Ewing sarcoma (ES) is the second most common pediatric bone cancer. It is an aggressive sarcoma of the bone and soft tissue with peak incidence in adolescence. The current treatment strategy relies on a multidisciplinary approach of chemotherapy and local control (surgical resection and/or radiation therapy) to optimize a chance for cure. Although overall survival for localized ES now approaches 65-75%, patients with metastatic ES continue to have extremely poor overall survival, with 5 year overall survival <25% that have remained stagnant for the past 20-30 years. In fact, metastatic status is the strongest prognostic factor at the time of diagnosis. However, the mechanisms that drive sarcoma metastasis, colonization and foci development and progression remain largely unknown. Our preliminary proteomic and transcriptomic studies using an in vivo model of ES metastasis compared expression profiles of primary ES tumors to the corresponding metastatic lesions found in the lung and secondary bone sites. Our studies showed significant proteomic alterations in key signaling molecules, including upregulation of integrin-linked kinase (ILK) in distal metastatic lesions compared to the primary bone lesion, suggesting that this pathway may play a key role in the ability of Ewing sarcoma to metastasize and establish distal foci. Furthermore, transcriptome analysis from the same primary and distal lesions validated the hyper-activation of this signaling pathway, with enhanced expression of ILK-mediated signaling transcripts. Prior studies have suggested that the interaction between integrins and the extracellular matrix is a key factor for allowing tumor cells to invade into the basal matrix of surrounding tissue, thus allowing for metastasis. However, no prior studies have implicated integrin-mediated signaling as being a targetable, key molecular event driving successful metastasis of Ewing sarcoma. Our long term goals are to use our extensive experience in sarcoma pathogenesis and innovative mouse models, including orthotopic, PDX transplantation and ex vivo pulmonary metastatic models to assess the role of ILK and its contributions to ES dissemination, colonization and foci progression. If successful, these studies will lead to a greater understanding of sarcoma metastasis and provide preliminary pre-clinical insights the ability to target ILK-mediated signaling for this aggressive disease.
Our aims i nclude:
Aim1. In vitro and in vivo studies into the functional role of ILK in driving ES metastatic dissemination, colonization and foci progression.
Aim 2 : In vitro and in vivo assessment of ILK as a viable therapeutic target for metastatic Ewing sarcoma.
Aim 3. Assess expression and clinical significance of ITGB3, ILK and phospho-Jun expression in localized, primary metastatic bone tumor and paired distal metastatic Ewing sarcoma tumor samples
Metastatic Ewing sarcoma (ES) is a highly aggressive and deadly bone tumor seen in adolescents and young adults with survival rates less than 25% due to ineffective therapeutic modalities. We have developed and molecularly profiled innovative models to investigate the molecular pathogenesis of metastatic ES and have identified integrin and integrin-linked kinase to be enhanced in distal sites of disease. We are proposing to expand upon these insights and use our expertise in mouse models to dissect ILK-mediated signaling and therapeutically investigate the functional significance of these signaling components towards the initiation and development of metastatic disease.
