Sonic Hedgehog Signature in Pediatric Primary Bone Tumors: Effects of the GLI Antagonist GANT61 on Ewing’s Sarcoma Tumor Growth

Abstract

Osteosarcoma (OS) and Ewing’s sarcoma (ES) are the most common malignant bone tumors in children and adolescents. In many cases, the prognosis remains very poor. The Sonic hedgehog (SHH) signaling pathway, strongly involved in the development of many cancers, regulate transcription via the transcriptional factors Gli1-3. In this context, RNAseq analysis of OS and ES cell lines reveals an increase of some major compounds of the SHH signaling cascade in ES cells, such as the transcriptional factor Gli1. This increase leads to an augmentation of the transcriptional response of Gli1 in ES cell lines, demonstrating a dysregulation of Gli1 signaling in ES cells and thus the rationale for targeting Gli1 in ES. The use of a preclinical model of ES demonstrates that GANT61, an inhibitor of the transcriptional factor Gli1, reduces ES primary tumor growth. In vitro experiments show that GANT61 decreases the viability of ES cell, mainly through its ability to induce caspase-3/7-dependent cell apoptosis. Taken together, these results demonstrates that GANT61 may be a promising therapeutic strategy for inhibiting the progression of primary ES tumors.

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

“…In addition to identifying individual therapeutic targets, we were interested in examining signaling pathways associated with the overexpressed genes to describe the LPS subtypes and to understand the possible mechanisms of tumorigenesis. The emerging hedgehog signaling in the DDLPS-specific pathway analysis is a compelling discovery, as targeting sonic hedgehog signaling and its key factor, GLI1, has been studied in other sarcomas [57]. Moreover, we identified GLI1 as the most upregulated gene in DDLPS, and previous studies have also shown high expression of two GLI homologs, GLI1 and GLI2, in DDLPS [43,46,64].…”

“…Figure 1 shows the top 10 enriched pathways, with their overlapping genes, in three LPS subtypes. The most important pathways in DDLPS were the hedgehog signaling pathway and the calcium-activated potassium channel, which were previously described as being involved in many cancers [57][58][59]. The two most upregulated genes identified in DDLPS, GLI1 and HHIP, are related to the hedgehog signaling pathways.…”

Chimeric protein EWS-FLI1 drives cell proliferation in Ewing Sarcomaviaoverexpression ofKCNN1

“…Several studies have shown that EWS-FLI1 is able to regulate various genes expression (Cidre-Aranaz & Alonso, 2015), such as Gli1 (Mullard et al, 2020;Merchant et al, 2009), or more recently LOXHD1 (Deng et al, 2022). Both FLI1 and the fusion protein EWS-FLI1 bind the canonical ETS binding motif, GGAA (Wasylyk et al, 1993;Boeva et al, 2010).…”

“…In 85% of cases, the chromosomal translocation found is (11;22)(q24;q12), between the EWS RNA-binding protein and the FLI1 transcription factor, leading to the EWS-FLI1 fusion protein (Delattre et al, 1992). This chimeric protein acts as an oncogene factor for various transcription factors (Cidre-Aranaz & Alonso, 2015), such as Gli1 (Mullard et al, 2020;Merchant et al, 2009), c-Myc (Dauphinot et al, 2001) or DAX1 (Kinsey et al, 2006;Mendiola et al, 2006). In 10% of cases, the chromosomal translocation leads to the emergence of the EWS-ERG chimeric protein (Zucman et al, 1993).…”

Ewing sarcoma from molecular biology to the clinic

“…In particular, EWS-FLI1 has been shown to regulate the expression of numerous transcription factors ( Cidre-Aranaz and Alonso, 2015 ). For example, EWS-FLI1 stimulates the expression of c-Myc ( Dauphinot et al, 2001 ), Gli1 (Glioma-associated Oncogene Homolog 1) ( Merchant et al, 2009 ; Mullard et al, 2020 ) or NR0B1 (Nuclear Receptor subfamily 0 group B member 1) ( Kinsey et al, 2006 ; Gangwal et al, 2008 ), genes involved in tumor progression and metastatic development. Conversely, EWS-FLI1 reduces the expression of genes involved in tumor suppressor mechanism (ex: apoptosis), such as FOXO1 (Forkhead Box O1) ( Yang et al, 2010 ), or IER3 (Immediate Early Response 3) ( Tsafou et al, 2018 ), tumor suppressor genes regulating mechanisms such as DNA repair, cell cycle arrest and apoptosis.…”