Translational Implications for Radiosensitizing Strategies in Rhabdomyosarcoma

Abstract

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and adolescence that includes FP-RMS, harboring the fusion oncoprotein PAX3/7-FOXO1 and FN-RMS, often mutant in the RAS pathway. Risk stratifications of RMS patients determine different prognostic groups and related therapeutic treatment. Current multimodal therapeutic strategies involve surgery, chemotherapy (CHT) and radiotherapy (RT), but despite the deeper knowledge of response mechanisms underpinning CHT treatment and the technological improvements that characterize RT, local failures and recurrence frequently occur. This review sums up the RMS classification and the management of RMS patients, with special attention to RT treatment and possible radiosensitizing strategies for RMS tumors. Indeed, RMS radioresistance is a clinical problem and further studies aimed at dissecting radioresistant molecular mechanisms are needed to identify specific targets to hit, thus improving RT-induced cytotoxicity.

Keywords: radiation therapy; radioresistance; radiosensitizers; radiotherapy; rhabdomyosarcoma.

Figure 1

The combination of radiation therapy and sensitizer agents able to target epigenetic enzymes, transcription factors etc., sensitizes RMS cells to ionizing radiation by impairing genomic stability, DNA repair, and oncogenic pathways. DNMTi: DNA Methyltransferase inhibitors; BETi: Bromo- and extra-terminal domain inhibitors; HDACi: Histone Deacetylase inhibitors.

Figure 2

Schematic representation of the principal radiosensitizer targets (MEK/ERK pathway, DNMTs, HDACs, and BRD4) discovered in RMS. Treatment with U0126, a MEK inhibitor, decreases the activation of MEK/ERK pathway thus affecting the pro-tumorigenic abilities of the transcription factor c-MYC. The treatment with 5′-azacitidine reduces DNA methylation by specifically inhibiting DNA methyltransferases (DNMTs). Romidepsin, Belinostat, and Entinostat pharmacologically target Histone Deacetylases (HDACs) increasing the acetylation of Lysine 27 of the Histone 3 (H3K27ac). Bromodomain-containing protein 4 (BRD4) is directly inhibited by OTX015 treatment thus affecting its ability to read and bind the H3K27ac residues. Pharmacologic perturbation of the identified molecules increases RT-induced cytotoxic effects.