Identification of causative mutations for Ewing sarcoma

Identification of causative mutations for Ewing sarcoma

Ewing sarcoma is the second most common form of bone childhood cancer, and its genetic hallmark is an aberrant fusion gene known as EWS/FLI1.  It is unclear whether the expression of EWS/FLI1 alone is sufficient, or additional mutations are required for malignant transformation.  Identifying the common mutations among Ewing sarcoma cells is a significant process for patient treatment because of the following reasons: i) mutations can be utilized as biomarkers and ii) chemical compounds that target the mutations are strong candidates for treatment.  Tumor cells are not suitable for identifying the causative mutations because additional mutations are already accumulated.  And…  Read More »

Crosstalk between EGFR and IGF1R mediated by polymorphisms in the EGFR promoter as a mechanism for resistance to IGF1R directed therapy in osteosarcoma

Osteosarcoma is the most common primary malignant tumor of bone, with a pea incidence in the second decade of life. New therapies are needed to improve survival especially among patients with recurrent or metastatic disease. Insulin growth factor-I (IGF-I) is essential for growth in osteosarcoma. Several of the fully humanized monoclonal antibodies targeting the IGF-I receptor (IGF-IR) currently in clinical trials have clear evidence of growth inhibition in osteosarocoma tumor lines. However, some osteosarcoma lines remain resistant to IGF signal inhibition. Preliminary data presented using a fully humanized monoclonal anti-IGF-IR antibody, indicates that osteosarcoma tumors may employ salvage signaling through…  Read More »

Functional analysis of Mirk/Dyrk 1B in osteosarcoma

Osteosarcoma is the most common primary malignant tumor of bone.  Standard treatment is surgery and chemotherapy, which has significantly improved the survival rate from 11% with surgery alone to 60-70% when surgery is combined with chemotherapy.  Unfortunately, progress has been limited over the past 20 years, and the identification of new therapies is critical to improving the survival rate of osteosarcoma patients.  Protein kinases have recently been targeted by pharmaceutical agents to decrease tumor growth (i.e. Bcr-Abl, EGFR, Her2, c-kit).  One of the less known kinases, Mirk/Dyrk1B, is a unique, multifunctional kinase, that has been observed to be amplified, upregulated,…  Read More »

A Quantitative Imaging-based Biomarker for Assessment of Therapy Response in Soft Tissue Sarcomas by Differential Volume Estimation of Viable and Non-viable Tumor Fractions

The rapid developments in imaging techniques and action of newer chemotherapeutic drugs have highlighted the limitations of response evaluation criteria in solid tumors (RECIST) for assessing treatment response in soft tissue sarcoma. Some chemotherapeutic agents may induce more tumor necrosis compared to another, causing enlargement of the total tumor size and thus leading to false positive interpretations of disease progression on RECIST of an otherwise stable or regressed disease state. Newer imaging techniques like tumor perfusion and positron emission tomography (PET) need standardization with regard to apparent diffusion coefficient values and tighter control on false positive detections respectively with added…  Read More »

Targeting GLI1 in Ewing Sarcoma

The EWS/FLI1 oncogenic transcription factor is both unique to and indispensable to the development of Ewing’s Sarcoma and peripheral Primitive Neuroectodermal Tumor (collectively known as the Ewing Sarcoma Family Tumors or ESFT). It is imperative that we translate our understanding of EWS/FLI1 biology into improved therapeutics for Ewing Sarcoma. We have recently published findings that EWS/FLI causes increased expression of Gli1 in ESFT in a Hedgehog independent fashion. We have further published data that inhibition of GLI1 expression by shRNA results in decreased tumorigenicity and that several known targets of EWS/FLI1 are diminished in their expression. This suggests that signaling…  Read More »

Developing a MicroRNA-Based Strategy for Targeting Uterine Leiomyosarcoma

MicroRNAs (miRNAs) are a novel class of small, non-coding RNA transcripts that broadly regulate patterns of gene expression. Recently, we used Next Generation Sequencing to dentify 49 individual miRNAs differentially expressed in uterine leiomyosarcoma (ULMS). We also identified potential targets for these miRNAs by using bioinformatic algorithms to screen gene products differentially expressed when genome-wide transcriptional profiling was used to examine our specimens. Based on these results, we hypothesize that miR-143 plays a central role in the pathogenesis of ULMS. To test this hypothesis, we intend to examine the function of miR-143 in uterine smooth muscle and smooth muscle tumors…  Read More »

Regulation of sarcomagenesis by the Piwi proteins and their interacting small RNAs (piRNAs)

Recently levels of HIWI (the human ortholog of Drosophila PIWI) HIWI, have been found to be expressed in sarcomas with higher HIWI levels correlating significantly with worse clinical outcomes. In lower organisms, PIWI family members silence mobile genomic elements (i.e., transposons) and thus help to maintain genomic integrity via regulating the production of a distinct class of small ‘silencing’ RNAs – aptly named Piwi-interacting RNAs or piRNAs. It is currently unclear as to why ‘higher’ levels of a gene that silences mobile genetic elements would correlate with worse clinical outcomes for sarcoma patients. Our studies have revealed that overexpression of…  Read More »

Lipid Metabolism in Liposarcoma: A Novel Target for Therapeutic Intervention

There is no effective medical therapy for patients with liposarcoma. We find that liposarcomas are dependent upon a constant supply of fatty acids to fuel their growth. Tumors may potentially acquire these lipids by a) de novo synthesis using fatty acid synthase (FASN), b) extracellular hydrolysis of circulating fat using lipoprotein lipase (LPL), followed by cellular uptake using CD36, or c) endocytosis of triglyceride-rich particles using Syndecan-1. We find that liposarcomas express high levels of FASN, LPL, CD36, and Syndecan-1. Moreover, Spot 14, a key nuclear driver of the genes encoding enzymes involved in lipogenesis, is also abundant in liposarcomas….  Read More »

How does a sarcoma circumvent fusion oncoprotein-mediated toxicity?

Alveolar rhabdomyosarcoma (ARMS) is an aggressive soft tissue sarcoma with a 2;13 translocation that generates a PAX3-FKHR fusion oncoprotein. Introduction of PAX3-FKHR into multiple cell types showed that this oncoprotein exerts growth suppression and/or cell death when expressed at levels comparable to those found in ARMS cells. Subclones from a myoblast population expressing MYCN and an inducible form of PAX3-FKHR showed increasing growth suppression in a plating assay as PAX3-FKHR activity was induced. However, when fibroblasts were added for a focus formation assay, numerous transformed foci formed when PAX3-FKHR was induced. Multiple ARMS cell lines have a similar phenotype of…  Read More »

Identification of the target genes of the EWS/NR4A3 fusion protein expressed in extraskeletal myxoid chondrosarcoma

Extraskeletal myxoid chondrosarcoma (EMC) are soft tissue tumors occurring mainly in the extremities, most commonly the thigh and knee. In approximately 75% of these tumors, at (9;22) chromosome translocation is present. This translocation encodes a fusion protein named EWS/NR4A3 which consists of the amino-terminal domain of the EWS protein fused to the complete amino acid sequence of the NR4A3 nuclear receptor.  In my laboratory we have shown that EWS/NR4A3 is a highly potent transcriptional activator, suggesting that one way in which it may contribute to tumorigenesis is by activating specific target genes. There are no cell lines established from EMC…  Read More »