ETS FAMILY OF TRANSCRIPTION FACTORS AS A THERAPEUTIC TARGET IN CANCER

Abstract

The ETS family of transcription factors share a conserved DNA binding domain that recognizes a purine rich consensus sequence with GGAA/T motif. ETS genes have been implicated in a wide array of malignancies including acute myeloid leukemia, Ewing sarcoma and prostate cancer. These genes are suppressed in most adult tissues, while in cancer; their expression is upregulated as a result of chromosomal rearrangements that leave the factors under a control of ubiquitously active promoters. In Ewing sarcoma (ES) patients, tumor specific chromosomal translocation involving FLI1 creates EWS-FLI1 protein. In previous studies, we identified a small molecule inhibitor, YK-4-279, that directly binds to EWS-FLI1 and inhibit its activities. Due to lack of an ES transgenic mouse model, we tested the in vivo therapeutic efficacy of YK-4-279 in the only available transgenic mouse model with EWS-FLI1 induced neoplasm. We showed that short-term YK-4-279 treatment led to correction of abnormal hematopoiesis and improved overall survival of EWS-FLI1+ leukemic mice. Thus far, a genetically engineered mouse model for EWS-FLI1 driven Ewing sarcoma has not been successfully generated. Here, we present data where we tried various approaches to conditionally express EWS-FLI1 using cre recombinase in order to generate a Ewing sarcoma transgenic mouse model. We used the Osx promoter to target Cre recombinase expression to the osteoblast lineage. Alternatively, we injected Cre expressing adenovirus to induce EWS-FLI1 expression locally. Most attempts resulted in embryonic lethality or developmental defects. Chromosomal translocations that involve members of the ETS transcription factor family are also present in a majority of prostate cancer patients. In order to understand how ETS transcription factors drive tumorigenicity in prostate cancer, we investigated their interacting protein partners. We identified and validated ezrin, RHA, and PARP as ERG interacting partners and show that YK-4-279 can inhibit these interactions. Overall, in this study, we demonstrate that direct targeting of ETS transcription factors with small molecules could be of significant therapeutic value in oncology.