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Interrupting Cancer's Travel Plans


Fighting Cancer With Cancer
The Vascular Biology Program at Children’s Hospital Boston was established by Judah Folkman, a visionary cancer researcher who, at least for a while, seemed to have made headway in the quest for a magic bullet—the kind desperately needed by patients like Hebert.

In 2003, Folkman recruited Watnick from his position at the Whitehead Institute in nearby Cambridge, Mass. Decades earlier, in the 1970s, Folkman had championed the idea that a tumor could be starved by cutting off its blood supply. His work led to the development of a new class of cancer drugs called angiogenesis inhibitors. (Angiogenesis is the formation of blood vessels.) Avastin (bevacizumab) was the first angiogenesis inhibitor to extend patients’ lives, and over the last eight years, it has boasted FDA approval for the treatment of some types of colorectal cancer, lung cancer, kidney cancer, brain cancer, and, until last year, breast cancer. Following on Avastin’s heels, more than 10 additional angiogenesis inhibitors have been approved by the FDA, and at least 50 more are now in clinical trials.

Yet, so far, angiogenesis inhibitors have not lived up to their initial promise. Although some patients experience quick responses, most develop resistance to the drugs over time. And in November 2011, the FDA revoked its 2008 approval of the use of Avastin for metastatic breast cancer, citing poor performance in recent clinical trials and a high risk of serious side effects. Researchers continue to explore how current angiogenesis inhibitors or their pharmaceutical descendants might aid in efforts to cripple cancer’s growth.​

“Do some cancers produce proteins that block the development of metastases?"
By the time Folkman recruited Watnick, the younger scientist had established himself as a promising researcher in the angiogenesis field. And Watnick soon felt right at home. Folkman, who died in 2007, encouraged his team of researchers to take bold risks, says Watnick. Before he joined Folkman’s department, Watnick and his colleagues had demonstrated the angiogenesis-inhibiting behavior of a protein called thrombospondin-1, or Tsp-1, publishing their results in the scientific journal Cancer Cell in 2003. Folkman was impressed and recognized a kindred creative spirit of investigation.

“Dr. Folkman believed anything was possible,” Watnick says. “He had the spirit of trying new things and not being afraid to fail. When the director of your program gives you the freedom and encouragement to do new things, that gives you a lot more confidence to go out and do them.”

So in 2005, following that near-sleepless night, Watnick felt comfortable that he could choose an unorthodox research project. Other scientists had already discovered that when primary tumors start to metastasize, they release proteins that act as a first wave of invasion, preparing healthy tissue to support the seeds of a secondary growth. Naturally, some researchers thought that if they could block that first surge of proteins with a drug, they might be able to stop metastasis before it starts. 


Randy Watnick’s metastasis research began when his 7-year-old daughter, Audrey (playing on the floor above near her father and her brother, Eytan), was just an infant.​
Watnick flipped the problem around, focusing instead on cancers that don’t metastasize, or that metastasize slowly. Watnick wondered: Do these cancers themselves produce proteins that block the development of metastases? “My thought was that some tumors actually inhibit their own metastasis,” he says. If such a hypothetical metastasis-blocking protein existed, and he could find it, then he could potentially fight cancer with cancer. 

A “Metastatic Switch”
Watnick first identified 20 possible proteins produced by tumors, and then whittled his list to two. By early 2006, he had narrowed the search to a large protein called prosaposin, or Psap. In healthy cells, the Psap protein plays a role in normal cellular metabolism. But Watnick had found that Psap also influences the behavior of Tsp-1—the angiogenesis-inhibiting protein—and when Psap is produced by a tumor, metastases are much less likely to develop. That suggested to him that Psap poisons the soil—the tissue where the seeds of secondary tumors might take hold. Still, Watnick remained skeptical of Psap’s potential until, one afternoon, Folkman wandered by and Watnick showed him his recent work.

“He said, ‘You could have a drug right there,’ ” Watnick recalls. “He was a very excitable person in general, so to have him latch on to that result so quickly got everyone in the lab more motivated and excited.”

Watnick was ecstatic. He had a starting place and Folkman’s blessing, and Psap was ready for testing. He began, as investigators do, with petri dishes, mice, and stored human tumor samples. The studies were small but promising: His team found low Psap levels in metastatic prostate and breast cancer cells they grew in lab dishes, as well as in metastatic prostate cancer samples obtained from patients. Cells engineered to have high Psap levels didn’t metastasize. And in mice injected with tumor cells that produced Psap, the researchers found that the disease was less likely to spread than in mice injected with tumor cells without Psap. 

Watnick and his colleagues bundled these promising initial results—showing how they found Psap, its effects on mice, and its presence in human patients with metastatic prostate cancer—and sent their work to major scientific journals. 

In 2009, Watnick and his team published their findings in the Proceedings of the National Academy of Sciences. They wrote that Psap has the potential to flip a “metastatic switch” by activating Tsp-1, which turns off the growth of new tumor-feeding blood vessels in parts of the body where metastases might grow. Psap, they believed, was prohibiting construction of new metastatic tumors. 

Since then, Watnick and his colleagues have collected patient data showing that individuals whose tumors have high levels of Psap live longer than patients with low levels of the protein, and they are much less likely to develop metastases. In lab dishes and mouse studies, the researchers have seen Psap work against the most common types of metastases—in lung, liver and bone. 

“We’re finding very striking results,” Watnick says. “When we treat with Psap [in mouse studies], we end up with tumors that are significantly smaller than in the control group.”

Watnick has submitted his most recent data for publication. He has also been meeting with potential investors, who—if Psap continues to demonstrate effectiveness at blocking metastasis in laboratory studies—may eventually finance the costly development and testing of a potential Psap-based drug.

Despite Psap’s promising start, however, Watnick cautions that the first clinical trials of any such drug in people are at least two years away. It’s also possible that his passionate investment could turn out to be a false start: Researchers have found thousands of molecules connected in some way to the spread of cancer. Most of these molecules never turn into plausible targets for cancer treatment—though a select few continue to advance slowly toward becoming potential new therapies.

If follow-up studies do continue to suggest that the protein can put up a metastatic roadblock, a Psap-based treatment would represent a new approach against cancer’s spread: It would work by boosting levels of a protective protein that’s already present in the human body, rather than introducing a chemical intended to attack individual cancer cells. What’s more, rather than trying to kill the seeds of metastasis, Psap would poison the soil where new tumors might try to grow, making those tissues poor environments for cancer’s growth. It wouldn’t be a cure, but the concept suggests the possibility of prolonging survival and turning some cancers into a chronic disease.

“This would probably be a treatment you have to take for your whole life,” Watnick says, looking forward. “But I would take a pill my whole life so I wouldn’t die from cancer.” 


Stephen Ornes is Cancer Today’s researcher and a contributing writer for the magazine. He lives in Nashville, Tenn.

03/29/2012
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