Sarcoma is an aggressive bone and soft tissue malignancy affecting children,
adolescents and young adults. High-dose, multi-agent chemotherapy cures
slightly more than half of patients with Ewing Sarcoma, but for the remainder
no effective therapeutic options currently exist. Thus, innovative approaches
are needed to improve clinical outcomes for this aggressive disease. Ewing
Sarcoma originates in stem or stem-like cells of mesenchymal or neural crest
origin, and, like many sarcomas, is driven by recurrent oncogenic fusions.
vast majority of these fusions consist of the N-terminus of the EWS protein and
the C-terminus, including the DNA-binding domain, of an Ets transcription
factor. EWS/Ets fusions, EWS/Fli1 being
the most common, result in profound alterations of gene expression in the cell,
through transcriptional, as well as other, mechanisms. While EWS/Ets fusions
represent a logical therapeutic target, such targeting has proven difficult.
alternative approach is the targeting of key pro-oncogenic mechanisms
downstream of EWS/Fli1. We have taken the approach of investigating microRNA-mediated
mechanisms downstream of EWS/Fli1, with the goal of identifying novel pathways
amenable to targeting by microRNA or/and other means. Mechanistic understanding
of microRNA-mediated pathways in Ewing Sarcoma has revealed both new regulatory
mechanisms affecting established oncogenic pathways, such as receptor tyrosine
kinase signaling, and a new oncogenic pathway involving modulation of the H3K9
histone methyl mark.
Our ongoing efforts are directed at further understanding
of how these pathways contribute to Ewing Sarcoma pathogenesis, and how they
could be manipulated for improved therapies for this aggressive cancer.
Jedlicka P. Ewing Sarcoma,
an Enigmatic Malignancy of Likely Progenitor Cell Origin, Driven by
Transcription Factor Oncogenic Fusions. International
Journal of Clinical and Experimental Pathology (2010).
EL, Parrish JK, Irwin AE, Niemeyer BF, Kern HB, Birks DK and Jedlicka P. A
novel oncogenic mechanism in Ewing Sarcoma involving IGF pathway targeting by
EWS/Fli1-regulated microRNAs. Oncogene
TP, Smith A, McKinsey E, Reaves L, Jedlicka P and Ford HL. EWS/Fli1 regulates Eya3 in Ewing's sarcoma via
modulation of microRNA-708, resulting in increased cell survival and
chemoresistance. Molecular Cancer Research (2012).
Dylla L, Moore C and Jedlicka P. MicroRNAs in Ewing
Sarcoma. Frontiers in Oncology
L and Jedlicka P. Growth-promoting role of the miR-106a~363 cluster in Ewing
Sarcoma. PLoS One (2013).
JK, Sechler M, Winn RA and Jedlicka P. The histone demethylase KDM3A is a
microRNA-22-regulated tumor promoter in Ewing Sarcoma. Oncogene (2013).