Johns Hopkins Magazine - February 1995 Issue

Health & Medicine

Picking out cancer-ness, etc.

At last, a conceptual step toward cancer cures

To cure cancer, you have to know it's there, and the earlier the better. David Sidransky, Hopkins associate professor of oncology and otolaryngology, reports that his research team has developed a test with potential to spot the genetic fingerprints of any cell that is cloning itself, reproducing aggressively. In short, the test picks out clonality--what you might call cancer-ness.

"Put it this way," says Sidransky. "We never find these genetic markers in people who do not have cancer."

The clonal probes are also extremely sensitive, able to home in on a single cancer cell among 200 to 1,000 normal ones. Therefore, if the right markers are used, probes can reveal very early cancers by looking at body fluids, like urine or sputum.

If the method proves out--and a related one is already in use on Hopkins head and neck patients--screening tests for people at risk will become a reality. Cancer surgeons will know in just a few days whether they "got it all"; they won't have to wait till recurrence to go in and cut some more. The result will be more actual cures, less need to make people suffer through protective radiation "just in case." In addition, treatment could come earlier and be more effective, Sidransky hopes.

Please remember that none of these advances has happened yet. The millennium has not arrived. But Sidransky's lab has found, in effect, a shortcut, for if marking clonality works, there will be no need to discover every mutation that can lead to a particular kind of cancer--a near-impossible task. Now you'll only need to test various clonal markers, then combine the best to produce a screening test.

As of early December, Sidransky had found 15 clonal markers that together detect 65 percent of all bladder cancers. "We're moving right along," he says cheerfully. "The bladder is probably going to be our first success story, I hope."

"We're working on the big five," he adds--"lung, breast, prostate, colon, and bladder." The proposed tests will seek the tell-tale markers in body fluids, such as sputum for lung cancer, nipple secretions for breast cancer. The oncologist estimates the cost at $50 per test.

Using a technique known as polymerase chain reaction (PCR, sometimes called DNA fingerprinting), Sidransky's method looks at repetitive strings of so-called "junk" DNA: CAG, CAG,CAG,CAG,CAG,CAG,CAG, for instance. Similar strings occur by the thousands in all DNA. They seem to be involved in the mechanics of genetic recombination, but they do not code for anything, and changes in them will not cause cancer. The repetitions are only important here, says Sidransky, because they get mutated as part of the general garbling of other mutations, including those that contribute to cancer. They become longer or shorter; (CAG)8, for instance, might grow to (CAG)19, or shrink to (CAG)3.

"Cells make mistakes in replication all the time," explains Sidransky, and most of the errors are harmless. When the mutation gives a cell some reproductive advantage, so it just keeps on cloning itself, however, the result is cancer. And here's the key point: mutations in "junk" DNA go along for the ride. They get cloned with the cancer, marking it.

Using PCR, Sidransky compares particular repetitive stretches from each patient's normal DNA with those from that person's suspect tissue. If they are long or shorter, says Sidransky, that indicates cancer.

The method was published in the October 11 issue of Proceedings of the National Academy of Science. Using a screen that picked out nine particular "junk" alterations, the group found clonal markers in the primary tumors of 26 people with neck, bladder, or lung cancer. For each patient tested, identical markers showed up in sputum, urine, or tissue from the margins of the surgical field. No markers appeared in normal DNA from the patient's blood.

That shows, Sidransky says, that the clonal markers do in fact reveal the cancer. More: they identify that particular person's particular cancer, and can be used for early warning of recurrence. "All cancers that come back do so precisely," says Sidransky. "At least, we think so. We ourselves have shown that in bladder, and we've shown it in brain. Once a cancer acquires a mutation, it doesn't lose it, because that gives it the growth advantage that it needs." Early evidence indicates that the absence of clonal cells predicts survival for any cancer patient.

It follows that the key to truly "curing" cancer is to get rid of every single cancer cell. Enter an application of Sidransky's new technique:

In head-and-neck cancer surgery at Hopkins, each patient now undergoes biopsy a week or two before surgery. The lab deciphers the tumor's genetic sequencing, in order to develop a molecular probe (based on p53 mutations) for that particular patient. These probes can detect invasive cancer cells so small they still look "normal." After surgery, the lymph-nodes and healthy-looking tissues from the surgical margins are tested with the probe, looking for clonal markers.

The doctors then know how to proceed. One patient may get a clean bill of health: no invading fingers of cancer. Another may need an immediate re-operation to deal with a spot of trouble. For a third, the probe may reveal so many invasive areas that all-out aggressive chemotherapy is indicated.

If you pass the Ross Research Building some evening, look up at the 8th floor. Chances are, you'll see the lights on in Sidransky's lab. They're in there testing probes, with all the excitement of Mr. Sutter panning for gold. -EH

A stamp of recognition for Apgar

Her name has long been familiar to parents of newborns. Now her face may become equally recognizable.

