Improving Breast Cancer Chemo By Testing The Tumors In A Dish

Time sequence shows the difference in response of organoids
 formed of drug-resistant cancer cells, top, and non-resistant
 cancer cells, bottom. Blue shades indicate that cell metabolism
levels are low while yellow and orange indicate higher metabolic
 levels. (Credit: Skala Lab, Vanderbilt University)
One of the tragic realities of cancer is that the drugs used to treat it are highly toxic and their effectiveness varies unpredictably from patient to patient. However, a new "tumor-in-a-dish" technology is poised to change this reality by rapidly assessing how effective specific anti-cancer cocktails will be on an individual's cancer before chemotherapy begins. A team of biomedical engineers has developed the 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 last month by the journal Cancer Research the engineers describe applying the technique to the three major forms of breast cancer. They report that 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.

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.

When breast cancer is diagnosed, the drug regimen that the patient receives is based primarily on the results of a biopsy that is used to identify the type of tumor she has. The effectiveness of the initial treatment is assessed after two to three months by determining whether the tumors are shrinking or continuing to grow.

According to several studies, in more than 100,000 cases each year the breast cancers do not 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 regimens. More than 100 different anticancer drugs are currently available, but only ten 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.

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.

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