UNCLOAKING CANCER; RESEARCHERS DEVISE NEW WAYS OF DETECTING THE INVADING CELLS.

Byline: Phil Davis Staff Writer

Cancer hunter Richard Cote's job would be easy if he were merely searching for that proverbial needle in a haystack. Try finding a single, imperceptibly unique needle in a pile of a million needles.

The University of Southern California pathologist hunts the most elusive of cancers - the occult metastases, a lethal microscopic rogue that easily slips past the most advanced diagnostic equipment.

``What we're talking about is the ability to detect one tumor cell in a background of 1 million normal cells, so this goes well beyond a pinpoint,'' Cote said.

Mission: Impossible?

Until recently, yes. Cancer is a hit-and-run, guerrilla fighter. It blends with healthy cells until it can mount an attack in the form of a tumor or lesion. In many cases, by the time a doctor or patient notices something out of the ordinary, cancer cells - too small to detect by conventional methods - are on their way to attack other parts of the body.

Cancer has a voracious appetite and unique abilities to draw on the body's resources to grow faster than normal cells, making it an efficient killer that claims roughly half a million American lives every year.

But those same unique traits may also be its Achilles' heel.

Southern California cancer hunters like Cote are refining methods to spot those differences and shed some light on the elusive disease. The scientists say that seeing cancer is crucial in designing more effective treatments and, hopefully, another step toward finding a cure.

Occult metastases

Using complex molecular probes designed to seek out traits specific to cancer, Cote and his associates at USC actually have been able to color cancer cells in bone marrow and lymph node samples.

It's a lot like flipping on a light switch inside the invading cells. A slide that once appeared to show only a field of healthy cells suddenly reveals a string of cancer cells on the move, a metastasis. Cote believes the cells are scouting sites to begin a new assault on the body.

The research is currently being evaluated in a multicenter clinical trial, but the implications are profound for patients. For example, most women with breast cancer undergo unpleasant chemotherapy after surgical removal of a tumor even though as many as 70 percent don't really need it. The problem: There is no effective way to tell which women still have cancer lurking in their bodies and which don't. Cote hopes his research will provide that.

``Patients who have these cells in their bone marrow or lymph nodes are at significantly greater risk for developing overt metastatic disease than are the patients who do not have these cells,'' Cote said. ``The tumor that has spread is the tumor that is going to kill the patient, so the consequences are profound. And the economic consequences are also quite profound because right now, basically, everyone is treated.''

It's intriguing news, but like many promising cancer studies, the medical profession demands solid proof before it embraces the concept.

``It's very exciting, but it's been a long road,'' Cote said of his 14-year pursuit of occult metastases. ``It seems to be a very straightforward concept, but it's taken many, many years for it to gain even a modest level of acceptance. It represents a fundamentally different way to look at a cancer patient, and there's always a natural resistance to that.''

PET scan 

Dr. Peter Conti is familiar with that resistance. As director of USC's positron emission tomography (PET) lab, Conti works with one of the most promising and powerful diagnostic tools in the fight against cancer.

But the machine is just now being accepted by health insurers despite the fact it's been around for more than a decade. (It was invented in 1973 at Washington University in St. Louis by Dr. Michael Phelps and his colleagues.)

Conti said the use of the machine has been clouded by regulatory red tape and resistance from insurance companies because of its cost: $2,000 per scan.

``It's only in the last year or two it's starting to take hold, but we've been fighting this battle for over a decade,'' Conti said.

Unlike X-rays and computed tomography (CT) scans that take pictures of the body's anatomy, PET scans peer into the body's metabolism. PET scans take advantage of cancer's voracious appetite for glucose, the body's fuel. Radiologists inject a patient with a glucoselike substance tagged with a radioactive tracer. Since tumors take in more glucose than healthy cells, they also suck up the tracer, which shows up on the PET scan.

Unlike magnetic resonance imaging (MRI), which uses the body's hydrogen atoms to create detailed internal images, PET often can differentiate between scar tissue and tumors more effectively, Conti said.

``We've been able to see a lot more disease,'' Conti said. ``It's opened up a lot more opportunities in terms of diagnosing the stage of the disease and monitoring the effectiveness of therapy.''

That can be a mixed blessing. Take the case of a 71-year-old man with metastatic melanoma. The disease was discovered first in his left shoulder; CT and bone scans later revealed the disease near his spine and in his leg.

