Castration-resistant prostate cancer (CRPC) is a particularly aggressive form of prostate cancer. Although the standard of care treatment, which involves disrupting androgen receptor (AR) signaling, is usually effective for 2-3 years, the treatment is not effective long-term and CRPC often develops into lethal metastases.
This is exactly why new research published in Molecular Cancer Research from scientists at Boston University School of Medicine (BUSM) is so exciting. Led by Gerald V. Denis PhD, the BUSM team has determined that blocking a particular protein could prevent the CRPC growth.
"Our findings are significant because current therapeutic options for CRPC are limited and focus primarily on suppressing prostate tumor cells that rely on AR signaling," explained first author Jordan Shafran. "Therefore, it is imperative to identify 'druggable' targets that regulate prostate cancer cell migration and invasion in cells that are either reliant on, or independent of, androgen receptor signaling," he added.
The group of proteins that the researchers investigated is called BET bromodomain proteins and consists of BRD2, BRD3 and BRD4, which regulate gene expression. Following the study’s results, inhibiting the protein BRD4 consistently regulated prostate cancer cell migration and invasion. The same was not found for the proteins BRD2 or BRD3.
The authors elaborate, writing, “We found that BRD4 regulates cell migration across all models of CRPC, regardless of aggressiveness and AR status, whereas BRD2 and BRD3 only regulate migration and invasion in less aggressive models that retain AR expression or signaling. BRD4, a co-regulator of gene transcription, controls migration and invasion through transcription of AHNAK, a large scaffolding protein linked to [the] promotion of metastasis in a diverse set of cancers. Furthermore, treatment of CRPC cell lines with low doses of MZ1, a small-molecule, BRD4-selective degrader, inhibits metastatic potential.”
This discovery could have significant implications for the future of CRPC treatments and could offer a new targetable pathway to treat metastatic CRPC, according to the authors.