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Technology born at USC may take guesswork out of chemotherapy

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 tumors within.

But the days of this educated guesswork may be ending.

USC researchers have commercialized a new technology that tells patients with certain cancers 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 are offered by Response Genetics, a new company that was founded in part by Kathleen Danenberg, research laboratory specialist at the USC/Norris Cancer Center, and Peter Danenberg, USC professor of biochemistry and molecular biology. Response Genetics offers a suite of promising new molecular services for cancer patients and their physicians. Response Genetics’ core technologies draw from research developed over the last decade by the Danenbergs and Heinz-Josef Lenz, associate professor of medicine at the Keck School 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 paraffin-preserved sample of tumor tissue to the Response Genetics laboratory for 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, in cases where such predictions were not previously available.

“Kathleen and Peter Danenberg have developed a method that allows for the examination of gene expression in a single tissue section,” said 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.

Three important enzymes go by somewhat intimidating names: thymidylate synthetase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD).

If a colon cancer patient’s tumor shows low levels of TS, TP and DPD, researchers find with 100 percent accuracy that a regimen of 5-FU alone would be effective in battling that cancer, Lenz explained. Colon cancer patients not tested for those enzymes and treated with 5-FU alone, a common practice, have a markedly lower response rate of 15 to 20 percent. Response to the drug means that the tumor’s volume shrinks by at least half.

A fourth gene expressing an enzyme called ERCC-1–known as a DNA repair gene–also is important. 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 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 list of agents is growing. 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.

The university’s Office of Technology Licensing has helped the researchers and colleagues get their venture moving by licensing the new company the right to use the technology.

USC/Norris oncologists are already using the tests for appropriate patients receiving treatment at the hospital, Lenz said.Oncologists and patients may read more about the services by visiting the company’s website at www.

Technology born at USC may take guesswork out of chemotherapy

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