Dataset Information

Tumor Vessel Development and Expansion in Ewing's Sarcoma: A Review of the Vasculogenesis Process and Clinical Trials with Vascular-Targeting Agents.

ABSTRACT: Ewing's sarcoma accounts for a disproportionately high portion of the overall pediatric mortality rate compared to its rare incidence in the pediatric population. Little progress has been made since the introduction of traditional chemotherapies, and understanding the biology of the tumor is critical for developing new therapies. Ewing's sarcomas rely on a functional vascular supply, which is formed by a combination of angiogenesis and vasculogenesis. Recent insights into the molecular regulation of bone marrow (BM) cell participation in vascular development have identified VEGF, SDF-1?, and DLL4 as critical players in the vasculogenesis process. Clinical trials using vascular targeting agents, specifically targeting VEGF or DLL4, are underway.

SUBMITTER: Stewart KS

PROVIDER: S-EPMC3137951 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Tumor Vessel Development and Expansion in Ewing's Sarcoma: A Review of the Vasculogenesis Process and Clinical Trials with Vascular-Targeting Agents.

Stewart Keri S KS Kleinerman Eugenie S ES

Sarcoma 20110616

Ewing's sarcoma accounts for a disproportionately high portion of the overall pediatric mortality rate compared to its rare incidence in the pediatric population. Little progress has been made since the introduction of traditional chemotherapies, and understanding the biology of the tumor is critical for developing new therapies. Ewing's sarcomas rely on a functional vascular supply, which is formed by a combination of angiogenesis and vasculogenesis. Recent insights into the molecular regulatio ...[more]

PMID: 21785569

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Project description:IGF system contributes significantly to many human malignancies. Targeting IGF-I receptor (IGF-IR) has been reported to be active against several tumors, but particular efficacy was observed only against a minority of Ewing's sarcoma patients. Identification of mechanisms of acquired resistance to anti-IGF-IR agents is mandatory to individualize their use in clinics and optimize cure costs. In this study, we compared gene expression profiles of cells made resistant with three different anti-IGF-IR drugs (human antibodies AVE1642, Figitumumab, or tyrosine kinase inhibitor NVP-AEW541) to highlight common and distinctive mechanisms of resistance. Among common mechanisms, we identified two molecular signatures that distinguish sensitive from resistant cells. Annotation analysis indicated some common altered pathways, such as insulin signaling, MAPK pathway, endocytosis, and modulation of some members of the interferon-induced transmembrane protein family. Among distinctive pathways/processes, resistance to human antibodies involves mainly genes regulating neural differentiation and angiogenesis, whereas resistance to NVP-AEW541 is mainly associated with alterations in genes concerning inflammation and antigen presentation. Evaluation of the common altered pathways indicated that resistant cells seem to maintain intact the IGF-IR internalization/degradation route of sensitive cells but constantly down-regulated its expression. In resistant cells, the loss of proliferative stimulus, normally sustained by IGF-I/IGF-IR autocrine loop in Ewing's sarcoma cells, is compensated by transcriptional up-regulation of IGF-II and insulin receptor-A; this signaling seems to favor the MAPK pathway over the v-akt murine thymoma viral oncogene homolog 1 pathway. Overall, complexity of IGF system requires analytical evaluation of its components to select those patients that may really benefit from this targeted therapy and support the idea of cotargeting IGF-IR and insulin receptor-A to increase the efficacy.

Dataset Information

Tumor Vessel Development and Expansion in Ewing's Sarcoma: A Review of the Vasculogenesis Process and Clinical Trials with Vascular-Targeting Agents.

Publications

Tumor Vessel Development and Expansion in Ewing's Sarcoma: A Review of the Vasculogenesis Process and Clinical Trials with Vascular-Targeting Agents.

Similar Datasets

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