A TAILORED PLAN
by Alicia Di Rado

A genetics-based diagnostic technology allows oncologists to better determine which cancer treatment will work best against a patient's specific cancer.

Imagine finding out you have cancer and face weeks of chemotherapy to battle the disease, but you must undergo the grueling therapy with no hint of whether it will work or not.

For hundreds of thousands of cancer patients, this is a harsh reality. Patients often must wait in agonizing suspense before they find out if the powerful chemotherapy drugs have vanquished the insidious tumors within.

But the days of this educated guesswork may be ending.

USC researchers have commercialized a new technology that tells patients and their oncologists which type of chemotherapy drug is most likely to be effective for their specific cancer-before treatment even begins-giving patients the best chance at positive results and avoiding other potentially unsuccessful, uncomfortable and costly therapies.

The advanced diagnostics draw from research developed over the last decade by Kathleen Danenberg, research laboratory specialist at USC/Norris, Peter Danenberg, Ph.D., USC professor of biochemistry and molecular biology, and Heinz-Josef Lenz, M.D., associate professor of medicine at the Keck School of Medicine and scientific director of cancer genetics at USC/Norris.

When physicians discover a patient has a cancerous tumor, they surgically remove it or remove a portion for a biopsy before starting chemotherapy or radiation. Under the new service, physicians can send a sample of the tumor tissue to the laboratory for advanced analysis. This allows physicians to incorporate valuable information into their decisions and helps them recommend the most effective treatment for a patient's specific cancer.

"Kathleen and Peter Danenberg have developed a method that allows for the examination of gene expression in a single tissue section," says Lenz, who has treated hundreds of patients with gastrointestinal cancers and performs research on cutting-edge therapies. "This will revolutionize the way we can screen for chemoresistance."

What it means for physicians is that cancer treatments can be tailored to best fit with each patient's genetic makeup. The USC researchers have identified important genetic markers in tumor tissue that can predict which tumors will respond best to certain types of chemotherapy. The chemotherapeutic agents currently being used are 5-FU (fluorouracil) and cisplatin, which are often given for colon, lung, pancreatic and stomach cancer, as well as other cancers.

The scientists currently look at four genetic markers that are associated with cancerous tumors' reaction to the two chemotherapy drugs. The genes express certain enzymes that are important in cancer (an enzyme is a protein that regulates the rate of a chemical reaction in the body-a sort of catalyst or switch that turns on a chemical process).

Researchers have found that the ability of a chemotherapeutic drug to fight a particular tumor depends in large part on the levels of various enzymes that the tumor's cells produce. That amount varies from patient to patient.

In the case of 5-FU, researchers are concerned with a trio of enzymes with somewhat intimidating names: thymidylate synthetase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD).

The 5-FU drug works by blocking replication of DNA, which slows the growth of and eventually kills the quickly dividing tumor cells. It does this by targeting the TS enzyme, one of the main building blocks of DNA. But when a patient's tumor expresses a lot of TS enzyme, it is more resistant to 5-FU.

The TP enzyme, meanwhile, activates 5-FU, but also plays an important role in creating new blood vessels that feed a growing tumor. The more TP expressed, the poorer the prognosis tends to be for the patient.

Finally, DPD influences the levels of 5-FU in a tumor, so it too is linked to how well a patient responds to 5-FU.

So, for example, if a colon cancer patient's tumor shows low levels of TS, TP and DPD, researchers using the advanced diagnostics find with 100 percent accuracy that a regimen of 5-FU alone would be effective in battling the cancer, explains Lenz. In contrast, using traditional biopsy analysis, 15 to 20 percent of colon cancer patients treated with 5-FU alone respond to the drug. Response means that the tumor's volume shrinks by at least half, he says.

A fourth gene expressing an enzyme called ERCC-1-known as a DNA repair gene-also is important. The higher the levels of ERCC-1 in the tumor, the better the tumor can repair the damage wreaked on its cells by chemotherapy. When researchers see low levels of TS and ERCC-1 from a tumor, they can predict with 80 percent accuracy that a patient will respond to a combination regimen of cisplatin and 5-FU, Lenz says.

If the tests find that 5-FU and cisplatin are not likely to be successful for a patient's cancer, oncologists have several other standard therapies they may try, as well as clinical trials for newly developed drugs. The information also helps oncologists decide whether a patient would respond better to a combination of chemotherapeutic drugs, instead of one alone.

The researchers already are investigating markers that may be associated with numerous other anti-cancer drugs, including: Taxol (paclitaxel), Taxotere (docetaxel), Herceptin (trastuzumab) and Camptosar (irinotecan, or CPT-11), as well as proteosome inhibitors (PS341), inhibitors of tyrosine kinase of the epidermal growth factor receptor (such as Cetuximab) and Gemzar (gemcitabine).

Scientists also have developed a test to monitor patients' success on chemotherapy, Lenz says. By analyzing a patient's blood, scientists can measure changes in the DNA shed by a patient's tumor. That way, they can monitor the success of chemotherapy while it is underway-and easily follow up on patients after chemotherapy is over, to make sure the tumor is not growing back.

Lenz believes the service will also be a helpful tool for obtaining second opinions and adjusting treatment for patients already in chemotherapy.

USC/Norris oncologists are already using the tests for appropriate patients receiving treatment at the hospital, Lenz says.

"Now we're making this technology available to cancer patients from throughout the country," Peter Danenberg says. "It means avoiding fruitless treatment for some patients, and designing highly effective treatments for others. The potential for improving lives is tremendously exciting." n

For more information about cancer prevention and treatment visit the USC/Norris Comprehensive Cancer Center's website at www.uscnorris.com, or to learn more about The Doctors of USC, call 1-800-USC-CARE (1-800-872-2273).