Virginia Apgar (MPH '59), the late originator of the widely used Apgar Score, an evaluative test for newborns, has become the first female physician to be honored by the U.S. Postal Service in the "Great Americans" series of stamps. She replaces Harry Truman on the 20-cent stamp that has been a staple in American post offices for the past decade.

Back in the early 1950s, Apgar was rushing through lunch one day when a medical student asked how she evaluated newborn babies. She jotted down five observations on a scrap of paper, then hurried off to the delivery room to test her new concept. The American Medical Association began teaching the Apgar Score in 1963, using the letters of her last name: A=appearance, P=pulse, G=grimace, A=activity, and R=respiratory effort. A baby can earn 0-2 points for each factor; thus, 10 is a "perfect" score.

Widely respected for her work in obstetric anesthesia, Apgar went on to become a leading advocate for the prevention of birth defects after completing her master's degree in public health at Hopkins in 1959. -SD

The last daily addiction

It's the last slow hour of the workday. I sink into a chair in the Bayview campus office of Roland Griffiths, wearily pop the tab on a can of diet Coke, and take a sip. Zap! The caffeine in the caramel elixir scoots through my central nervous system. I am revived.

I am also a tad self-conscious since Griffiths, a professor of behavioral biology and psychiatry and an authority on caffeine, assuredly calls the caffeine in my afternoon Coke a drug. He and his colleagues also reported in the October 5 Journal of the American Medical Association that regular caffeine users can experience caffeine dependence syndrome--in other words, they may get hooked on the stuff.

While many people (myself included) joke about being caffeine addicts, Griffiths, psychiatrist Eric Strain, and a team of behavioral pharmacologists take the idea seriously. They found that some regular caffeine users fit a clinical description of caffeine dependence analogous to dependence on drugs like alcohol, cocaine, or heroin.

When Griffiths and his team applied a set of criteria similar to that the American Psychiatric Association uses to test for dependence upon alcohol or other drugs, they found that 16 out of 27 volunteers showed classic signs of dependence. For example, the volunteers had become tolerant to their drug; they needed more cups of coffee to get the kick one cup used to provide. When they tried to quit, they suffered throbbing headaches and other withdrawal symptoms. One woman told reporters that she had once driven to the grocery store, while in the throes of labor, to buy a bottle of caffeine-laden Mountain Dew.

Volunteers, who identified themselves as physically or psychologically dependent on caffeine at the start of the study, consumed on average 357 milligrams of caffeine a day (the equivalent of three-and-a-half six-ounce cups of coffee), with one man maxing out at 2,548 milligrams (more than 25 cups of coffee).

I push my Coke can to a less conspicuous spot on the table. So caffeine is addictive. Does that mean everyone should give it up? "If you don't have a medical condition it's fine for you to consume caffeine," says Griffiths, himself a moderate coffee drinker. (His mug is decorated with a chemical model of a caffeine molecule.)

However, people with certain medical conditions such as heart palpitations, arrhythmias, anxiety, or insomnia certainly should consume little or no caffeine, Griffiths notes. While several studies have examined caffeine as a potential risk factor for miscarriage or infertility, the results are "ambiguous," he says. Until more is known, Griffiths advises pregnant women to give up caffeine. - MH

"Abortion drug" tried on brain tumors

Hopkins researchers are investigating the abortion drug RU- 486 as a treatment for a type of brain tumor called meningioma.

The rationale for the study is the same as the reason that RU-486 induces abortion. RU-486 blocks progesterone, a hormone that is necessary to maintain a pregnancy, and which also appears to spur on the growth of meningiomas. The tumors grow dramatically during pregnancy, when progesterone levels are elevated.

"I'd hope this drug would be one measure to use in combination with surgery and radiation," says John Laterra, associate professor of neurology and oncology, and director of the Hopkins team participating in the multicenter trial. RU-486 might help attack those tumors that are inaccessible to the surgeon's scalpel, or keep in check tumors that might otherwise recur, he says. More than half of all meningioma patients experience a recurrence of the tumor. Pregnant women are ineligible for the study.

RU-486, which is used in Europe to induce abortions, is banned as an abortion drug in the United States. -MH

Genetic flaw in prostate cancer

A particular genetic aberration appears to occur in the early stages of all prostate cancers, the most common cancer in American men, according to a group of Hopkins urologists and oncologists. "We examined a very large variety of pathology of prostate cancers, of various stages and grades," from 20 different patients, says associate professor of urology and oncology William Isaacs. In every one, a chemical called a methyl group had attached itself to the anti-cancer gene glutathione S-transferase (GSTP1), squelching the gene's activity. The scientists report their findings in the November 21 Proceedings of the National Academy of Sciences.

