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. Although 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 (TF), 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 preclinical 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.

Figure 1. Molecular genetics and targeted therapies in ES

Molecular genetics and targeted therapies in ES. (A) Schematic of EWS-FLI1 t(11;22)(q24;q12) translocation. The EWS-FLI1 fusion includes the N-terminal activation domain of EWS, which contains multiple degenerate hexapeptide repeats (consensus SYGQQS), and the C-terminal ETS DNA-binding domain (ETS-DBD) of FLI1. The RNA recognition motif (RRM) of EWS and the activation domain (AD) of FLI1 are not retained in the fusion. Variation in the sites of chromosomal break points leads to multiple fusion types (bracketed region). (B) Putative molecular function of the EWS-FLI1 protein and selected protein–protein interactions. As an aberrant transcription factor, EWS-FLI1 regulates genes in part by binding to GGAA microsatellites upstream of target genes. EWS-FLI1 has been shown to interact with the splicing factor U1C (also known as SNRPC, small nuclear ribonucleoprotein polypeptide c), RNA helicase A (RHA), and the hRBP7 subunit of RNA polymerase II (Pol II), which links the protein to splicing and transcription. The small molecule that blocks the EWS-FLI1–RHA interaction is indicated in red. (C) Signaling pathways and targeted therapies in ES. EWS-FLI1 modulation of IGFBP3 and IGF1 and overexpression of IGF1R promote increased IGF1 signaling. ES also expresses PDGFR, c-KIT, and VEGFR. Activation of IGF1R, PDGFR, c-KIT, and VEGFR leads to downstream signaling through the PI3K and MAPK pathways (indicated by gray dashed line and arrows). EWS-FLI1 upregulates Aurora kinase A and cyclin D1, promoting progression through the cell cycle. Targeted therapeutic agents used in recent clinical trials for ES are indicated in red. Genes modulated by EWS-FLI1 are indicated in purple. Receptors overexpressed in ES are indicated in red. ES, Ewing sarcoma; ETS, erythroblast transformation-specific; FLI1, Friend leukemia virus integration 1; IGFBP, insulin-like growth factor binding protein; IGF1, insulin-like growth factor 1; IGF1R, IGF1 receptor; MAPK, mitogen-activated protein kinase; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; PI3K, phosphoinositide-3-kinase; VEGFR, vascular endothelial growth factor receptor.

Figure 2. Molecular genetics and targeted therapies in SS

(A) Schematic of the SS18-SSX t(X;18)(q11.2;q11.2) translocation. The SS18-SSX fusion contains both the SNH and QPGY activation domains of SS18 as well as the SSXRD. The SSX KRAB domain is not retained in the fusion. (B) Putative molecular function of SS18-SSX and selected protein–protein interactions. The SNH domain facilitates binding to components of the SWI/SNF complex while the SSXRD interacts with polycomb group proteins, which results in chromatin remodeling. Interactions with transcription factors (TFs) may also lead to transcriptional activation and repression. (C) Signaling pathways and targeted therapies in SS. Activation of growth factor receptors leads to downstream signaling through the PI3K and MAPK pathways (indicated by gray dashed line and arrows). Histone deacetylases (HDACs) remove acetyl groups (Ac) from histones, resulting in condensed chromatin. Targeted therapeutic agents used in recent clinical trials for SS are indicated in red. Genes modulated by SS18-SSX are indicated in purple. Receptors overexpressed in SS are indicated in red. EGFR, epidermal growth factor receptor; IGF1, insulin-like growth factor 1; KRAB; Kruppel-associated box; MAPK, mitogen-activated protein kinase; PDGFR, platelet-derived growth factor receptor; PI3K, phosphoinositide-3-kinase; SNH, SYT N-terminal homology; SS, synovial sarcoma; SSXRD, SSX repression domain; SWI/SNF, switch/sucrose nonfermentable; SYT, synovial sarcoma translocation; VEGFR, vascular endothelial growth factor receptor.

Figure 3. Molecular genetics and targeted therapies in DFSP

(A) Molecular genetics and targeted therapies in DFSP. (a) Schematic of the COL1A1-PDGFB t(17;22)(q22;q13.1) translocation. The COL1A1-PDGFB fusion joins the α-helical region of COL1A1 to PDGFB lacking its signal sequence. The COL1A1 N-terminal signal sequence replaces that of PDGFB. Break points occur throughout the α-helical region in COL1A1 but occur only within the first intron of PDGFB. PDGFB post-translational cleavage sites are retained in the fusion. (B) Putative molecular function of the COL1A1-PDGFB fusion. The COL1A1 signal sequence allows for protein export and posttranslational cleavage results in the generation of mature PDGFB. Ligand binding of the PDGFB homodimer dimer results in receptor dimerization, autophosphorylation, and activation. (C) Signaling pathways and targeted therapies in DFSP. Activation of PDGFR by the PDGFB dimer results in downstream signaling through the PI3K, MAPK, and Jak/Stat (Janus kinase/signal transducer and activator of transcription) pathways. VEGFR is also activated in DFSP and signals through the PI3K and MAPK pathways. Targeted therapeutic agents in current clinical trials for DFSP (imatinib and dasatinib) and soft tissue sarcomas expressing PDGFR-α (IMC-3G3) are indicated in red. Growth factors overexpressed in DFSP are indicated in red. DFSP, dermatofibrosarcoma protuberans; MAPK, mitogen-activated protein kinase; PDGFB, platelet-derived growth factor B chain; PDGFR, platelet-derived growth factor receptor; PI3K, phosphoinositide-3-kinase; VEGFR, vascular endothelial growth factor receptor.