Molecular Switch Identified as Treatment Target in Castration-Resistant Prostate Cancer

Myles A. Brown, MD

Researchers have discovered that the oncogenic function of a particular protein in castration-resistant prostate cancer (CRPC) can cause the cancer to spread without stimulation by male hormones, suggesting that using drugs to target this protein may serve as an effective treatment option in patients who express it. The findings were published in the journal Science.

The protein researchers studied is called enhancer of zeste homolog 2 (EZH2), a subunit of Polycomb repressive complex 2 (PRC2), and it is found in increased quantities in patients with CRPC. EZH2 is an epigenetic regulator, or a protein that regulates genes without changing their DNA structure. Normally, the complex is responsible for shutting off the expression of genes.

EZH2 had been found in high levels in cases of late-stage CRPC, but researchers believed it functioned by turning off gene activity, which is its normal role. However, co-senior authors Myles A. Brown, MD, and X. Shirley Liu, PhD, of the Dana-Farber Cancer Institute, and their colleagues found that in CRPC, EZH2 switches to a different mode in which it is able to activate cell-growth genes that promote the ability of these cancers to spread. EZH2 is also able to operate independently of the presence of androgen hormones, which are also associated with the growth of prostate cancer cells.

Many cases of CRPC eventually operate independently of androgen hormones and become resistant to treatment. Tumor cells are able to reprogram the androgen receptors so that cell-growth genes are activated despite the lack of stimulation through hormones.

EZH2 is being explored as a therapeutic target in other types of cancer, such as certain types of non-Hodgkin lymphoma and breast cancer. The authors noted that these drugs are designed to block EZH2’s gene-suppressing role. However, they cited studies that suggested these current drugs might cause serious hematologic side effects.

In a press release, Brown said that since the gene-suppressing role of EZH2 is not the important function of the protein in CRPC, but rather its ability to work with the androgen receptor to turn on genes involved with cell growth, designing inhibitors of EZH2 that avoid targeting the gene-repressor function—thus perhaps avoiding the hematologic side effects currently associated with these inhibitors—might provide a safe and effective alternative therapy for CRPC.

Additionally, the EZH2 protein is activated by the PI3K signaling pathway. Many PI3K inhibitors are in various stages of clinical development. Brown suggested that using a combination of drugs that would inhibit both the PI3K pathway and the EZH2 protein may be another strategy to consider in treating patients with CRPC.

Xu K, Wu ZJ, Groner AC, et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science. 2012;338(6113):1465-1469.