There's got to be something better than PSA, and HHMI investigators (left to right) Daniel A. Haber and Arul Chinnaiyan have set their sights on finding it.

For Foley, an MRI technique considered experimental at the time revealed that his cancer had already spread to his seminal vesicles, so a course of radiation and hormone therapy seemed the best option. In his case, PSA was a valid warning sign that caught his cancer before it spread even further. PSA and scans leave others in the dark as to whether their cancer is growing and how aggressive treatment should be. There is a lack of useful diagnostic tests to classify a prostate cancer. In the near future, though, genetic analysis of tumors may fill this void.

Chinnaiyan's team studies genes that, when rearranged incorrectly, cause prostate cancer. His research relies on a large bank of prostate cancer tissue samples at the University of Michigan. Using microarrays—a technology that can quickly analyze the activity of massive numbers of genes in a sample—Chinnaiyan has looked at the molecular signatures of hundreds of prostate cancers. Traditionally, researchers sort through such data by looking for genes expressed in all the cancers. But Chinnaiyan didn't think that was the best approach. Instead, he looked for genes that were expressed at high levels in some, but not necessarily all, of the cancers. He calls these genes “outliers” and reasons that typical averaging techniques would cause scientists to miss them.

His analysis paid off—it found parts of two normal genes that had been combined into one single cancer-causing “fusion gene” in about half the tumors he analyzed. One of the normal genes was in a family of transcription factors; the proteins produced by these genes bind directly to DNA and can activate cancer-causing genes that are turned off in a healthy prostate. This “ETS transcription factor” was fused with the on-off switch from an unrelated prostate gene—one regulated by male hormones. So whenever this fusion gene came into contact with testosterone, a constant presence in the prostate, the ETS transcription factor was switched on and went into action turning on other cancer-causing genes.

Chinnaiyan's work was published in 2005; his fusion gene was the first to be linked to prostate cancer, and the discovery drew wide acclaim from the prostate cancer community. Chinnaiyan believes the fusion gene could lead to treatments and, even sooner, to new ways to detect and track prostate cancer if the gene can be monitored in blood or urine.

He has already found a related indicator in urine, a metabolite called sarcosine that's elevated when prostate cancer exists. According to Chinnaiyan, one ETS fusion gene boosts sarcosine production. Screening men's urine for sarcosine levels, he says, could be one way to monitor disease, alongside or instead of blood tests for PSA.

Screening men's blood for genetic markers of prostate cancer—which could potentially differentiate cancer types, unlike PSA—is also on the horizon. HHMI investigator Daniel Haber, of Massachusetts General Hospital, thinks blood holds clues not only for prostate cancer but also for most other cancers. Haber wanted to study genetic mutations in various cancers and, because repeated biopsies of tumors are often invasive and costly, he turned to an emerging technology to detect rare cancer cells—called circulating tumor cells, or CTCs—that break off tumors and enter the bloodstream.

“The initial literature [on CTCs] goes back to the 1800s, when a woman with advanced breast cancer was found to have tumor cells in her blood,” Haber says. “Really, we've always known that cancer spreads through the bloodstream, but we haven't been able to see the CTCs.”

Photos: Haber: Darren McCollester / PR Newswire, ©HHMI Chinnaiyan: Don Alley / PR Newswire

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