Since every prostate cancer appears to contain GSTP1 genes that have been methylated, the abnormality probably arises early in the disease, says William Nelson, lead author of the study. He is developing a genetic test that could be used to diagnose early prostate cancer by detecting methylation of these genes. Such a test might yield more precise results than the widely used prostate specific antigen (PSA) test. When a PSA reading is neither high nor low but in-between, there is often no easy way to tell whether a patient has cancer or benign enlargement of the prostate.

Nelson is also planning a study to see whether a diet rich in cruciferous vegetables (such as the famous broccoli) might rev up the activity of GSTP1-like enzymes, which are known to detoxify carcinogens. He is working closely with molecular pharmacologist Paul Talalay, who showed in earlier studies that such vegetables boost the production of cancer- fighting enzymes. -MH

Hopkins alumnus garners Nobel

Last October Martin Rodbell '49 became the 22nd person with a Hopkins link to win a Nobel Prize.

Rodbell, scientist emeritus at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina, shares the $930,000 prize in medicine with Alfred Gilman, chair of the department of pharmacology at the University of Texas in Dallas. In the 1970s, the two men unraveled how environmental signals such as hormones, drugs, or light can trigger changes within cells through proteins in the cell membrane called G proteins.

Rodbell is fun-loving, the type of person who attracts people, recalls Robert Coplan '48, a friend from Phi Sigma Delta days. "You wouldn't believe he was studious." Rodbell majored in biology at Hopkins, then headed for graduate school in biochemistry at the University of Washington in Seattle.

Two decades later, at the National Institute of Arthritis and Metabolic Diseases, in Bethesda, Maryland, he proposed that the accepted view of cell signaling was incomplete. Scientists knew that substances such as certain hormones bind to receptors on a cell's surface, triggering changes such as growth of the cell. Rodbell posited that specific proteins within the cell membrane act as transducers in this process, in effect as middlemen. When a chemical binds to a receptor, he said, it activates the transducer, which then transmits the message to the cell. He said the fuel for the process comes from a molecule called GTP, which binds to intramembrane proteins. Through a series of experiments, Rodbell gathered evidence for the existence of GTP-binding proteins, or G proteins.

Rodbell's idea was heretical, recalls Michael Levine, now a Hopkins professor of medicine, who worked around the corner from Rodbell in the late 1970s. Levine remembers "robust discussions" in the halls of NIH over whether signal transducers could exist. "Rodbell was provocative, daring, one might almost say fearless," he recalls. The final confirmation of Rodbell's hypothesis came when Gilman, then at the University of Virginia, isolated and purified the proteins.

The researchers' work spawned a whole generation of scientists whose research hinges on G proteins. At Hopkins alone there are at least 50 scientists working on G proteins, says molecular biologist Randall Reed, who is investigating G proteins involved in the perception of smell. -MH

A dark side to the radium wand?

Today, people are acutely aware of the dangers of radiation. But in pre-Hiroshima days, radiation was more accepted in everyday life. Shoe store clerks X-rayed customers' feet to see if their shoes fit. Surgeons used X-ray instruments called fluoroscopes to view a patient's bones while setting fractures. And in the 1920s, Hopkins physicians Samuel Crow and Curtis Burnum developed a radium-tipped wand that was inserted into patients' nostrils to shrink tissue and alleviate chronic ear, nose, and throat conditions.

Now, Hopkins researchers are investigating whether former patients treated with radium through the Washington County Health Clinic, in Hagerstown, Maryland, have increased rates of cancer or other medical problems.

Until 1970, the wand was touted as the best hope for such ailments as deafness due to chronic ear infections in children, or middle ear problems in submariners due to undersea pressure changes. Tens of thousands of people received the treatment and are now wondering whether they are at increased risk for head and neck cancer or various other medical ailments.

A study reported by Hopkins epidemiologists in 1979 found no increased cancer in adults who had been treated with nasopharyngeal irradiation as children. But had enough time passed? If the treatment did indeed sow the seeds for cancer, the disease would be showing up now, says George Comstock, professor of epidemiology at the School of Public Health. Along with doctoral student Jessica Yeh and professor of epidemiology Genevieve Matanoski, he is tracking down the medical records of 2,000 patients to compare those of individuals who were exposed to the wand with those who were not. The researchers are looking specifically for cancers of the head and neck, and for medical problems linked to the pituitary, which sits just two to four centimeters from where the radium tip lay.

Only such a controlled study can lead to any meaningful conclusions about the hazards, if any, of the nasopharyngeal applicator, says Comstock. -MH

Written by Sue De Pasquale, Elise Hancock, and Melissa Hendricks

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