Targeting the Hedgehog Pathway in Rhabdomyosarcoma

SIMPLE SUMMARY: In the first sections of this review, we provide a comprehensive description of the Hedgehog signalling pathway in mammals and the main general models of pathway activation. Subsequently, the review focuses on the oncogenic role played by this pathway in rhabdomyosarcoma and the inhibitors developed to date, as well as the clinical trials available in sarcomas. Finally, we provide a discussion and critical review of the results obtained in the clinical setting and their strong dependency on the type of tumour. In some cases, strong discrepancies between encouraging preclinical data and clinical trial results are clearly evident. ABSTRACT: Aberrant activation of the Hedgehog (Hh) signalling pathway is known to play an oncogenic role in a wide range of cancers; in the particular case of rhabdomyosarcoma, this pathway has been demonstrated to be an important player for both oncogenesis and cancer progression. In this review, after a brief description of the pathway and the characteristics of its molecular components, we describe, in detail, the main activation mechanisms that have been found in cancer, including ligand-dependent, ligand-independent and non-canonical activation. In this context, the most studied inhibitors, i.e., SMO inhibitors, have shown encouraging results for the treatment of basal cell carcinoma and medulloblastoma, both tumour types often associated with mutations that lead to the activation of the pathway. Conversely, SMO inhibitors have not fulfilled expectations in tumours—among them sarcomas—mostly associated with ligand-dependent Hh pathway activation. Despite the controversy existing regarding the results obtained with SMO inhibitors in these types of tumours, several compounds have been (or are currently being) evaluated in sarcoma patients. Finally, we discuss some of the reasons that could explain why, in some cases, encouraging preclinical data turned into disappointing results in the clinical setting.