A5032142783- Sarcoma Diagnosis and Treatment
- RNA modifications and cancer
- Epigenetics and DNA Methylation
- RNA Research and Splicing
- Protein Degradation and Inhibitors
- Cancer Genomics and Diagnostics
- Lymphoma Diagnosis and Treatment
- Cardiac tumors and thrombi
- Cancer, Hypoxia, and Metabolism
- PARP inhibition in cancer therapy
- Cancer-related gene regulation
- Histone Deacetylase Inhibitors Research
- Genomics and Chromatin Dynamics
- Cancer-related molecular mechanisms research
- Lung Cancer Treatments and Mutations
- Ubiquitin and proteasome pathways
- Virus-based gene therapy research
- CAR-T cell therapy research
- Angiogenesis and VEGF in Cancer
- Childhood Cancer Survivors' Quality of Life
- Cancer, Lipids, and Metabolism
- Kruppel-like factors research
- Hematological disorders and diagnostics
- Neuroblastoma Research and Treatments
- Peptidase Inhibition and Analysis
The Ohio State University
2015-2024
Nationwide Children's Hospital
2015-2024
University of Utah
2010-2023
Huntsman Cancer Institute
2010-2023
Center for Children
2015-2023
Hospital for Sick Children
2019
SickKids Foundation
2019
University of Toronto
2019
Columbus Center
2018
Center for Cancer and Blood Disorders
2018
The 11;22 chromosomal translocation specifically linked to Ewing sarcoma and primitive neuroectodermal tumor results in a chimeric molecule fusing the amino-terminal-encoding portion of EWS gene carboxyl-terminal DNA-binding domain encoded by FLI1 gene. We have isolated fourth EWS-FLI1 fusion cDNA that is structurally distinct from three forms previously described. To determine transforming activity this gene, alternative were transduced into NIH 3T3 cells. Cells expressing either type 1 or...
EWS/FLI-1 is a chimeric protein formed by tumor-specific 11;22 translocation found in both Ewing's sarcoma and primitive neuroectodermal tumor of childhood. has been shown to be potent transforming gene, suggesting that it plays an important role the genesis these human tumors. We now demonstrate characteristics aberrant transcription factor. Subcellular fractionation experiments localized nucleus cells. specifically bound vitro ets-2 consensus sequence similarly normal FLI-1. When coupled...
The transcription factor Microphthalmia-associated (MITF) is a lineage-determination factor, which modulates melanocyte differentiation and pigmentation. MITF was recently shown to reside downstream of the canonical Wnt pathway during from pluripotent neural crest cells in zebrafish as well mammalian lineage cells. Although expression many melanocytic/pigmentation markers lost human melanoma, remains intact, even unpigmented tumors, suggesting role for beyond its differentiation. A...
Ewing sarcoma (EWS) is an aggressive bone tumor of uncertain cellular origin. CD99 a membrane protein that expressed in most cases EWS, although its function the disease unknown. Here we have shown endogenous expression modulates EWS differentiation and malignancy. We determined knocking down human cell lines reduced their ability to form tumors metastases when xenografted into immunodeficient mice diminished tumorigenic characteristics vitro. Further, reduction resulted neurite outgrowth...
Abstract Purpose: Ewing sarcoma is a pediatric bone tumor that absolutely relies on the transcriptional activity of EWS/ETS family fusion oncoproteins. While most common fusion, EWS/FLI, utilizes lysine-specific demethylase 1 (LSD1) to repress critical suppressors, small-molecule blockade LSD1 has not yet been thoroughly explored as therapeutic approach for sarcoma. We therefore evaluated translational potential potent and specific inhibition with HCI2509 program both EWS/FLI EWS/ERG well...
New prognostic markers are needed to identify patients with Ewing sarcoma (EWS) and osteosarcoma unlikely benefit from standard therapy. We describe the incidence association outcome of circulating tumour DNA (ctDNA) using next-generation sequencing (NGS) assays. A NGS hybrid capture assay an ultra-low-pass whole-genome were used detect ctDNA in banked plasma EWS osteosarcoma, respectively. Patients coded as positive or negative for tested clinical features outcome. The analytic cohort...
PURPOSE The R2Pulm trial was conducted to evaluate the effect of busulfan-melphalan high-dose chemotherapy with autologous stem-cell rescue (BuMel) without whole-lung irradiation (WLI) on event-free survival (main end point) and overall survival, compared standard WLI in Ewing sarcoma (ES) presenting pulmonary and/or pleural metastases. METHODS From 2000 2015, we enrolled patients younger than 50 years age newly diagnosed ES only or Patients received six courses vincristine, ifosfamide,...
