‘Tumor-in-a-dish’ predicts if chemo drugs will work

"We hit the tumor with a punch and see how it responds," says Melissa Skala, "It is cheap and fast and adaptable to high-throughput screening so it can be used to test dozens of drugs or drug combinations at the same time." (Credit: iStockphoto)

One of the tragic realities of breast cancer is that the drugs used to treat it are highly toxic and their effectiveness varies unpredictably from patient to patient.

Now researchers are using a new type of test to quickly predict how effective chemotherapy drugs will be on a woman’s specific breast cancer before chemo starts. If results pan out, the test could be available clinically within 5 to 10 years.

More than 100 different anticancer drugs are currently available, but only 10 to 15 are used regularly.

Biomedical engineers developed the “tumor-in-a-dish” technique, which uses fluorescence imaging, to monitor the response of three-dimensional chunks of tumors removed from patients and exposed to different anti-cancer drugs.

In an article published in the journal Cancer Research, engineers describe applying the technique to the three major forms of breast cancer.

The test can detect significant drops in the metabolic activity levels of all three types of tumors within 72 hours when exposed to an effective drug whereas tumors that were resistant to a drug show no change.

Guessing game

One in eight women in the United States will develop invasive breast cancer in their lifetime. Breast cancer kills about 40,000 women annually making it the second leading cause of cancer death in women, exceeded only by lung cancer, according to the American Cancer Society.

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When breast cancer is diagnosed, the drug regimen the patient receives is based primarily on the results of a biopsy used to identify the type of tumor. The effectiveness of the initial treatment is assessed after two to three months.

According to several studies, in more than 100,000 cases each year the breast cancers never respond to the standard drugs, either initially or after repeated doses. As a result, 33 to 43 percent of patients must be switched to different drug combinations.

“Right now it’s a guessing game,” says Melissa Skala, assistant professor of biomedical engineering at Vanderbilt University. “We hope that our test will significantly improve the odds of survival of breast cancer patients by allowing doctors to identify the most effective but least toxic form of chemotherapy for each individual patient before the treatment begins.”

More than 100 different anticancer drugs are currently available, but only 10 to 15 are used regularly.

The new “tumor-in-a dish” method begins by taking the cancerous tissue removed during surgery or biopsy, cutting it up into small pieces and putting them in a special collagen gel that maintains them as “organoids” that retain the three-dimensional structure of the original tumor and include supporting cells from the tumor’s environment.

The traditional method of culturing tumor cells produces a single layer of cells that behave much differently from the original tumor. So cancer researchers have developed methods for culturing three-dimensional tumor organoids that mimic the behavior of the original tumors so they can study how they grow.

Cheap and fast

“This is the first time the 3D culturing method has been used to predict the effectiveness of different drugs on tumors from individual patients,” says graduate student Alex Walsh.

The researchers use a technique called “optical metabolic imaging” to measure the activity level of the organoids. The technique uses a laser that is tuned to the frequencies that cause two key enzymes in the cells to fluoresce. Measuring the variations in the intensity of the resulting fluorescence provides a “dynamic readout of cellular metabolism,” which is a sensitive biomarker of drug response. Their tests show responses to drug exposures within 24 hours.

“We hit the tumor with a punch and see how it responds,” says Skala, “It is cheap and fast and adaptable to high-throughput screening so it can be used to test dozens of drugs or drug combinations at the same time.”

The test also measures the responses of all the individual cells in the organoid. This is important because tumors are not all alike and some types of tumor cells may respond differently to a specific drug than another.

If a given drug cocktail kills 90 percent of the cancer cells but doesn’t affect the remaining 10 percent, the resistant tumor cells can take over and cause the tumor to grow back.

Next step

“Our test should make it possible to find drug combinations that kill all the cancerous cells in a tumor,” Skala says.

So far they have tested the method extensively in mice and with six samples of human tumors using four anticancer drugs commonly used to treat breast cancer and two experimental drugs.

“The next step is to test tumors from more human patients and see how the results compare to the response that the patients have to chemotherapy,” Walsh says.

If these experiments validate the test results, as the researchers expect, then they estimate that it could become available clinically within 5 to 10 years.

After validating the test for breast cancer, they intend to see how well it works with pancreatic cancer. Although pancreatic cancer is relatively rare, accounting for about 3 percent of all the cases of cancer in the United States, it has an extremely high mortality rate, so it accounts for about 7 percent of all cancer deaths.

Other researchers from Vanderbilt University Medical Center and from Takis Biotech in Rome, Italy and from the IRCCS National Cancer Institute in Naples, Italy contributed to the research.

The National Science Foundation, the Department of Defense, the National Institutes of Health, the National Cancer Institute, and Vanderbilt University supported the study.

Source: Vanderbilt University