanding of the mechanisms mediating sensitivity and resistance to RT could have a significant impact by guiding their successful clinical development in RMS. This will represent a promising approach to improve the efficacy of RT and, consequently, patient survival, mainly through the development of new clinical protocols using RT in combination with novel targeted therapies, to completely eradicate RMS tumor cells and to 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 tumors.