title: A small molecule inhibitor of ETV1, YK-4-279, prevents prostate cancer growth and metastasis in a mouse xenograft model.
abstract: BACKGROUND
  The erythroblastosis virus E26 transforming sequences (ETS) family of transcription factors consists of a highly conserved group of genes that play important roles in cellular proliferation, differentiation, migration and invasion. Chromosomal translocations fusing ETS factors to promoters of androgen responsive genes have been found in prostate cancers, including the most clinically aggressive forms. ERG and ETV1 are the most commonly translocated ETS proteins. Over-expression of these proteins in prostate cancer cells results in a more invasive phenotype. Inhibition of ETS activity by small molecule inhibitors may provide a novel method for the treatment of prostate cancer.
  
  
  RESULTS
  We recently demonstrated that the small molecule YK-4-279 inhibits biological activity of ETV1 in fusion-positive prostate cancer cells leading to decreased motility and invasion in-vitro. Here, we present data from an in-vivo mouse xenograft model. SCID-beige mice were subcutaneously implanted with fusion-positive LNCaP-luc-M6 and fusion-negative PC-3M-luc-C6 tumors. Animals were treated with YK-4-279, and its effects on primary tumor growth and lung metastasis were evaluated. YK-4-279 treatment resulted in decreased growth of the primary tumor only in LNCaP-luc-M6 cohort. When primary tumors were grown to comparable sizes, YK-4-279 inhibited tumor metastasis to the lungs. Expression of ETV1 target genes MMP7, FKBP10 and GLYATL2 were reduced in YK-4-279 treated animals. ETS fusion-negative PC-3M-luc-C6 xenografts were unresponsive to the compound. Furthermore, YK-4-279 is a chiral molecule that exists as a racemic mixture of R and S enantiomers. We established that (S)-YK-4-279 is the active enantiomer in prostate cancer cells.
  
  
  CONCLUSIONS
  Our results demonstrate that YK-4-279 is a potent inhibitor of ETV1 and inhibits both the primary tumor growth and metastasis of fusion positive prostate cancer xenografts. Therefore, YK-4-279 or similar compounds may be evaluated as a potential therapeutic tool for treatment of human prostate cancer at different stages.
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Said
authors.initials: S
authors.lastname: Rahim
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Tsion
authors.initials: T
authors.lastname: Minas
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Sung-Hyeok
authors.initials: SH
authors.lastname: Hong
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Justvig
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Haydar
authors.initials: H
authors.lastname: Çelik
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Yasemin Saygideger
authors.initials: YS
authors.lastname: Kont
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Jenny
authors.initials: J
authors.lastname: Han
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Abraham T
authors.initials: AT
authors.lastname: Kallarakal
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Yali
authors.initials: Y
authors.lastname: Kong
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, United States of America.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Milton L
authors.initials: ML
authors.lastname: Brown
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Kallakury
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Toretsky
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Aykut
authors.initials: A
authors.lastname: Üren
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000071230:Transcriptional Regulator ERG; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; C072312:ERG protein, human; C095239:ETV1 protein, human; D007211:Indoles; D015514:Oncogene Proteins, Fusion; D015534:Trans-Activators; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; C562345:YK 4-279