But a PET scan revealed cancer lesions throughout his body - a fatal diagnosis. Surgeons canceled a planned amputation of his leg, where they originally thought most of the cancer was concentrated; the surgery would not have saved him. It's grim news, Conti admits, but it also allowed the man to spend the remainder of his life with his family instead of recovering from a traumatic and pointless surgery. And, on a more commercial level, his insurance company saved thousands of dollars.

On the positive side, PET scans can help doctors plan the amount of chemotherapy to give a patient, based on the rate the cancer has spread.

Molecular `LoJack'

PET also promises to help researchers evaluate gene therapy, a potentially exciting cancer treatment that is just now being evaluated in humans.

Dr. Harvey Herschman, a molecular biologist at the University of California, Los Angeles, is refining a method that will track genes that have been modified by scientists to fix a variety of maladies - from cancer to cystic fibrosis.

For example, so-called therapeutic genes may one day be used to suppress or shut down cancer genes before they start working (called expression), replace bad genes with improved genes, or even kick the body's immune response to cancer into overdrive.

Unfortunately, just as cancer is tough to see inside the body, gene therapy pioneers have no idea where their treatment goes and how - or even if - it's working once it enters the body.

``We don't have any way to measure that,'' Herschman said. ``Essentially, all you can do is ask if the patient is getting any better. So what we've done is develop techniques where we link the therapeutic gene to a gene whose expression we can measure with PET. We can give a positron-labeled compound that gets taken up only in the tissue where our reporter gene is being expressed, so if it is on in the liver, then you figure the therapeutic gene must also be on in the liver.

``It's sort of like a molecular LoJack,'' he said, comparing the therapy to the satellite tracking system used to track stolen cars.

Hot cancer

If color-coding cancer cells or tracking tumors with a PET scan doesn't lead to a cure for cancer, another breakthrough area could lie in thermal imaging.

``The technology is similar to what we saw in the Gulf War and on what police use on those 911 shows to look for a suspect behind a bush,'' said Dr. Yuri Parisky, a USC radiologist.

Parisky is testing thermal imaging as a method to detect breast cancer as compared to a benign lesion. Again, it's a promising hypothesis that is just now entering the human testing stage.

Cancer tumors seem to give off more heat than healthy cells. Parisky and his colleagues aren't exactly sure why, but they think it could be related to cancer's unique ability to recruit blood vessels that help it grow and form a sort of scaffolding for the tumor or lesion to spread. Since more blood is going to that area, there should be more heat.

Another theory: Cancer's higher metabolism and turnover rate generates more heat.

Thermal images peer down into the cellular level. Researchers use a sophisticated computer program to locate the hot - or malignant - cells.

So far, Parisky said, analysis of thermal images showed that 40 percent of the patients in his study could have been spared a painful biopsy to check out a suspicious mass detected in a mammogram. He hopes to improve those odds.

``We've done a hundred or so patients with very promising results,'' Parisky said. ``We'll never be more accurate than a biopsy, but in the patients we did, it correctly identified 96 to 97 percent of the cancer.''

The only cancerous incident it missed was a DCIS (ductal carcinoma in situ, a less invasive form of breast cancer) measuring about 1/10th of an inch, and refinements in the detection method may one day eliminate those oversights. ``Forty percent of the women in our study wouldn't have had to go into surgery,'' Parisky said. ``That's our starting point and we're going to do better.''

CAPTION(S):

5 Photos

Photo: (1--Cover--Color) CANCER HUNTERS

Local doctors deep in the trenches of battle against killer cells

(2--3) The work of USC's Dr. Richard Cote to make cancer cells appeared colored in tissue samples, as shown below, has major implications for women being treated for breast cancer. ``What we're talking about is the ability to detect one tumor cell in a background of 1 million normal cells,'' says Cote.

David Sprague/Staff Photographer

(4) Dr. Harvey Herschman, a molecular biologist at UCLA's Jonsson Cancer Center, is developing a scan to let doctors know whether gene therapy is working in patients.

Gus Ruelas/Staff Photographer

(5) A PET scan revealed malignant tumors throughout the body of a 71-year-old man, who was scheduled for a leg amputation. The surgery, which would have been ineffective, was canceled as a result.