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Supplementary Data from Targeting the p300/CBP Axis in Lethal Prostate Cancer

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posted on 2023-04-03, 23:41 authored by Jonathan Welti, Adam Sharp, Nigel Brooks, Wei Yuan, Christopher McNair, Saswati N. Chand, Abhijit Pal, Ines Figueiredo, Ruth Riisnaes, Bora Gurel, Jan Rekowski, Denisa Bogdan, William West, Barbara Young, Meera Raja, Amy Prosser, Jordan Lane, Stuart Thomson, Jenny Worthington, Stuart Onions, Jonathan Shannon, Silvia Paoletta, Richard Brown, Don Smyth, Gareth W. Harbottle, Veronica S. Gil, Susana Miranda, Mateus Crespo, Ana Ferreira, Rita Pereira, Nina Tunariu, Suzanne Carreira, Antje J. Neeb, Jian Ning, Amanda Swain, David Taddei, Matthew J. Schiewer, Karen E. Knudsen, Neil Pegg, Johann S. de Bono

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Movember Foundation

Prostate Cancer UK

Department of Defense

Prostate Cancer Foundation

Stand Up To Cancer

Cancer Research UK

UK Department of Health

Experimental Cancer Medicine Centre

NCI

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ARTICLE ABSTRACT

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. 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

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    cancer

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