期刊
ONCOTARGET
卷 6, 期 35, 页码 37678-37694出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.5520
关键词
EWS-FLI1; ETS fusion proteins; YK-4-279; ewing sarcoma; erythoid leukemia
资金
- National Cancer Institute [P30 CA51008]
- Austrian Science Fund (FWF) [SFB-F2807, SFB-F4707]
- Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria
- Children's Cancer Foundation (Baltimore MD)
- St. Baldrick's Foundation
- Go 4 the Goal
- Burroughs Wellcome Clinical Scientist Award in Translational Research
- NIH [RC4CA156509, R01CA133662, R01CA138212]
Ewing sarcoma is an aggressive tumor of bone and soft tissue affecting predominantly children and young adults. Tumor-specific chromosomal translocations create EWS-FLI1 and similar aberrant ETS fusion proteins that drive sarcoma development in patients. ETS family fusion proteins and over-expressed ETS proteins are also found in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients. Transgenic expression of EWS-FLI1 in mice promotes high penetrance erythroid leukemia with dense hepatic and splenic infiltrations. We identified a small molecule, YK-4-279, that directly binds to EWS-FLI1 and inhibits its oncogenic activity in Ewing sarcoma cell lines and xenograft mouse models. Herein, we tested in vivo therapeutic efficacy and potential side effects of YK-4-279 in the transgenic mouse model with EWS-FLI1 induced leukemia. A two-week course of treatment with YK-4-279 significantly reduced white blood cell count, nucleated erythroblasts in the peripheral blood, splenomegaly, and hepatomegaly of erythroleukemic mice. YK-4-279 inhibited EWS-FLI1 target gene expression in neoplastic cells. Treated animals showed significantly better overall survival compared to control mice that rapidly succumbed to leukemia. YK-4-279 treated mice did not show overt toxicity in liver, spleen, or bone marrow. In conclusion, this in vivo study highlights the efficacy of YK-4-279 to treat EWS-FLI1 expressing neoplasms and support its therapeutic potential for patients with Ewing sarcoma and other ETS-driven malignancies.
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