Fall 2004 Volume 16, Number 4	A Matter of Expression The status of brain tumor genes makes a difference.
	Shotguns. Sledgehammers. The disparaging words oncologists use for traditional brain cancer chemotherapy are often deserved. Use concentrations high enough to cross the blood-brain barrier and toxicity can overwhelm patients. Moreover, the principle behind classic chemo -- to cull only the fast-growing, malignant cells -- has become suspect. Not all tumor cells, we now realize, divide faster than normal ones.
In short, says neurosurgery's Gregory Riggins, M.D., Ph.D., "We've probably gone as far as we can go with existing brain cancer chemotherapy. That's not far." So what lies ahead-metaphor-wise-are the lasers, the magic bullets. New therapy, Riggins explains, will come from teasing out fine molecular targets on or near the surface of patients' cells, where they're reachable, and then finding ways to defuse them. That means blocking molecules that either promote malignancy or that prevent a cancer cell's self-destruction. The new drug Gleevec, for example, jams the enzyme tyrosine kinase before it can assemble agents that spur new cell growth. As a molecular biologist who specializes in oncology, Riggins recently came to Hopkins because he's skilled in studying gene expression. He's an unusual recruitment for the Department of Neurosurgery, but a necessary one. Cancer treatment as a whole has but a handful of the new targeted therapies. And none of them, so far, apply to brain cancer, where the need is great. So Riggins and his colleagues are part of a conscious speed-up in treatment research. They study which genes are most commonly expressed in brain tumors as a way to home in on those with cancer-causing mutations. That, in turn, leads to targets. Fortunately, Riggins' work comes at a time when improved technology makes it relatively cheap to assay ever larger numbers of genes. "Even now," he says, "we're finding many more mutations and better targets than, say, a decade ago." Many of the studies use serial analysis of gene expression, or SAGE, a technique that tells which genes are active by registering their protein products. The method was developed by the team of Hopkins scientist Burt Vogelstein, who collaborates with Riggins' group. With SAGE, they can check the on or off status of some 20,000 genes. Recent work, for example, compared genes expressed in 25 astrocytomas of various stages with normal brain tissue. Astrocytomas are the most common malignant brain tumor. By ruling out genes active in healthy brains, Riggins' team was left with a small, exclusive set of astrocytoma-linked ones. Interestingly, the gene profiles differed in subtle but telling ways depending on how advanced tumors were. Most exciting, Riggins says, was finding a handful of astrocytoma linked genes no one had suspected. With those in mind, the team has begun trolling for small molecules-small, biologically active substances-that will block the genes' action. The scientists hope their screen of some 30,000 small molecules nets a candidate or two. Assuming they find some, the question of delivery pops up. "Fortunately," says Riggins, "Hopkins has expertise in delivering therapy locally to brain tumors." He has in mind the Gliadel wafers, co-developed by neurosurgeon Henry Brem, that deliver chemotherapy to the cavity left by excised brain tumors. "I see our group offering better things to put in the wafers." Riggins is the recipient of the Irving J. Sherman research professorship.