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Interrupting Cancer's Travel Plans

Could a protein produced by some tumors be an effective metastasis blocker? Story by Stephen Ornes & photos by Doug Sanford

Randy Watnickʼs pursuit of a better drug against metastatic cancer began late at night in early 2005. His infant daughter had woken up in tears at their home in Newton, Mass., near Boston. The molecular biologist climbed out of bed, scooped up the sobbing baby, and helped her get back to sleep. Normally able to maintain a healthy distance between work and family, Watnick was unable to fend off thoughts about tumor biology. 

“I just couldn’t sleep,” he says. “My daughter woke me up, but what kept me awake was work.”
​Support for Patients With Metastatic Disease​
Resources for patients with metastatic disease.​

He couldn’t help it—work was frustrating. Barely a year earlier, Watnick had joined the Vascular Biology Program at Children’s Hospital Boston. His research centered on understanding how primary tumors use their environments to grow, the cancer biology equivalent of a botanist figuring out how an invasive weed thrives in a garden. Watnick was particularly interested in understanding the role of the soil, or stroma—healthy cells that provide fertile ground for cancer’s growth—but the work wasn’t going well. 

His frustration wasn’t with the lab. It was a case of molecular mismatch. Watnick, 40, could obtain tumor samples, and he could obtain stromal cell samples, but not from the same patients. Tumors—even of the same type of cancer—can vary from person to person, and mismatched cells might not lead to reliable results. Plus, he felt intimidated by other players in the field. Established researchers with bigger labs and more funding were already deciphering the molecular conversations between diseased cells and healthy host cells. Watnick, whose lab was then barely older than his daughter, couldn’t imagine how his work would make a difference.

“I thought, ‘I can’t compete with them,’ ” he says. “That was a crowded space.”

Watnick slept a bit that night, and when he awoke the next morning, he knew what he would do: Study metastatic disease. Few researchers were studying the mechanics of metastasis, and even though his work wasn’t guaranteed to be useful, it could potentially play a role in the development of a therapy to help prevent cancer’s spread or to treat patients with stage IV disease. 

“People die of metastatic disease,” he says. “They don’t generally die from primary tumors.”

The decision seemed momentous at the time, but Watnick was closer than he had imagined to a potential advance. In his earlier research on primary cancers, he had investigated how molecules produced by tumors corrupt nearby healthy cells to obtain the fuel they need to grow. That work had grounded him with the confidence to shift his perspective: He would look for proteins that could make healthy tissue inhospitable to metastases. This unconventional research project was by no means a sure thing—even the most encouraging laboratory studies only rarely result in human benefit—but Watnick wasn’t one to shy away. And, though he didn’t know it, he was already on his way to discovering a promising protein that might act as a metastatic roadblock.

The Anatomy of Metastasis
Metastasis begins when cancerous cells leave the primary tumor and circulate through the body, traveling in blood or lymph. Despite the best efforts of the human body’s patrolling immune cells, these seeds—called circulating tumor cells—can invade distant organs and grow out of control. Metastatic disease is diagnosed when cancerous cells from one organ are found in another organ, such as when a mass of breast cancer cells are discovered in the brain. In rare cases, doctors will find metastatic disease without knowing where the primary tumor started. 


​Searching for clues to the prevention or treatment of metastases, Randy Watnick has focused his research on cancers that don’t metastasize, or that metastasize slowly.
About 30 percent of new cancer patients face an initial diagnosis of metastasis, and nine out of 10 cancer deaths are due to metastatic disease. But these broad statistics fail to show the radical diversity of metastatic disease among different kinds of cancer and among individual patients. Part of the complexity is that tumors contain a variety of diseased cells, which arise from different types of genetic mutations. So even when two people are diagnosed with the same type of cancer, they might have drastically dissimilar diseases.

Metastasis is often described as something that happens late in the disease, after tumors have had a chance to develop and shed cells into the body. As a tumor grows, its cells divide rapidly and undergo multiple mutations, accumulating changes and eventually releasing tumor cells. Experimental evidence linking large tumors to a greater likelihood of metastasis supports this hypothesis. 

Other studies suggest the picture may be more complex: Metastatic cells at the outset may differ from cancer cells that will remain behind in primary tumors—mutating and evolving in different ways. If this is the case, treatment against one type of cancer cell in the primary tumor (the kind that will stay put regardless) may not work against other types (the ones that can develop the mutations necessary to spread). Both scenarios are unsettling because they suggest that cancer spreads before it becomes detectable. “When someone receives a diagnosis of cancer, that tumor has been there for months already,” says Joan Massagué, the director of the Metastasis Research Center at the Memorial Sloan-Kettering Cancer Center in New York City. “And that tumor has been fed by blood vessels, and all of those vessels are open windows for cancer cells to escape. The majority of the [escaped] tumor cells die, but some are going to manage to stay alive, hiding in the bone marrow, hiding in the lungs, in tissues that are large and have lots of capillary vessels.”

Scientists like Watnick and Massagué who study the complexity of metastatic disease toil in uncertainty. They may spend years hoping—but not knowing—if experiments will yield useful results. “You make a discovery, but not all discoveries provide the opportunity for the development of new drugs,” says Massagué. “Some do, some don’t.” Nevertheless, he’s optimistic that current research will yield treatments that extend patients’ lives. In the last 10 years, Massagué says, studies have begun to crack open the mysterious machinery of metastatic disease, and knowledge is accumulating quickly. But the silent nature of metastasis—hidden but growing—makes it a particularly daunting research subject.

Although research has led to new treatments, most metastatic disease remains incurable. For individuals with metastatic disease, when hope arrives, it arrives in “these very tiny increments,” says Suzanne Hebert, the vice president of the Metastatic Breast Cancer Network, an organization that strives to raise awareness of metastatic patients’ needs. In 2004, Hebert was diagnosed with stage IV breast cancer. She says she’s “guarded” when she hears news about new treatments for metastatic disease. 

“After more than eight years of living with this, I’ve seen so many things that sound like the next great thing,” she says. “You never hear anything else.”

As an example, she points to the drug Halaven (eribulin), which was approved in November 2010 by the U.S. Food and Drug Administration (FDA) for use against metastatic breast cancer. News articles heralded the introduction of a “successful” new drug, but clinical studies showed that it extends life by an average of two and a half months. It was hardly the magic bullet for which patients like Hebert are waiting.

“That’s not really something to bring the trumpets out about, but that’s the best that we get,” she says. Still, it’s better than nothing. “I’m 46 and the mother of two,” says Hebert. “I’ll take it.”

03/29/2012
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