PAX–FOXO1 fusion status in children and adolescents with alveolar rhabdomyosarcoma: Impact on clinical, pathological, and survival features

Abstract

Background Alveolar rhabdomyosarcoma (ARMS) is an aggressive pediatric cancer and cases with fusion PAX3–FOXO1 and PAX7–FOXO1 seem to have a poor prognosis. The aim is to evaluate whether PAX–FOXO1 alterations influence clinical outcome in childhood and adolescence population with ARMS. Procedure A population‐based study was conducted between 2011 and 2016 in patients less than 17 years with a diagnosis of ARMS. Overall survival (OS) depending on fusion status with clinical factors was analyzed. Results Out of 111 ARMS patients recorded in the French National Childhood Cancer Registry during the 2011–2016 period, 61% expressed PAX3–FOXO1, 15% expressed PAX7–FOXO1, 13% were FOXO1 fusion‐positive without PAX specification, and 7% were PAX–FOXO1 negative (n = 4 missing data). Compared to patients with PAX7–FOXO1 positive ARMS, those with PAX3–FOXO1 positive tumor were significantly older (10–17 years: 57.4% vs. 29.4%), and had more often a metastatic disease (54.4% vs. 23.5%). Poorer 5‐year OS for patients with PAX3–FOXO1 and PAX not specified FOXO1‐positive tumor were observed (44.0% [32.0–55.4] and 35.7% [13.1–59.4], respectively). After adjustment for stage at diagnosis, patients with positive tumor for PAX3–FOXO1 were 3.6‐fold more likely to die than those with positive tumor for PAX7–FOXO1. Conclusion At the population level, PAX3–FOXO1 was associated with a significant higher risk of death compared to PAX7–FOXO1‐positive and PAX–FOXO1‐negative tumors, and could explain poorer 5‐year OS observed in adolescence population diagnosed with ARMS. A continuous risk score derived from the combination of clinical parameters with PAX3–FOXO1 fusion status represents a robust approach to improving current risk‐adapted therapy for ARMS.

A Systematic Approach to the Discovery of Protein–Protein Interaction Stabilizers

“…The stabilizing fragments we discovered can be further optimized for chemical biology and therapeutics applications. For instance, 14-3-3/FOXO1 stabilization could inhibit FOXO1-fusion proteins in rare cancers and correct metabolism in diabetes. , Additionally, 14-3-3-mediated inhibition of C-RAF is strongly implicated in RAS-mediated cancers and in the developmental disorder Noonan’s syndrome, where mutations in C-RAF and other proteins in the pathway lead to slight upregulation of MAP kinase signaling. , …”

“…For instance, 14-3-3/FOXO1 stabilization could inhibit FOXO1-fusion proteins in rare cancers and correct metabolism in diabetes. 43,44 Additionally, 14-3-3-mediated inhibition of C-RAF is strongly implicated in RAS-mediated cancers and in the developmental disorder Noonan's syndrome, where mutations in C-RAF and other proteins in the pathway lead to slight upregulation of MAP kinase signaling. 32,39 While the focus of the screen was the discovery of fragment stabilizers, the screen also identified selective inhibitors, nonselective inhibitors, and neutral compounds for each client peptide and 14-3-3 (Figure S18).…”

A systematic review of the prevalence of pathogenic or likely pathogenic germline variants in individuals with FOXO1 fusion‐positive rhabdomyosarcoma

“…These ARMS are termed fusion-positive ARMS (FP-ARMS) and are associated with worse event-free survival (EFS) than ERMS or FOXO1 fusion-negative ARMS (FN-ARMS). [3][4][5][6][7] FN-ARMS have gene expression profiling and clinical outcome similar to ERMS. 8,9 Pathogenic germline variants in cancer predisposition genes (CPGs) have been reported in 7.6%-14% of the children and adolescents with cancer.…”

“…Approximately 80% of ARMS cases are driven by balanced chromosomal translocations involving chromosomes 2 or 1 and chromosome 13 resulting in expression of the fusion oncoproteins PAX3–FOXO1 or PAX7–FOXO1, respectively. These ARMS are termed fusion‐positive ARMS (FP‐ARMS) and are associated with worse event‐free survival (EFS) than ERMS or FOXO1 fusion‐negative ARMS (FN‐ARMS) 3–7 . FN‐ARMS have gene expression profiling and clinical outcome similar to ERMS 8,9 …”

Piperacetazine Directly Binds to the PAX3::FOXO1 Fusion Protein and Inhibits Its Transcriptional Activity

“…Patients with FP-RMS tumors have a lower survival rate than those with fusion-negative RMS (FN-RMS; refs. 19, 20 ). Therefore, these oncogenic fusion proteins are important factors for initiation and maintenance of RMS and can be exploited for therapeutic purposes.…”