Glutamate in Prostate Cancer: New Therapeutic Target, Biomarker?

Researchers have identified a targetable metabolic pathway important for the growth of prostate cancer. The research may also have identified a potentially useful biomarker that can measure the aggressiveness of primary prostate tumors.

Ball-and-stick model of glutamic acid

Shahriar Koochekpour, MD, PhD, of the department of cancer genetics at Roswell Park Cancer Institute in Buffalo, and colleagues from the University of Washington School of Medicine and Tulane Cancer Center found that high levels of serum glutamate, a nonessential amino acid that has a role in cancer metabolism, to be associated with aggressive primary and metastatic prostate cancer. The research is published in Clinical Cancer Research.

“This is an interesting study that demonstrates something that we have understood better in recent years-namely that metabolism is important in driving cancer growth,” said William Oh, MD, chief of the division of hematology and medical oncology at the Mount Sinai School of Medicine and associate director for clinical research at the the Tisch Cancer Institute in New York.

A total of 366 men were analyzed for the study-60 healthy adult males, 197 patients with newly diagnosed primary prostate cancer, and 109 patients with metastatic castration-resistant prostate cancer (mCRPC) who had progressed following androgen-deprivation therapy. Those primary prostate cancer patients with a higher Gleason score had statistically significant higher levels of serum glutamate. The Gleason score is the standard rating for prostate cancer aggressiveness and prognosis based on microscopic primary tumor tissue analysis.

Overall, patients with mCRPC had normal serum glutamate levels but those with primary prostate cancer had significantly higher levels compared to healthy controls. However, levels of glutamate among mCRPC patients differed by race-while Caucasians had lower glutamate levels, African Americans with mCRPC tended to have higher glutamate levels. As African Americans tend to have a higher prostate cancer mortality compared to Caucasians, this result warrants further exploration, according to Dr. Oh.

Glutamate Deprivation May Have Potential as Clinical Approach

The researchers demonstrated that glutamate receptor levels, as measured by immunohistochemical staining, were high in primary and metastatic prostate cancer samples but low or undetectable in benign prostate tissue samples. Inhibition of the glutamate pathway with either riluzole or BAY36-7620, a noncompetitive inhibitor of the glutamate receptor, in prostate cancer cell lines resulted in decreased growth and invasiveness, demonstrating a potentially important role of the glutamate pathway in prostate cancer growth. In tissue culture, riluzole induced prostate cancer cell death. These results demonstrate a potential clinical utility of glutamate metabolism inhibition. Riluzole (Rilutek) is an oral, marketed drug currently used to treat amyotrophic lateral sclerosis (ALS) and is being studied as a therapy for mood disorders including bipolar disorder.

A New Biomarker?

Biomarkers to predict the aggressiveness of prostate cancer are needed as serum prostate-specific antigen (PSA) levels, while helpful, do not always provide reliable prognosis information. Because rapidly growing and dividing cancer cells requires increased metabolism and nutrient turnover, glutamate may be a good marker for this activity. Besides being a precursor to other amino acids and nucleotides, glutamate is involved in a variety of different receptor and transporter systems that activate proliferative signaling pathways that significantly favor malignant cells, said Dr. Koochekpour.

Dr. Koochekpour and colleagues are currently undertaking preclinical studies to better understand the link between glutamate serum levels and levels of glutamate receptor in prostate cancer cells, both primary and metastatic. Because the current study showed that depriving cells of extracellular glutamate can cause cell death, dietary restrictions may potentially have a therapeutic effect, said Dr. Koochekpour. Many foods contain or can be enriched with glutamate, including monosodium glutamate (MSG). Research is needed to understand the effect of food on prostate cancer, Dr. Koochekpour emphasized.

“If blocking glutamate or its receptor could slow prostate cancer growth, then that suggests that medications or even dietary changes could influence the progression of prostate cancer, or eventually even its development,” said Dr. Oh.

While an easy blood test-just a drop or two of blood can assess serum glutamate levels-would be very easy to screen for prostate cancer aggressiveness, “at this stage I believe it is premature to go for that kind of set-up or diagnostic plan,” said Dr. Koochekpour. “I am hoping many investigators in different disciplines and with different expertise will dissect further the biology of [this single] amino acid, glutamate, in different types of cancers,” said Dr. Koochekpour.

“As a biomarker, [glutamate] could be looked at more extensively to see if it could predict changes in Gleason score in patients who opt for active surveillance, to see if a blood test could predict a change in Gleason score without the ultimate need for a prostate biopsy to do so,” said Dr. Oh.

The importance of the study, according to Dr. Oh, is the insights it provides on the biology of the cancer. “It is more than just a blood test-we hope we are learning about prostate cancer's Achilles' heel.”