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Time and Its Toll

Early detection is an elusive aim in ovarian cancer

The headline of a New York Times editorial on February 27, 1955, was “Population Upsurge.” Commenting on a record number of births the previous year, the writer said: “Man knows more efficient ways of
creating mass death than ever before, yet life answers back defiantly, by producing more life ... the people of this country are reflecting their confidence in the future in the most fundamental and impressive way possible, by simply having more babies, many more babies.”

It was during this year of newborn promise when Mary, a 40-year-old wife and mother of six, began to feel something was different. Her belly swelled, her body ached. She figured it was time to prepare for lucky child number seven—new life, new beginnings. But her doctor soon told her it wasn’t an embryo taking root in her body. It was ovarian cancer. Her health deteriorated quickly. Within months of her diagnosis, Mary died. She didn’t live to see the lives of her children and grandchildren unfold as the 20th century rolled on.

Despite more than 50 years of subsequent medical research, Mary’s story is strikingly similar to the disease’s course today. The symptoms of ovarian cancer—which may include bloating, fatigue, and difficulty with digestion—are vague at best, altogether absent at worst, and usually don’t appear until the cancer has progressed to a life-threatening stage.

Women with this late-stage cancer generally die within a few years of learning their diagnoses—and some, like Mary, within months. Ovarian cancer remains notoriously difficult to detect in its early stages, yet that’s the key to successful treatment.

For decades, researchers have tried in vain to develop a means of detecting ovarian cancer before it has time to spread to organs and lymph nodes. Now, a University of Pittsburgh researcher may have found a way.

Pitt’s Anna Lokshin began her career as a cancer researcher studying lung-cancer cell formation. As she tested potential new therapies in the lab, the cells remained stubbornly resilient. What looked promising under a microscope invariably failed the animal tests—a continuous loop, a disheartening story repeating itself.

“It was always the same thing,” she says. Frustrated, she made a decision. “I realized just how deadly cancer was and thought the best way I could fight it would be to focus on early detection.”

Typically, scientists have looked for a single protein in the blood that would reliably indicate the presence of cancer. Although many studies have found proteins associated with the disease, a single smoking gun has remained elusive.

A few years ago, new evidence suggested that the trick to reliable detection may not be any one protein but rather a combination of several. It was then that Lokshin proposed using a powerful technology called xMAP to create a blood test for ovarian cancer. Using xMAP, she could measure the quantity of multiple proteins at once, then apply mathematical processes to hunt for patterns.

Lokshin and her research team put her hypothesis to the test in a pilot study. Using blood-serum samples from healthy patients and from patients in various stages of ovarian cancer, they began testing for 34 proteins that previously had been shown to coincide with the disease. In analyzing the data, they found that certain combinations of these proteins not only indicated the difference between healthy people and those with ovarian cancer, but also appeared to distinguish between early-stage and late-stage ovarian cancer.

The team decided to cast a wider net, testing for even more proteins—a total of 46—and looking for the most reliable combination among them. The result: Last year, they announced the assembly of a 20-protein panel that appears to detect ovarian cancer in the blood with 97 percent accuracy, making it the most accurate biomarker of the disease to date.

From the beginning, Lokshin’s priority has been fine-tuning the test for the earliest possible detection. Samples from the initial stages are difficult to find, but not impossible; in rare cases, patients show symptoms early on. Encouragingly, the panel has proven just as reliable in detecting cancer even in the first two of its four main stages.

In February, Lokshin—an assistant professor in Pitt’s School of Medicine—received some exciting news that will widen her pool of early-stage samples significantly. The National Cancer Institute gave her the green light to use samples from the largest long-term cancer-screening trial in U.S. history—the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The study includes a wealth of samples from 120 ovarian-cancer patients—some dating back 10 years prior to diagnosis. The month-long process of testing these samples, which will begin in June, is the last step before her panel is ready for clinical trials.

The growing momentum of her research is exciting for Lokshin, but she remains patient, knowing that several more hurdles must be cleared—over the course of years—before this potentially powerful new blood test might become available to the public. In the meantime, Lokshin is doing all she can to speed the process along. “The fewer proteins on the panel,” she says, “the less costly it will be to produce, and the more quickly it can gain FDA approval and become available to the public.” To date, her panel is down to six proteins, which appear to detect ovarian cancer’s very earliest stage (Stage 1A) with a record-high accuracy rate of 93 percent.

Amazingly, this exciting research may not have happened at all without funding support from a local foundation. “I was sending grant proposals all the time, and they were going unfunded,” says Lokshin.

In 2004, Pittsburgh’s Henry L. Hillman Foundation launched a pilot fellowship program at the University of Pittsburgh Cancer Institute (UPCI) with a $2 million gift to fund particularly innovative research projects. Lokshin was one of 14 UPCI researchers selected. That initial seed money enabled her to conduct an early study with encouraging results—so encouraging, in fact, that she won a $565,000 grant in 2005 from the National Institutes of Health to expand the research.

“The seed funds were critical,” says Lokshin, who also directs UPCI’s Luminex Core Facility, a shared and specially equipped resource for University researchers. “The Hillman funds gave us what we needed to develop our preliminary data.”

The UPCI pilot program was so successful that the Hillman family created The Hillman Fellows Program for Innovative Cancer Research the following year with a $20 million gift—the largest contribution ever made to Pitt and its affiliated medical center, UPMC.

Lokshin hopes that, eventually, doctors will be able to detect ovarian cancer in its early, curable stages through routine tests requiring only a single drop of blood, as her panel does now.

It’s a dream that has the potential to rewrite the story that many families know all too well—Mary, who died of ovarian cancer in 1955, is this writer’s grandmother. Perhaps where previous generations knew the pain and loss of a story’s end, there will one day be a new chapter. —Elaine Vitone

 

Breakthroughs in the Making


  Götz Veser
 

Safer Science

Think of the tragedy of the Hindenburg—the hydrogen-filled zeppelin that exploded in 1937. What might have prevented that disaster? Pitt’s Götz Veser has developed microreactors that allow hydrogen or other gases to burn without the threat of explosion, regardless of temperature or composition. The microreactors, crafted on tiny silicon chips, absorb explosion-causing “free radical” atoms and also keep pollutants from forming. The work of Veser, a Pitt assistant professor of chemical and petroleum engineering, could lead to safer, cleaner energy production and storage.

Model with Muscles

Walking through a lab at the University of Pittsburgh, it’s possible to come upon a petri dish with a throbbing spot of gel. A certain class of polymer gels—called Belousov-Zhabotinsky gels—expand and contract like a pumping heart when doused with certain chemicals. But exactly how these gels pulsate remained a mystery until recently.

Pitt’s Anna Balazs, Distinguished Professor and Robert Von der Luft Professor in the Department of Chemical and Petroleum Engineering, and postdoctoral researcher Victor Yashin recently developed the first computer model to show, theoretically, how these pulsating gels work. Using this understanding, researchers may be able to develop intriguing advances like synthetic muscles to power microrobots or biomotors for drug delivery. The model’s results were published recently in the prominent journal Science.

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