Investigators Hone in on Aggressive Prostate Tumors

Neil Osterweil

November 25, 2013

Investigators an ocean apart are proposing very different strategies for determining which prostate tumors are cause for worry and which can be pretty much left alone.

Aggressive metastatic prostate cancer cells express high levels of the NAALADL2 (N-acetyl-L-aspartyl-L-glutamate peptidase-like 2) protein, which can serve as a diagnostic and prognostic biomarker for prostate cancer, report Hayley Whitaker, PhD, and colleagues at Cancer Research UK in Cambridge, United Kingdom.

"This is early research, but if clinical trials confirm our results, it could help clinicians to tell which patients have a more aggressive tumor and need proportionally aggressive treatment, while sparing patients with low-grade tumors unnecessary radiotherapy or surgery," Dr. Whitaker said in a statement.

The study was published online November 18 in Oncogene.

Meanwhile, investigators in California see diagnostic and prognostic potential in the large circulating extracellular vesicles (EV), known as oncosomes, that carry prostate cancer cells and micro (mi)RNA and can signal rapidly proliferative cancers.

"Our findings suggest that large oncosomes in the circulation report metastatic disease in patients with prostate cancer, and that this class of EV harbors functional molecules that may play a role in conditioning the tumor microenvironment," write senior author Dolores Di Vizio, MD, PhD, associate professor of surgery, pathology, and laboratory medicine, and biomedical sciences at Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute in Los Angeles, and collegues.

Their findings were published in the November 15 issue of Cell Cycle.

If the study findings are validated in clinical trials, the process could be used to personalize therapy for men with prostate cancer, Dr. Di Vizio noted.

"These latest research findings provide tangible insight into the molecular and structural phenomena that result in prostate cancer metastases. They have the potential to create a new source of biomarkers and an innovative standard of care. These findings may also help distinguish individualized treatment plans best suited for each patient," she said.

PSMA Relative

NAALADL2 is a molecular cousin of prostate-specific membrane antigen, also known as NAALAD1, which the authors show to be overexpressed in prostate tumor samples, compared with normal tissues.

To test whether the expression of NAALADL2 correlates with disease severity, they evaluated tissue microarray samples from Cancer Research UK and from the Karolinska Institute in Stockholm, and found that NAALADL2 overexpression in prostate cancer could distinguish between benign and tumor tissue with 86% sensitivity and 86% specificity (P < .0001).

They also found that expression of the protein increased with Gleason grade (P = .028) and tumor stage (P = .004), and could distinguish between organ-confined (stage T2) disease and locally advanced (stage T3) disease (P =.0018).

"We also determined the levels of circulating NAALADL2 RNA found in the peripheral blood and found a significant increase in patients with biopsy-confirmed prostate cancer compared to those with a raised PSA but negative biopsy who were assumed to be largely benign," they write.

Furthermore, expression of the protein predicted worse 5-year recurrence-free survival (hazard ratio [HR], 1.9; P =.0038) in the Karolinska tissues (although not in the smaller UK set). This relation remained significant after adjustment for age, Gleason score, extraprostatic extension, positive surgical margins, seminal vesicle invasion, clinical stage, and preoperative PSA levels (HR, 1.7; P = .036).

NAALADL2 expression, also associated with lower 5-year survival, was more common in patients with low expression than in those with high expression (93% vs 45%; P = .015).

Additionally, the researchers found evidence that NAALADL2 promotes cell adhesion, migration, and invasion, and that the gene that expresses the protein is coexpressed with androgen-regulated genes.

Oncosome Analysis

Dr. Di Vizio and colleagues used a new filtration-based method to isolate large oncosomes, and found that oncosomes positive for the oncoprotein caveolin-1 identified blood samples from patients with metastatic disease.

They used the same isolation technique to validate results from a miRNA array analysis of EVs isolated from cancerous and noncancerous prostate cells.

"The results showed that distinct classes of miRNAs are expressed at higher levels in EVs derived from the tumorigenic cells in comparison to their nontumorigenic counterpart," they write.

The researchers also found that large oncosomes appear to be involved in the spread of malignancies, as evidenced by their ability to enhance the migration of cancer-associated fibroblasts.

Not Ready for Primetime

A specialist in genitourinary oncology told Medscape Medical News that the tests seem promising, but whether they will be able to replace or improve on current genetic assays is not known.

"There is a lot of research related to pathways that might make some cancers more aggressive and trying to predict that very early. These two studies are at a very early stage of research, because they identify pathways that might be implicated in aggressive cancers," said Julio Pow-Sang, MD, chair of urology and urological oncology at the H. Lee Moffitt Cancer Center in Tampa, Florida.

"Yes, they have potential, but there are currently available commercial tests that might help predict whether a cancer is going to be aggressive or not that were not available only a couple of years ago," he said.

Commercially available prostate cancer tests include Prolaris (Myriad Genetics), which can predict biochemical recurrence and death, and Oncotype DX (Genomics Health), which predicts whether tumors will progress to high-grade disease.

Dr. Whitaker's team was supported by the UK National Institute for Health Research and a National Cancer Research Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT) grant. Dr. Di Vizio's team was supported by the National Cancer Institute and the Steven Spielberg Discovery Fund in Prostate Cancer Research. The study authors and Dr. Pow-Sang have disclosed no relevant financial relationships.

Oncogene. Published online November 18, 2013. Abstract

Cell Cycle. 2013;12:3526-3536. Abstract

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