New Target to Prevent Castration-resistant Prostate Cancer Metastases
Researchers at Boston University School of Medicine have discovered that BRD4, a member of the BET bromodomain protein family (BRD2, BRD3 and BRD4), could be an important new target to prevent castration-resistant prostate cancer metastases.
Castration-resistant prostate cancer is a highly aggressive form of prostate cancer that often leads to the development of lethal metastases. These metastases kill over 31,000 American men every year. The standard of care treatment for patients with castration-resistant prostate cancer typically includes disruption of androgen receptor signaling with drugs, called ‘androgen deprivation therapy’. While effective for an average of 2-3 years, this therapy eventually fails to impede cancer progression, due to acquired resistance to the drugs. Patients then develop metastases, and cure is no longer possible.
In this study, Shafran et al., examined prostate cancer cell lines that model common forms of prostate cancer that are resistant to androgen deprivation therapy, and found that BRD4, but not similar family members BRD2 or BRD3, regulates the expression of key proteins that directly contribute to prostate cancer disease progression. These findings are novel because, until now, it was not clear which of the BET family of proteins regulate transcriptional programs, or how they influence prostate cancer cell morphology (shape and polarity), motility (the ability to move independently) and invasiveness, each of which are associated with ability to metastasize.
“Our findings, which appear in Prostate Cancer and Prostatic Diseases, are significant because current therapeutic options for castration-resistant prostate cancer are limited and focus primarily on suppressing prostate tumor cells that rely on androgen receptor signaling. Castration-resistant prostate cancer is a complex, heterogenous disease, with different androgen receptor states and expression patterns across individual tumor cells in the same patient. As prostate tumor cells become resistant to therapy, their reliance on androgen receptor signaling is reduced and alternative signaling mechanisms are activated. Out of this complex mixture, the metastatic cells arise. Therefore, it is imperative to identify new, druggable targets, as we have done here, that regulate the expression of critical transcription factors across diverse prostate cancer cell types, to block migration and invasion and eventual metastasis,” explained Jordan Shafran, PhD.