Studies shed light on mechanism of aggressive PCa

Two new studies provide insights into aggressive prostate cancer that may suggest novel approaches to treatment.

In one study, researchers from the University of California-Davis, UC San Diego, and other institutions have identified a key mechanism behind aggressive prostate cancer. The study shows that two long non-coding RNAs (PRNCR1 and PCGEM1) activate androgen receptors, circumventing androgen-deprivation therapy, as reported online in Nature (Aug. 14, 2013). In their active state, these receptors turn on genes that spur growth and metastasis, making these cancers highly treatment resistant.

Researchers say the study illustrates how prostate cancer can thrive, even when deprived of hormones, and provides tempting targets for new therapies.

“Androgen-deprivation therapy will often put cancer in remission, but tumors come back, even without testosterone,” said co-author Christopher Evans, MD, of the UC Davis School of Medicine. “We found that these long non-coding RNAs were activating the androgen receptor. When we knocked them out, cancer growth decreased in both cell lines and tumors in animals.”

Using patient samples from UC Davis, the research team determined that both PRNCR1 and PCGEM1 are highly expressed in aggressive tumors. These RNAs bind to androgen receptors and activate them in the absence of testosterone, turning on as many as 617 genes.

Further investigation determined that one of these long non-coding RNAs is turning on androgen receptors by an alternate switching mechanism. This is critically important, according to the researchers, because many prostate cancer agents work by blocking a part of the androgen receptor, the C-terminus. However, PCGEM1 activates another part of the receptor, called the N-terminus, which also turns on genes.

“The androgen receptor is unique; if you knock out the C-terminus, that remaining part still has the ability to transcribe genes,” Dr. Evans said.

In addition, about 25% of these cancers have a mutated version of the androgen receptor that has no C-terminus. These receptors are locked in the “on” position, activating genes associated with tumor aggression.

Regardless of the receptor’s status, PRNCR1 and PCGEM1 are crucial to prostate cancer growth. In turn, knocking out these RNAs has a profound impact on gene expression, both in cell lines and animal models. The team used antisense to knock out the RNAs and observe how the tumors and cells responded. In each case, there was a direct relationship between RNA activity, gene expression, and cancer growth.

In a second study, researchers at Rutgers Robert Wood Johnson Medical School in Piscataway, NJ have identified a key transcription factor that is over-produced in treatment-resistant prostate cancer, as well as the two protein kinases that trigger the process.

The finding, published in Molecular Cancer Research (2013; 11:736–47), could be used to develop treatments for prostate cancer that is resistant to current therapies, researchers say.

Study authors, led by Joseph Fondell, PhD, found that in clinically localized prostate cancer, the key transcription factor, MED1, is overexpressed. According to Dr. Fondell, the finding potentially could be used as a biomarker in cancer screenings, indicating that the cancer has become aggressive.

“As MED1 is a known co-activator of androgen receptors, the overexpression of MED1 is thought to facilitate alternative gene expression patterns that drive treatment-resistant cancer cell growth in the prostate,” he said.

“Our study showed for the first time that MED1 expression is elevated in malignant cells of a statistically significant number of patients with clinical prostate cancer and that this overexpression correlates with an increase in cancer cell growth and invasiveness,” added first author Feng Jin, PhD. “In addition to accelerated tumor growth, our study showed that overexpression of MED1 may also be involved with inflammation of the prostate.”

Further study of the process using mouse models that mimic human prostate cancer showed that two protein kinases, ERK and PI3K/AKT, were overactive and responsible for MED1 overproduction, ultimately accelerating the progression and spread of prostate cancer.

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