Toppling the HAT to Treat Lethal Prostate Cancer
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Updated: Nov 6, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Reyaz Ur Rasool1, Ramakrishnan Natesan1, Irfan A Asangani2,3
1Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Abstract:
In this issue of Cancer Discovery, Welti and colleagues demonstrate a positive correlation between the expression of the histone acetyltransferase paralogs CBP and p300 with increased androgen receptor (AR) signaling and androgen deprivation therapy resistance in advanced prostate cancer. CCS1477, a selective inhibitor of p300/CBP bromodomain, disrupts AR- and MYC-regulated gene expression, suppresses tumor growth in vivo in multiple castration-resistant prostate cancer xenograft models, and modulates biomarker expression in early clinical evaluation, providing a novel therapeutic approach for AR-addicted advanced prostate cancer.See related article by Welti et al., p. 1118.
Insights
Researchers found that higher levels of CBP and p300 proteins correlate with treatment resistance in advanced prostate cancer. A new drug targeting these proteins shows promise in suppressing tumor growth and offers a potential therapy for advanced prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Androgen receptor (AR) signaling is crucial in prostate cancer progression.
- Resistance to androgen deprivation therapy (ADT) is a major challenge in advanced prostate cancer.
- Histone acetyltransferases CBP and p300 are implicated in cancer development.
Purpose of the Study:
- To investigate the role of CBP and p300 in ADT resistance in advanced prostate cancer.
- To evaluate the therapeutic potential of a selective p300/CBP bromodomain inhibitor, CCS1477.
Main Methods:
- Correlation analysis of CBP/p300 expression with AR signaling and ADT resistance.
- Assessment of CCS1477's effect on AR- and MYC-regulated gene expression.
- Evaluation of CCS1477's efficacy in preclinical castration-resistant prostate cancer xenograft models.
- Analysis of biomarker modulation in early clinical trials.
Main Results:
- Positive correlation observed between CBP/p300 expression and increased AR signaling.
- Elevated CBP/p300 expression linked to ADT resistance in advanced prostate cancer.
- CCS1477 effectively suppressed tumor growth in preclinical models.
- CCS1477 demonstrated modulation of biomarkers in early clinical evaluation.
Conclusions:
- CBP and p300 are key drivers of AR signaling and ADT resistance in advanced prostate cancer.
- CCS1477 represents a novel therapeutic strategy for AR-addicted advanced prostate cancer.
- Targeting p300/CBP bromodomains offers a promising avenue for prostate cancer treatment.
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