Hedgehog Blockers:Can They Stop Advanced Prostate Cancer? Scientists One Step Closer To Finding Out

There's a "point of no return" in prostate cancer, a moment when it grows too big to be killed by surgery or radiation, when it is able to spread far beyond the prostate, when it is considered unstoppable. Or is there? Forthe first time, scientists at Hopkins believe they may have found a way to turn back the clock on cancer - to thwart metastasis by blocking every possible escape route the cancer cells can create.

Their key to stopping metastasis is a protein pathway so common, so routine, that it's involved in embryonic development of th elung, pancreas, prostate, part of the brain, and other organs. But in prostate cancer -and, it turns out, in many other cancers - this pathway has been commandeered for harmful purposes. It's called the Hedgehog pathway, and in exciting research (published in the journal Nature, and described in theWinter 2005 issue of Discovery), Hopkins scientists learned that this pathway serves as a lifeline that enables cancer cells to live and spread outside their original home tumor.They also proved that they can block this pathway, and stop cancer from spreading.

How does the Hedgehog pathway work? Patrick C. Walsh, M.D., describes it to hispatients like this: "It's like soil and seeds.The soil is the stroma of the prostate - the connective tissue that serves as its framework - and the cancer cells are the seeds." And the Hedgehog protein is compost, sunlight and water - everything the seeds need to grow. "If these cells spread but try to grow in poor soil, they can't survive. But if

"We believe this may in time offera completely new way to treatmetastatic prostate cancer."

they can manufacture the Hedgehog signal, they can make the soil that they need - they can pack their lunch and take it with them."In laboratory research, "we found that we could shrink human prostate tumors growing in animals, and prolong their lives with a drug that blocks signaling by the Hedgehog pathway," says David Berman, M.D., Ph.D., assistant professor of pathology, urology and oncology. "We believe this may in time offer a completely new way to treat metastatic prostate cancer." Bermanhas been named the R. Christian B. Evensen scholar from The Patrick C. Walsh Prostate Cancer Research Fund.

Berman and colleagues Sunil Kahadkar, M.D., and Philip Beachy, Ph.D., professor of molecular biology and genetics and a Howard Hughes Medical Institute investigator, also believe that this and similar drugs,called Hedgehog blockers, can be useful for cancers in the brain, skin, lung, breast, andupper digestive tract.

But, except for testing a Hedgehog blocker on a common skin cancer - performed by dermatologists in Turkey, who found that the drug, given as a skin cream, had therapeutic benefit - researchers have not yet studied these agents in humans. There's a good reason for that: The government is extremely cautious about allowing drugs to make the transition from pure laboratory studies toclinical trials in patients. "When a drug does get this far," explains Berman, "the first step, and the most risky one, is the Phase I trials -testing whether humans can tolerate the drug. We are excited to report that Hedgehog blockers are now entering this stage."

However, Berman points out, it's possible that the drug might pose significant risks, at least to some people: "The pathway is absolutely critical for normal embryonic development, so it couldn't be given to pregnant or nursing patients," he explains. "In adult mice, Hedgehog blockers appear to be tolerated at therapeutic doses, but Hedgehog signaling appears to be active in a smattering of adult tissues, including the brain, and its function in adults is not understood."

A Massachusetts biotechnology firm,Curis, has licensed cyclopamine, a naturally occurring compound, extracted and purified from plants, from Johns Hopkins University,and is also developing other forms of Hedgehog blockers with another company, Genentech, Inc. The Hedgehog blocker to be used in the upcoming trials will be given in topical form to people with certain skin cancers. If the tests prove safe, the next step will be to administer a Hedgehog-blocking drug systemically - in pill form, or as an injection. "We are very hopeful that the project will progress to this stage," says Berman, "and that the drugs show some benefit for patients. But more importantly, we hope that these agents do no harm."

And as these trials are being carried out, Berman and colleagues at Hopkins will keep plugging away, in hopes of identifying new diagnostic, prognostic, and therapeutic strategies for prostate cancer. Are there anyother "Hedgehogs" out there? Are there other embryonic signaling pathways that mightal so regulate prostate growth? The Hopkins scientists are exploring this lead. They are also investigating whether Hedgehog signaling - like PSA levels - can be used as a crystal ball, to identify men whose prostate cancer warrants more aggressive treatment.

Note: Under a licensing agreement between Curis Inc. and the Johns Hopkins University, Berman and Beachy are entitled to a share of royalty received by the University on sales of products described in this article. JHU owns Curis Inc.stock, which is subject to certain restrictions under University policy. Berman and Beachy are paid consultants to Genentech and Curis. The terms ofthis arrangement are being managed by the JohnsHopkins University in accordance with its conflict-of-interest policies.

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