Targeting the Hedgehog Pathway in Rhabdomyosarcoma

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.

Hedgehog signaling in tissue homeostasis, cancers, and targeted therapies

“…Rhabdomyosarcoma (RMS) is known to be the most common type of soft tissue sarcoma in children whose cells tend to undergo myogenic differentiation. 347 Two major subtypes of this condition are embryonal subtype of RMS (ERMS) and alveolar subtype of RMS (ARMS). 348 …”

“… 351 However, activating mutations of HH signaling pathway reported to date only account for a small subset of patients. 347 A particular study proposed a different model of RMS in HH signaling pathway activation, where a wide distribution of Dhh and Ihh ligands were detected by immunohistology in RMS samples, in which Shh was only found to be expressed in a small set of RMS cell lines. These findings demonstrated the potential mechanism of the ligand-dependent activation of HH signaling pathway in RMS.…”

SALIQ in Rhabdomyosarcoma: A Repurposed Multidrug Regimen to Augment Standard Treatments by Adding Simvastatin, All Trans Retinoic Acid, Lithium, Itraconazole, and Quercetin

“…Hh signaling engagement participates in facilitating growth and treatment resistance across a wide variety of cancers [102][103][104][105][106][107]. This is also the case in rhabdomyosarcoma [88,[108][109][110][111][112][113]. Multiple interventions are being explored to add Hh signaling inhibition to current rhabdomyosarcoma treatments [110,114].…”

Epigenetic regulation of mRNA mediates the phenotypic plasticity of cancer cells during metastasis and therapeutic resistance (Review)

“…The results indicated good tolerability of LGK974, but no significant clinical benefit was observed ( 100 ). In addition, the hedgehog pathway inhibitor vismodegib was investigated in a phase II trial of patients with metastatic colorectal cancer, but the results were disappointing ( 101 ). In addition, clinical trials have investigated the effect of epigenetic regulators to inhibit EMT in cancer therapy.…”