EWS/FLI-responsive GGAA microsatellites exhibit polymorphic differences between European and African populations

The genetics of Ewing sarcoma development remain obscure. The incidence of Ewing sarcoma is ten-fold less in Africans as compared to Europeans, irrespective of geographic location, suggesting population-specific genetic influences. Since GGAA-containing microsatellites within key target genes are necessary for Ewing sarcoma-specific EWS/FLI DNA binding and gene activation, and gene expression is positively correlated with the number of repeat motifs in the promoter/enhancer region, we sought to determine if significant polymorphisms exist between African and European populations which might contribute to observed differences in Ewing sarcoma incidence and outcomes. GGAA microsatellites upstream of two critical EWS/FLI target genes, NR0B1 and CAV1, were sequenced from subjects of European and African descent. While the characteristics of the CAV1 promoter microsatellites were similar across both populations, the NR0B1 microsatellite in African subjects was significantly larger, harboring more repeat motifs, a greater number of repeat segments, and longer consecutive repeats, than in European subjects. These results are biologically intriguing as NR0B1 was the most highly enriched EWS/FLI bound gene in prior studies, and is absolutely necessary for oncogenic transformation in Ewing sarcoma. These data suggest that GGAA microsatellite polymorphisms in the NR0B1 gene might influence disease susceptibility and prognosis in Ewing sarcoma in unanticipated ways.     

Ewing tumor fusion proteins block the differentiation of pluripotent marrow stromal cells

The Ewing family of tumors are poorly differentiated pediatric solid tumors arising in bone and soft tissues from an unknown cell of origin. Ewing tumors are molecularly defined by in-frame genomic fusions that combine EWS with one of several ETS genes, most commonly FLI-1. We considered pluripotent marrow-derived stromal cells a likely candidate for the origin of Ewing tumors and assessed the effects of EWS/ETS proteins in this cell background. EWS/ETS expression in marrow-derived stromal cells caused a dramatic change in cellular morphology that was dependent on the presence of the ETS domain and unique to the fusion proteins. EWS/ETS fusion proteins blocked differentiation along osteogenic and adipogenic lineages, consistent with the undifferentiated appearance of Ewing tumors. Inhibition of differentiation may be an important function of EWS/ETS proteins in the genesis of Ewing tumors.     

Vers une thérapeutique ciblée du sarcome d’Ewing par une stratégie antisens

The Ewing sarcoma family of tumors is characterized by a translocation between chromosomes 11 and 22. This creates a rearranged chromosome 22 containing a chimeric oncogene: EWS/Fli-1. The EWS/Fli-1 protein plays an important role in the transformation of Ewing cells. The fusion region at them RNA level coding for EWS/Fli-1 is a specific target for antisense strategies. It is indeed present only in cancer cells. We describe the in vitro and in vivo results obtained according to this idea first with antisense oligonucleotides and then with siRNAs. Finally prospects for clinical applications with antisense molecules are discussed.     

IGF-1R as an anti-cancer target—trials and tribulations

Type I insulin-like growth factor receptor (IGF-1R) has long been recognized for its role in tumorigenesis and growth, but only recently have the tools for targeting the IGF pathway become available. More than 10 IGF/IGF-1R inhibitors have entered clinical trials, and these belong to three main classes: (1) monoclonal antibodies against IGF-1R, (2) monoclonal antibodies against IGF-1R ligands (IGF-1 and IGF- 2), and (3) IGF-1R tyrosine kinase inhibitors. These IGF-1R-targeting agents share common effects on IGF-1R signaling but differ in mechanisms of action, spectrum of target inhibition, and pharmacological features. Clinical activity of IGF-1R inhibitors has been demonstrated with sustained responses in a small number of patients with select tumor types, such as Ewing sarcoma and thymoma. However, many large clinical trials involving patients with adult tumors, including non-small cell lung cancer, breast cancer, and pancreatic cancer, failed to show clinical benefit in the overall patient population. Possible reasons for failure include the complexity of the IGF-1R/insulin receptor system and parallel growth and survival pathways, as well as a lack of patient selection markers. While IGF-1R remains a valid target for selected tumor types, identification of predictive markers and rational combinations will be critical to success in future development.     

The Rationale and Development of Therapeutic Insulin-like Growth Factor Axis Inhibition for Lung and Other Cancers

The insulin-like growth factor (IGF) axis involves elements of endocrine, paracrine, and autocrine control. It is centrally involved in normal development and growth. Core signaling is driven through the IGF-1 receptor (IGF-1R) in either homo-multimeric complexes or hetero-multimeric complexes with the insulin receptor (IR). Signaling is affected by a large number of upstream and downstream factors, including the differential expression of various intracellular IR substrates, a range of stimulatory ligands (insulin, IGF-1, and IGF-2), the expression of specific clearance receptors (eg, IGF-2R), and different IGF-binding proteins. Considerable evidence exists to implicate aspects of the IGF axis in the development and maintenance of many different nonneoplastic and neoplastic diseases, including both small-cell lung cancer and Non–Small-cell lung cancer (NSCLC). A large number of different anticancer strategies directed against the IGF axis are being developed. Monoclonal antibodies directed against the IGF-1R are the furthest advanced clinically. Hyperglycemia appears to be a class effect. To date, the major difference among the antibodies used in clinical trials seems to be their plasma half-lives, leading to a number of different administration regimens being taken forward. Early signals of monotherapy activity have been notably reported in patients with Ewing sarcoma and in several other cancers. Encouraging increases in the NSCLC response rate have already been reported after the addition of an anti—IGF-1R antibody to first-line carboplatin and paclitaxel. Explorations of aspects of ligands, binding proteins, receptors, and receptor substrates are all ongoing to identify potential biomarkers predictive of benefit from IGF axis intervention.