Targeting the p300/CBP Axis in Lethal Prostate Cancer
| Autor: | Matthew J. Schiewer, Susana Miranda, William West, Suzanne Carreira, Stuart Thomson, Gareth W. Harbottle, Ana Ferreira, Stuart Thomas Onions, Donald Smyth, Nigel Brooks, Jonathan Shannon, Jonathan Welti, Nina Tunariu, Johann S. de Bono, Christopher McNair, Jenny Worthington, Wei Yuan, Karen E. Knudsen, Adam Sharp, Barbara Young, Amy Prosser, Jan Rekowski, Su C, Rita Pereira, Amanda Swain, Jian Ning, Abhijit Pal, Jordan Lane, Ruth Riisnaes, Bora Gurel, Ines Figueiredo, Mateus Crespo, Richard J. C. Brown, Saswati N. Chand, David Michel Adrien Taddei, Denisa Bogdan, Veronica Gil, Silvia Paoletta, Meera Raja, Neil Anthony Pegg, Antje Neeb |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male 03 medical and health sciences Prostate cancer Mice 0302 clinical medicine Cell Line Tumor Gene expression Androgen Receptor Antagonists Medicine Animals Humans p300-CBP Transcription Factors Oxazoles Cell Proliferation biology Cell growth business.industry Alternative splicing Imidazoles Histone acetyltransferase medicine.disease Xenograft Model Antitumor Assays Biomarker (cell) Bromodomain Androgen receptor Prostatic Neoplasms Castration-Resistant 030104 developmental biology Oncology 030220 oncology & carcinogenesis biology.protein Cancer research business |
| Zdroj: | Cancer discovery. 11(5) |
| ISSN: | 2159-8290 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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