Targeting the p300/CBP Axis in Lethal Prostate Cancer
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 11, 2021
- Source ID
- 10.1158/2159-8290.cd-20-0751
Entities
People
- Abhijit Pal
- Adam Sharp
- Amanda Swain
- Amy Prosser
- Ana Ferreira
- Antje Neeb
- Barbara Young
- Bora Gurel
- Christopher Mcnair
- David Taddei
- Denisa Bogdan
- Don Smyth
- Gareth W. Harbottle
- Ines Figueiredo
- Jan Rekowski
- Jenny Worthington
- Jian Ning
- Johann de Bono
- Jonathan Shannon
- Jonathan Welti
- Jordan Lane
- Karen E. Knudsen
- Mateus Crespo
- Matthew J. Schiewer
- Meera Raja
- Neil Pegg
- Nigel Brooks
- Nina Tunariu
- Richard Brown
- Rita Pereira
- Ruth Riisnaes
- Saswati N Chand
- Silvia Paoletta
- Stuart Onions
- Stuart Thomson
- Su2c/pcf International Prostate Cancer Dream Team
- Susana Miranda
- Suzanne Carreira
- Veronica Gil
- William West
- Yuan Wei
Organizations
- Cancer Research UK
- Movember Foundation
- National Cancer Institute
- Stand Up to Cancer
- United States Department of Defense