Pediatric sarcomas: translating molecular pathogenesis of disease to novel therapeutic possibilities

Abstract

Pediatric sarcomas represent a diverse group of rare bone and soft tissue malignancies. Though the molecular mechanisms that propel the development of these cancers are not well understood, identification of tumor-specific translocations in many sarcomas has provided significant insight into their tumorigenesis. Each fusion protein resulting from these chromosomal translocations is thought to act as a driving force in the tumor, either as an aberrant transcription factor, constitutively active growth factor, or ligand-independent receptor tyrosine kinase. Identification of transcriptional targets or signaling pathways modulated by these oncogenic fusions has led to the discovery of potential therapeutic targets. Some of these targets have shown considerable promise in pre-clinical models and are currently being tested in clinical trials. This review summarizes the molecular pathology of a subset of pediatric sarcomas with tumor-associated translocations and how increased understanding at the molecular level is being translated to novel therapeutic advances.

Olaratumab Exerts Antitumor Activity in Preclinical Models of Pediatric Bone and Soft Tissue Tumors through Inhibition of Platelet-Derived Growth Factor Receptor α

“…Although PDGFRA is not frequently altered in childhood cancers (19,38,39), receptor expression is associated with progressive disease and poor prognosis in some pediatric malignancies of bone and soft tissue (11,26,40). Expression of the receptor was readily detected in several osteosarcoma cell lines and PDX models, which was expected, as 50% of osteosarcoma primary samples were previously found to be PDGFRa positive (23).…”

“…Despite intensive multimodal therapy, which typically includes a combination of chemotherapies, surgery, and/or radiotherapy, the current 5-year overall survival rate for pediatric sarcoma patients is approximately 60%; for those who experience a relapse or have metastatic disease, survival drops to only 20% to 30% (11). Malignant rhabdoid tumor (MRT) is a highly aggressive pediatric cancer typically occurring in the kidney and soft tissues or the central nervous system [where it is referred to as atypical teratoid/rhabdoid tumor (AT/RT)] and is characterized by a loss of SMARCB1 (12,13).…”

Identification of cytotoxic agents disrupting synovial sarcoma oncoprotein interactions by proximity ligation assay

“…Driving protein complexes are often recruited and deregulated in translocation-associated sarcomas [32]. Uncovering new methods of study and utilizing emerging technologies such as the proximity ligation assay may allow better means to identify therapeutic strategies.…”

The Hippo signal transduction pathway in soft tissue sarcomas

“…Genetically, sarcomas can show either aberrant, chimeric transcription regulators as a consequence of fusion genes such as PAX3/7-FOXO1 [6,8], somatic point mutations of well-known cancer genes such as oncogenic RAS isoforms, PIK3CA or TP53, or DNA copy number gains or losses [6,[9][10][11][12]. As we will show later, there is no evidence for recurrent Hippo gene point mutations in sarcomas, while there is abundant evidence for mutations of typical cancer genes [13,14] that can cross-talk to the main members of the Hippo pathway.…”