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Telomere ExpressDung Hoang

Telomere Express

How an evening conversation on the Acela train to Baltimore and almost  a decade of research are reshaping  the science of prostate cancer.

 On an otherwise nondescript evening in 2005, a team of three investigators huddled in the quiet car of an Acela train headed back to Baltimore. They were on the trail of an elusive foe, an important clue in the deaths of countless men across the world. These were not police detectives, however, but prostate cancer researchers from Johns Hopkins.

On this night, their muffled discussion veered in a novel direction that seemed particularly promising. Soon, whispers rose to an excited chatter about a new hypothesis.  Because the quiet car is an inviolable sanctum for business travelers, it wasn’t long before a conductor emerged in the half-light to squelch the spirited discussion.

Eight years later the outburst on the Acela would lead to a notable discovery in prostate cancer research: a prototype test to predict aggressiveness of the disease.

The resulting study, published in October 2013 in the journal Cancer Discovery, would implicate otherwise-harmless DNA fillers known as telomeres as key factors in predicting prostate cancer mortality in men with this cancer.

A Tale of Two Outcomes
From a public health perspective, the costs of prostate cancer are profound.

Aside from nonmelanoma skin cancer, prostate cancer is the most common cancer among men in the U.S., according to the CDC, and one of the leading causes of cancer death among men. It accounted for 28,560 deaths nationwide in 2010.  One in seven American men will be diagnosed with prostate cancer in their lifetimes.

Every one of those diagnoses will hit like a sledgehammer.

A typical course of action involves surgery. In the past, prostate cancer surgery was bloody and complex. Pioneering work by Patrick C. Walsh, MD, at Johns Hopkins revolutionized this surgery, substantially reducing complications. However despite these improvements, and the advent of less invasive laparoscopic and robotically assisted techniques, potential side effects still include incontinence and impotence.  A small number of surgeries result in patient death.

“These are serious quality-of-life issues. Prostatectomy is not something you want to go through if you don’t have to,” says Alan Meeker, PhD, an associate professor of Pathology at the Johns Hopkins School of Medicine.

Meeker and Elizabeth Platz, ScD, MPH, a professor of Epidemiology at the Bloomberg School, were the lead investigators on a perplexing cold case that had stumped medical professionals for years: Two men can have prostate cancers that look identical even to expert pathologists, but result in wildly divergent outcomes.

Pathologists review prostate cancers for their characteristics including size (volume) and the Gleason sum, which is based on the degree to which the cancer cells differ in appearance and growth pattern from normal cells. A treating physician can then consider these indicators in combination with the man’s age and the stage of his cancer along with the PSA test, which measures prostate-specific antigen (PSA) in the bloodstream, to estimate the man’s prognosis.

“Take two patients who are the same on paper. Their Gleason score is the same. The volume of the tumor is the same. They’re the same age. They have the same PSA level. And yet, one patient will be dead in seven years, and the other will live two decades and die of old age,” Meeker says flatly.

Balanced against this is the reality that most prostate cancers grow slowly. Current research shows that many men live with it for years and later die of something else.

“Most patients, understandably, want the cancer out. Recent data suggest, however, that for some men surgery can wait or is not needed at all. The trick is to be able to know which men,” says Angelo De Marzo, MD, PhD, a professor and prostate cancer pathologist at the Johns Hopkins School of Medicine and the third investigator on the Acela that night.

From the outset, the trio was looking to address shortcomings of the currently used prognostic tools by finding a biological marker for the severity of this cancer. Like a fingerprint to a homicide detective, such a biomarker would help identify prostate cancer patients with aggressive cancers who require immediate removal of the prostate and those suffering less threatening forms of the disease who might forgo treatment in favor of disease surveillance.

Eventually, the team hopes to apply the test they are developing to men whose cancers are detected at a very early stage by screening. “Some of these guys may have a cancer that probably shouldn’t even be picked up, but if it is, now they face the difficult decision about whether to be treated, and if so, the type of treatment,” Meeker says.

“Tissue-based markers like this have the potential to greatly improve treatment and decision-making in men with prostate cancer. This study is an important advance,” says Jerry W. Shay, PhD, an expert in telomeres and cancer at the University of Texas Southwestern Medical Center. Dr. Shay was not involved in the research but penned a commentary accompanying the study in Cancer Discovery.

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