Targeting the p300/CBP Axis in Lethal Prostate Cancer.
View/ Open
Date
2021-05-01ICR Author
Author
Welti, J
Sharp, A
Brooks, N
Yuan, W
McNair, C
Chand, SN
Pal, A
Figueiredo, I
Riisnaes, R
Gurel, B
Rekowski, J
Bogdan, D
West, W
Young, B
Raja, M
Prosser, A
Lane, J
Thomson, S
Worthington, J
Onions, S
Shannon, J
Paoletta, S
Brown, R
Smyth, D
Harbottle, GW
Gil, VS
Miranda, S
Crespo, M
Ferreira, A
Pereira, R
Tunariu, N
Carreira, S
Neeb, AJ
Ning, J
Swain, A
Taddei, D
SU2C/PCF International Prostate Cancer Dream Team,
Schiewer, MJ
Knudsen, KE
Pegg, N
de Bono, JS
Type
Journal Article
Metadata
Show full item recordAbstract
Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of AR (AR-SV). Inhibitors of transcriptional coactivators that regulate AR activity, including the paralog histone acetyltransferase proteins p300 and CBP, are attractive therapeutic targets for lethal prostate cancer. Herein, we validate targeting p300/CBP as a therapeutic strategy for lethal prostate cancer and describe CCS1477, a novel small-molecule inhibitor of the p300/CBP conserved bromodomain. We show that CCS1477 inhibits cell proliferation in prostate cancer cell lines and decreases AR- and C-MYC-regulated gene expression. In AR-SV-driven models, CCS1477 has antitumor activity, regulating AR and C-MYC signaling. Early clinical studies suggest that CCS1477 modulates KLK3 blood levels and regulates CRPC biopsy biomarker expression. Overall, CCS1477 shows promise for the treatment of patients with advanced prostate cancer. SIGNIFICANCE: Treating CRPC remains challenging due to persistent AR signaling. Inhibiting transcriptional AR coactivators is an attractive therapeutic strategy. CCS1477, an inhibitor of p300/CBP, inhibits growth and AR activity in CRPC models, and can affect metastatic CRPC target expression in serial clinical biopsies.See related commentary by Rasool et al., p. 1011.This article is highlighted in the In This Issue feature, p. 995.
Collections
Research team
Cancer Biomarkers
Prostate Cancer Targeted Therapy Group
Language
eng
Date accepted
2020-12-11
License start date
2021-01-11
Citation
Cancer discovery, 2021
Publisher
AMER ASSOC CANCER RESEARCH