W H Y f i l e s

Caloric restriction and cancer

Endocrine disrupters and cancer

Fighting breast cancer

Of mice and men

Natural DNA repair

Social support and cancer

Feeling receptive to a cancer treatment
28 JAN 1999. Just as a telephone links house-bound teenagers to the world, a receptor molecule links cells to the bloodstream. Honed by evolution, each type of receptor can link only to a molecule with the exact chemical structure -- with the correct phone number, in our analogy.

Every year, about 24,000 new people are diagnosed with this cancer, called gliomaWhen these linking molecules, called ligands, are absent, their receptors sit idle, like a teenager waiting for a phone call. But when the correct ligand binds to the receptor, it directs the cell to act in some specific way.

The system of ligands and receptors is as powerful as it is selective. It allows endocrine glands to secrete traces of hormones into the blood that spark specific changes in tissues having the receptors. Cells without the receptors don't even know the hormones are present.

This specificity intrigues cancer scientists who want to target cancer cells while sparing healthy ones. Here's the idea:

  1. Find a receptor that appears only on cancer cells.

  2. Isolate its ligand -- the molecule that uniquely fits into the receptor.

  3. Attach a cancer drug to the ligand.

  4. Use the ligand to ferry the drug to the receptors.

Theoretically, this elegant biological approach would destroy cancer cells, but not healthy cells -- a precise targeting that's the Holy Grail of cancer therapy. You could think of it as speed-dialing all cancer cells -- and only cancer cells.

Smart bomb for brain cancer
The hang-up is that unique receptors are scarce. But on January 23, 1999, University of Alabama neuroscientist Harald Sontheimer announced the discovery of a chemical that binds only to a receptor found on primary brain cancer cells.

Speaking at the annual meeting of the American Association for the Advancement of Science in Anaheim, Calif., Sontheimer said he hopes preliminary human tests of a ligand called chlorotoxin will begin later this year. Although Sontheimer is widely published in medical studies on glial cells, The Why Files could not find a published reference for this work.

Three brain scans of a patient with an aggressive glioma of the variety called glioblastoma. Note the black area of dead cells within the contrast enhancing (white) mass. Isolated tumor cells have reached normal brain tissue around this lesion. Courtesy of Department of Neurological Surgery, New York University Medical Center.
3 scans
Tomorrow would not be too soon. Primary brain cancer -- the kind that originates in the brain -- is almost invariably fatal. Every year, about 24,000 new cases of the disease -- called glioma -- are diagnosed. About 18,000 of those people die within a year, especially from the most malignant forms, astrocytoma or glioblastoma.

Glioma arises not in the cells that do our thinking -- neurons cannot divide in adults, and cancer requires cell division. Rather, glioma begins in the glial cells. Once considered simple packing material between neurons, they are now known to feed and care for neurons.

Only glioma patients could benefit from the new research. It seems to hold no promise for metastatic brain tumors, which originate elsewhere in the body and lack the unique receptor.

Cellular slimming system
All cancer treatment in the brain is difficult. But gliomas are especially bad because some cancerous glial cells have usually moved around in the brain before being recognized and removed. With no good treatment, recurrences generally kill the patient.

A triple-labeled immunofluorescence image of a mixed culture of glial cells. © 1997 Dr. Steven Levison, Dept. of Neuroscience and Anatomy, College of Medicine, Penn State.
glial cellsHealthy glial cells do not move in adult brains. But during fetal development -- and in glioma -- the cells can lose fluid, slim down and slip between nerve cells. Eventually, the glial cells take up fluid, swell, and become fixed in position.

The fluid enters and exits the cell by passing through thousands of structures called ion channels. Nerve cells also use ion channels -- different ones -- to supply energy to the cell. And that leads us, oddly enough, to Israel's Negev Desert.

The sting of the scorpion
Enter the giant Israeli scorpion, a 4- to 5-inch critter with a mild sting. Neuroscientists have long been fascinated with the venoms that insects and arachnids like scorpions and spiders use to paralyze prey. Some of these venoms block nerve signals by binding to the ion channels in nerve cells, preventing the neurons from getting energy and making easy dinner for the insect or, in this case, the scorpion.

Could a venom selectively affect the ion channels on human gliomas? To find out, Sontheimer tested hundreds of insect venoms against human gliomas growing in lab mice. Eventually he found that chlorotoxin, an agent previously isolated at Harvard University from the venom of the Israeli giant scorpion, indeed binds to the ion channels.

Next came the critical question: Would chlorotoxin bind to any normal tissue? Sontheimer says that during more than 1,000 tests on human tissue freshly removed during unrelated surgeries, the agent bound only to glioma cells.

Acid test
Although the venom-derived compound did bind to the human tumors growing in mice, Sontheimer has not tried to kill those cells. "Treating a mouse doesn't tell you anything," he says. "Tumors grow very differently in mice." Sontheimer is a founder of Transmolecular, Inc., a drug-development company that is working on the ligand.

But with the idea of using chlorotoxin as a ferrying agent to carry a lethal cargo to glioma cells, he has already attached a radioactive atom and, separately, a conventional cancer drug, to chlorotoxin.

Yet while the ingredients of a successful assault on glioma seem to be in place, it's far too early to declare victory. The mechanism is unproven. Many promising cancer drugs reach this stage but fail in human trials.

Such a trial -- with between one and ten patients -- is planned for the City of Hope Hospital in California later in 1999. The goal is to find out if chlorotoxin linked to radioactive atoms will bind to and kill the cancerous cells in human cancer patients. In a subsequent test, chlorotoxin would be bound to a cancer drug.

Will it work?
In light of last year's hubbub over cancer drugs that stop blood-vessel growth, how should we view the news? Let's say with guarded optimism.

Sontheimer says enough chlorotoxin should be available (difficulties in synthesis could slow trials of the anti-angiogenesis drugs). He also says that adding a radioactive atom should not prevent the drug from slipping through the barrier that protects the brain from large molecules.

Still, it's simply too early to predict that the drug will work. In fact, if we Why Filers were betting folks, we'd probably want good odds before placing money on ultimate success.

Yet glioma patients have few good options at this point. For them, the stakes are far higher than money. If problems of drug delivery, drug metabolism and side effects can be overcome, and if chlorotoxin continues to be utterly selective for cancer cells, the discovery will be hopeful.

It may not eradicate every last cancer cell. It may not work on every type of glioma. But if judged against reasonable standards, it could be a welcome advance nonetheless. "I don't think we're going to find a miracle cure against cancer," says Sontheimer. "We're trying to find a treatment with some benefits -- improving the quality of life, prolonging life. Even in the absence of a complete cure, that can be helpful."


-- David Tenenbaum

The Why Files
S E E .A L S O
Molecules Give New Insights Into Deadliest Brain Cancers, Marcia Barinaga, Science, 14 November 1997, p. 1226.

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