A new study suggests that chemoprevention with anti-androgen therapies may not benefit all patients at risk for prostate cancer and could cause harm to some. Researchers at the Dana-Farber Cancer Institute and Harvard Medical School have identified a genetic mutation that actually results in a more robust transition from a precancerous to cancerous state when exposed to androgen deprivation.
The observation that spurred the current laboratory study was the bolus of patients, part of either the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial or the Prostate Cancer Prevention Trial (PCPT) with Finasteride, who ended up with a higher risk for high-grade prostate cancer after being treated with androgen inhibitors. The men in both trials had high-grade prostatic intraepithelial neoplasia (HG-PIN), considered a precursor to prostate cancer. Androgen deprivation is thought to help prevent the neoplasia from becoming full-blown prostate cancer.
The therapies worked for most men. The REDUCE trial demonstrated a 23% lower chance for those in the experimental arm to be diagnosed with prostate cancer and the PCPT trial showed that men who took finasteride had a 26% lower chance of developing prostate cancer compared to men who were given a placebo. But in June 2012, the US Food and Drug Administration (FDA) issued a warning that 5α-reductase inhibitors (5-ARIs) like dutasteride and finasteride can increase the risk of aggressive forms of prostate cancer in some men. In the REDUCE trial, 1% of men taking dutasteride developed aggressive prostate cancer compared to 0.5% of men taking a placebo.
Treatment with 5-ARI results in androgen deprivation as these inhibitors function by decreasing serum levels of dihydrotestosterone (DHT), an androgen hormone. 5α-reductase synthesizes DHT in the prostate, adrenal glands, and testes. Testosterone is readily converted into DHT, a more potent androgen.
The current study, published in Cancer Discovery may explain the higher incidence of these aggressive cancers, although the study was done using a mouse model and needs to be further studied in prostate cancer patients.
When Thomas M. Roberts, PhD, of the Dana Farber Cancer Institute and colleagues surgically castrated a mouse model of prostate neoplasia, HG-PIN, tumor growth was prevented in the majority of cases, but the researchers observed that those tumors with a PTEN deletion exhibited castration-resistant growth. Those mice whose tumors lacked the PTEN gene and were surgically castrated and treated with androgen deprivation had even more unchecked growth and neoplasia that turned into invasive castration-resistant prostate cancer (CRPC). Treatment of the mice after surgical castration with the androgen receptor antagonist enzalutamide (Xtandi), approved earlier this year as treatment of CRPC, had a similar effect in inducing CRPC.
Inhibiting two gene products part of the phosphoinositide 3-kinase (PI3K) pathway, p110-β or p110-α, blocked the growth of the neoplasms, suggesting that inhibiting the activity of the PI3K pathway in a PTEN–deficient background can prevent initiation of aggressive prostate cancer. Treatment with either the experimental drug BEZ235, a dual mTOR/PI3K inhibitor or BKM120, a pan-inhibitor of PI3Ks, had a similar effect as genetic inhibition, restoring slower growth of the tumor.
The study found the signaling in already established CRPC tumors was different, however. Unlike with earlier-stage prostate tumors, addition of a mitogen-activated protein kinase (MAPK) inhibitor was necessary to block growth of the CRPC tumors in the mice. Treatment of the CRPC mice with BEZ235 and AZD6224, a MEK inhibitor led to arrest of the advanced-stage tumor growth.
While the researchers believe that these findings may have relevance for prostate cancer development in humans, more research needs to be done to confirm the signaling pathways and biology in human tumors. “Obviously, mice are not men, and it remains to be seen whether similar processes might be occurring in humans,” state the authors in their discussion.
Between 9% and 45% of HG-PIN cases have a loss of the PTEN gene, according to the study authors. If these results are validated, one concern is whether patients can tolerate the PI3K and MAPK inhibitors over long treatment periods. Regardless, this type of study demonstrates the need to understand the signaling pathways that underlie tumorigenesis and the genetic variability among the tumors of different patients.