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From Bench to Bedside:
Fusion Reaction
Looking for something better than a PSA test in screening for prostate cancer

A Voice For PatientsThe research team of Arul Chinnaiyan, M.D., Ph.D. (left), shown here with Scott Tomlins, is using gene sequencing to learn more about the aggressiveness of different prostate cancers. Recent studies have found that the PSA, or prostate specific antigen, test - the most widely used screening test for prostate cancer - leads to more cancers diagnosed but with little to no impact on the number of men dying from the disease. This suggests a need for a new, more reliable way to screen for this disease.

Enter Arul Chinnaiyan, M.D., Ph.D., and the Michigan Center for Translational Pathology, where a team of 78 researchers is looking at the genes, proteins and other markers in cells to develop new diagnostic tests or screening tools.

The Concept

In 2005, MCTP researchers reported the ground-breaking finding that pieces of two chromosomes can trade places with each other and cause two genes to fuse together. Further research has shown that this gene fusion then overrides the "off" switch that keeps cells from growing uncontrollably, causing prostate cancer to develop.

Now, Chinnaiyan and his team are using a technique called gene sequencing, which involves creating a library of certain single-strand cell molecules, called RNA, in a cell. Sequencing machines then run 24 hours a day for days at a time, reading the RNA. Once the sequencing is finished, researchers study the data searching for the gene fusions.

Their research has found that it's not just one set of genes that fuse - any one of several in a family of genes can become scrambled and fuse.

"Each of these switches, or gene fusions, represents different molecular subtypes. This tells us there's not just one type of prostate cancer. Its a more complex disease and potentially needs to be treated differently in each patient," says Chinnaiyan, S.P. Hicks Endowed Professor of Pathology.

Spotting Aggressive Cancers

"One of the biggest challenges we face in prostate cancer is determining if the cancer is aggressive. We end up overtreating our patients because physicians don't know which tumors will be slow-growing," Chinnaiyan says.

In a paper published this year in Nature, the MCTP researchers identified a panel of small molecules (metabolites) that appear to indicate aggressive prostate cancer. They believe the finding could lead to a simple test that will determine which prostate cancers are slow-growing and which require immediate, aggressive treatment.

"When we're looking at metabolites, we're looking several steps beyond genes and proteins. It allows us to look at some of the functions of the cells and the biochemistry that occurs during cancer development," Chinnaiyan says.

One metabolite in particular, sarcosine, appeared to be one of the strongest indicators of advanced disease. Levels of sarcosine, an amino acid, were elevated in 79 percent of the metastatic prostate cancer samples and in 42 percent of the early stage cancer samples. None of the cancer-free samples had detectable levels of sarcosine.

Treatment Tomorrow

Sarcosine was found in the study to be a better indicator of advancing disease than the current PSA test. Even more encouraging: Sarcosine was detected in urine, which has researchers hopeful that a simple urine test can be used.

With both the gene fusion and metabolomics work, MCTP researchers believe the biomarkers they're identifying can become targets for screening or possible new treatments.

"We hope to develop tests for diagnosis or prognosis. Long-term, we hope this will lead to better therapies to treat prostate cancer. The key challenge is to find a drug that goes after the gene fusion or the metabolite," Chinnaiyan says.

Their findings are being used to develop a screening tool to detect gene fusions in urine, which could one day supplement or replace the PSA test. -NF

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