Targeting the undruggable: exploiting neomorphic features of fusion oncoproteins in childhood sarcomas for innovative therapies

Abstract

While sarcomas account for approximately 1% of malignant tumors of adults, they are particularly more common in children and adolescents affected by cancer. In contrast to malignancies that occur in later stages of life, childhood tumors, including sarcoma, are characterized by a striking paucity of somatic mutations. However, entity-defining fusion oncogenes acting as the main oncogenic driver mutations are frequently found in pediatric bone and soft-tissue sarcomas such as Ewing sarcoma (EWSR1-FLI1), alveolar rhabdomyosarcoma (PAX3/7-FOXO1), and synovial sarcoma (SS18-SSX1/2/4). Since strong oncogene-dependency has been demonstrated in these entities, direct pharmacological targeting of these fusion oncogenes has been excessively attempted, thus far, with limited success. Despite apparent challenges, our increasing understanding of the neomorphic features of these fusion oncogenes in conjunction with rapid technological advances will likely enable the development of new strategies to therapeutically exploit these neomorphic features and to ultimately turn the "undruggable" into first-line target structures. In this review, we provide a broad overview of the current literature on targeting neomorphic features of fusion oncogenes found in Ewing sarcoma, alveolar rhabdomyosarcoma, and synovial sarcoma, and give a perspective for future developments.

Sarcoma treatment in the era of molecular medicine

“…While oncogenic gene fusions involving transcription factors remain largely undruggable (Knott et al , 2019), clinical trials using larotrectinib, a kinase inhibitor targeting gene fusions involving NTRK1 /2/3, have shown promising results and could offer a strategy for the treatment of NTRK ‐fusion‐positive sarcomas (Doebele et al , 2015; Fig 3). In addition, DNA minor groove‐binding agents in DNA, such as trabectedin or mithramycin, have been described as potent inhibitors of EWSR1‐FLI1‐mediated transcription with anti‐tumor potential (Bailey et al , 2019; Harlow et al , 2019).…”

Cooperative treatment effectiveness of ATR and HSP90 inhibition in Ewing’s sarcoma cells

“…The fusion protein EWS-FLI1 suppresses wild-type EWSR1 functions to activate RNAPII and transcription [2,3,58]. BCOR and epigenetic modi ers are involved in the transcriptional regulation of ES cells [58,3]. We found BCOR and several epigenetic modi ers, including KATs/KDACs and KDMs/KMTs downregulated after AUY-VE, potentially thwarting EWS-FLI1 activities.…”

“…Intriguingly, we found reduced levels of SIRT1, SIRT2, AKT and PI3K subunits together with several cytoskeletal proteins in A673 cells. The fusion protein EWS-FLI1 suppresses wild-type EWSR1 functions to activate RNAPII and transcription [2,3,58]. BCOR and epigenetic modi ers are involved in the transcriptional regulation of ES cells [58,3].…”

CDK9 as a Valuable Target in Cancer: From Natural Compounds Inhibitors to Current Treatment in Pediatric Soft Tissue Sarcomas

“…Pediatric soft tissue sarcomas (STSs) are rare malignancies of children and adolescents that accounts for 8% of all pediatric cancers (Kattner et al, 2019). They are highly heterogeneous under a cellular and genomic point of view including subgroups mainly characterized by chromosomal translocations or genomic abnormalities (Gröbner et al, 2018;Knott et al, 2019). Indeed, STSs have a low number of gene mutations, as pediatric cancers in general (Monje, 2018), and some of them do not have any mutation, suggesting that developmental epigenetic dysregulations rather than genetic alterations could be involved in their pathogenesis (Shern et al, 2014;Tirode et al, 2014;Pishas and Lessnick, 2016).…”

“…A group of soft tissue sarcomas (STSs) of childhood express chimeric transcription factors from which they are dependent for survival or have mutations or loss of key components of transcriptional complexes (Finetti et al, 2020;Knott et al, 2019). STSs include highly metastatic sub-entities often unresponsive to conventional therapies and characterized by dismal prognosis.…”