A Master Regulator of Aggressive Prostate Cancer Variants
Technical Report,30 Sep 2016,29 Sep 2018
Cedars-Sinai Medical Center Los Angeles United States
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Treatment of PC by androgen suppression is known to promote the emergence of aggressive variants that are AR-independent. In a studyfunded by this grant and published in Nature Medicine in December 2018 Rotinen, You et al. Nat Med 241887-1898, 2018, PMID 30478421 we identified the developmental transcription factor ONECUT2 OC2 as a master regulator of AR networks in metastatic castration-resistant prostate cancer CRPC. We showed that OC2 acts as a survival factor in metastatic CRPC mCRPC models, suppresses the AR transcriptional program by direct regulation of AR target genes and the AR licensing factor FOXA1, and activates genes associated with neural differentiation and progression to lethal disease. OC2 appears active in a substantial subset of human prostate adenocarcinoma and neuroendocrine tumors. Inhibition of OC2 by a newly identified small molecule, CSRM617, suppresses metastasis in mice. These findings suggest that OC2 displaces AR-dependent growth and survival mechanisms in many cases where AR remains expressed, but where its activity is bypassed. We also demonstrated that OC2 is also a potential drug target in the metastatic phase of aggressive PC.
- Medicine and Medical Research
- Genetic Engineering and Molecular Biology