Abstract Background The prognostic significance of having extraskeletal (EES) versus skeletal Ewing sarcoma (ES) in the setting modern chemotherapy protocols is unknown. purpose this study was to compare clinical characteristics, biologic features, and outcomes for patients with EES ES. Methods Patients had localized ES were treated on two consecutive using five‐drug (INT‐0154 AEWS0031). analyzed based an (n = 213) or 826) site tumor origin. Event‐free survival (EFS) estimated Kaplan–Meier...
Monoclonal antibodies directed against insulin-like growth factor-1 receptor (IGF-1R) have shown activity in patients with relapsed Ewing sarcoma. The primary objective of Children's Oncology Group trial AEWS1221 was to determine if the addition IGF-1R monoclonal antibody ganitumab interval-compressed chemotherapy improves event-free survival (EFS) newly diagnosed metastatic
Ewing sarcoma is a prototypical fusion transcription factor-associated pediatric cancer that expresses EWS/FLI or highly related FET/ETS chimera. dysregulates to induce and maintain sarcomagenesis, but the mechanisms utilized are not fully understood. We therefore sought define global effects of on chromatin conformation in cells using well-validated 'knock-down/rescue' model function combination with next generation sequencing assays evaluate how landscape changes loss, recovery,...
Abstract Transcription factors (TFs) are frequently mutated in cancer. Paediatric cancers exhibit few mutations genome-wide but harbour sentinel that affect TFs, which provides a context to precisely study the transcriptional circuits support mutant TF-driven oncogenesis. A broadly relevant mechanism has garnered intense focus involves ability of TFs hijack wild-type lineage-specific self-reinforcing circuits. However, it is not known whether this specific type circuitry equally crucial all...
The EWS/FLI-1 fusion gene results from the 11;22 chromosomal translocation in Ewing's sarcoma.The product of is one a growing number structurally altered transcription factors implicated oncogenesis.We have employed subtractive cloning strategy representational difference analysis conjunction with model transformation system to identify genes transcribed response EWS/FLI.We characterized eight transcripts that are dependent on EWS/FLI for expression and two repressed EWS/FLI.Three former...
EWS/FLI-1 is a chimeric protein formed by tumor-specific 11;22 translocation found in both Ewing's sarcoma and primitive neuroectodermal tumor of childhood. has been shown to be potent transforming gene, suggesting that it plays an important role the genesis these human tumors. We now demonstrate characteristics aberrant transcription factor. Subcellular fractionation experiments localized nucleus cells. specifically bound vitro ets-2 consensus sequence similarly normal FLI-1. When coupled...
Significance Ewing sarcoma is a pediatric bone malignancy driven by the fusion protein EWS/FLI. EWS/FLI mediates oncogenesis through its role as an aberrant transcription factor, but little known about molecular mechanisms underlying this function. We demonstrate in cells that activates gene targets binding at associated GGAA-microsatellites, and these repetitive sequences are necessary for cell proliferation anchorage-independent growth. Furthermore, we show previously unknown EWS portion...
<ns4:p>Ewing sarcoma is a small round blue cell malignancy arising from bone or soft tissue and most commonly affects adolescents young adults. Metastatic relapsed Ewing have poor outcomes recurrences remain common. Owing to the associated with advanced disease need for clear research strategy, Children’s Oncology Group Bone Tumor Committee formed New Agents Sarcoma Task Force bring together experts in field evaluate prioritize new agents incorporation into clinical trials. This group’s...
Abstract Purpose: The goal of this study was to identify second-generation mithramycin analogues that better target the EWS-FLI1 transcription factor for Ewing sarcoma. We previously established as an inhibitor, but compound's toxicity prevented its use at effective concentrations in patients. Experimental Design: screened a panel mithralogs establish their ability inhibit compared IC50 with MTD mice determine relationship between efficacy and toxicity. confirmed suppression promoter, mRNA,...
Multi-agent chemotherapeutic regimes remain the cornerstone treatment for Ewing sarcoma, second most common bone malignancy diagnosed in pediatric and young adolescent populations. We have reached a therapeutic ceiling with conventional cytotoxic agents, highlighting need to adopt novel approaches that specifically target drivers of sarcoma oncogenesis. As KDM1A/lysine-specific demethylase 1 (LSD1) is highly expressed cell lines tumors, elevated expression levels associated worse overall...
<ns4:p>Ewing sarcoma is an aggressive, poorly differentiated neoplasm of solid bone that disproportionally afflicts the young. Despite intensive multi-modal therapy and valiant efforts, 70% patients with relapsed metastatic Ewing will succumb to their disease. The persistent failure improve overall survival for this subset highlights urgent need rapid translation novel therapeutic strategies. As associated a paucity mutations in readily targetable signal transduction pathways, targeting key...