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BET inhibitors in metastatic prostate cancer: therapeutic implications and rational drug combinations
Mark C Markowski1, Angelo M De Marzo1,2,3, Emmanuel S Antonarakis1,3
1a Department of Oncology , Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins , Baltimore , MD , USA.
Introduction:
The bromodomain and extra-terminal (BET) family of proteins are epigenetic readers of acetylated histones regulating a vast network of protein expression across many different cancers. Therapeutic targeting of BET is an attractive area of clinical development for metastatic castration-resistant prostate cancer (mCRPC), particularly due to its putative effect on c-MYC expression and its interaction with the androgen receptor (AR). Areas covered: We speculate that a combination approach using inhibitors of BET proteins (BETi) with other targeted therapies may be required to improve the therapeutic index of BET inhibition in the management of prostate cancer. Preclinical data has identified several molecular targets that may enhance the effect of BET inhibition in the clinic. This review will summarize the known preclinical data implicating BET as an important therapeutic target in advanced prostate cancer, highlight the ongoing clinical trials targeting this protein family, and speculate on rationale combination strategies using BETi together with other agents in prostate cancer. A literature search using Pubmed was performed for this review. Expert opinion: Use of BETi in the treatment of mCRPC patients may require the addition of a second novel agent.
Insights
Targeting bromodomain and extra-terminal (BET) proteins shows promise for prostate cancer. Combination therapies involving BET inhibitors may be necessary for effective treatment of metastatic castration-resistant prostate cancer (mCRPC).
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Bromodomain and extra-terminal (BET) proteins are epigenetic readers involved in gene regulation across various cancers.
- BET proteins influence c-MYC expression and interact with the androgen receptor (AR), making them a therapeutic target in prostate cancer.
- Metastatic castration-resistant prostate cancer (mCRPC) is a significant area for BET inhibitor development.
Purpose of the Study:
- To review preclinical data on BET proteins as therapeutic targets in advanced prostate cancer.
- To summarize ongoing clinical trials investigating BET inhibitors (BETi).
- To explore potential combination strategies for BETi in prostate cancer management.
Main Methods:
- Literature search conducted using PubMed.
- Review of preclinical data and ongoing clinical trials.
- Speculation on rational combination therapies.
Main Results:
- Preclinical data supports BET proteins as important targets in advanced prostate cancer.
- Several molecular targets have been identified that may enhance BET inhibition efficacy.
- Ongoing clinical trials are evaluating BET inhibitors in prostate cancer.
Conclusions:
- BET inhibitors (BETi) represent a promising therapeutic strategy for prostate cancer.
- Combination therapy with BETi and other agents may be required to improve outcomes in mCRPC.
- Further research into rational combination strategies is warranted.