Faster and more accurate method for testing new cancer drugs

Dec 2 2014

Finding faster and more accurate ways to test new cancer drugs is always a priority for cancer researchers. Shrikant Anant, Ph.D., associate director of Cancer Prevention and Control at The University of Kansas Cancer Center, is hoping to make that happen with his innovative "tumor in a dish" method.

By combining the different cells that make up a lung, Dr. Anant was able to insert cancer cells and see how they grew in a real "in vivo" environment, or one that closely resembles human anatomy.

The process could also make it quicker and easier to test standard and experimental drugs on individual cancers as current drug testing methods can be time-consuming, imprecise or controversial.

For example, while genetic testing has become easier, it often shows what treatments won't work as opposed to which ones will. Growing tumor cells from scratch in a petri dish is not an accurate representation of the microenvironment in which cancer lives inside the body. Testing on animals creates a more human-like environment to grow a tumor, but draws ire from animal-rights groups and can take a long time to yield results.

Dr. Anant also wanted to be able to test drugs on cancer metastases, which accounts for 90 percent of all cancer deaths. He decided to team up with Prabhu Ramamoorthy, Ph.D., a gastrointestinal physiologist and member of the KU Cancer Center's Cancer Biology Program, to try and develop a model for studying colon cancer metastasis.
"We decided to put a cancer cell inside a three dimensional multi-cell spheroid in vitro, and watch it colonize," said Dr. Anant.

They then selected the type of cells in which to grow the tumor. Although colon cancer most often spreads to the lungs and liver, Dr. Anant and Dr. Prabhu chose to use lung cells for his "tumor in a dish."

"The lung makes more sense because 80 percent of all cancers metastasize there," he said. "If we can build a lung we can look at how almost any type of cancer spreads, not just colon. Then we've really done service to society because researchers can use it to study different cancers."

Dr. Anant combined all the different things that make up a lung—lymphatic endothelial cells (these form the lining of lymphatic vessels), endothelial cells (these form the lining of blood vessels), lung fibroblasts (these create the connective tissue of the lung) and lung epithelial cells (these line the insides of lungs).

Just because all these cells were combined in a dish didn't necessarily mean it was a lung. Dr. Anant needed to show that these cells would do their jobs and perform just as a regular human lung would.

This is where Dr. Prabhu's knowledge came to play. He created the culture environment that ultimately resulted in the creation of the lung in the dish. As the cells reproduced and melded together, they came to life. The tiny lung started making surfactant protein, a key lung function that acts as a "cleaner" in the lungs, removing anything that shouldn't be there. The mass also formed alveoli sacs, which allow oxygen and carbon dioxide to move between the lungs and the bloodstream.
With everything in place, it was time to see if this "lung" could grow a colon cancer tumor. A colon cancer cell was injected into the mass along with a green fluorescence protein, so Dr. Anant and his team could track where the cancer was and if it would take root inside the lung mass and form blood vessels to sustain itself.

And it did.

"We said 'wow, we've got something really cool going here," said Dr. Anant. "But then we had to figure out: Can we use it to test cancer drugs with actual patient tumor samples? Seeing is believing when you're testing the drug on that patient's tissue."

Dr. Anant obtained a sample from an ovarian cancer patient who had yet to receive any kind of treatment. He added some cancer cells from ascites fluid (which builds up in the abdomen as certain cancers spread) into the tumor in a dish, and tested both the standard drug for ovarian cancer, cisplatin and a novel compound he is studying in his lab, marmelin. Marmelin is the active ingredient in the stone apple, and in early studies has shown to reduce tumor sizes in mice and blocks the growth of colon cancer stem cells.

The cancer cells did respond to the cisplatin since the patient had never been treated before. The lung tissue, however; was also breaking up and dying (known as toxicity) and a small number of cancer cells were still growing even while most were dying—a sign that the cancer would eventually return.

A new version of the marmelin drug, which was developed by Dharma Subramaniam, Ph.D., a research assistant professor in the department of molecular and integrative physioloigy, appeared to kill the malignant cells without killing the healthy lung cells, which is ideal for a cancer drug. According to Dr. Anant, the tumor in a dish can help determine which drugs will and won't be effective, and it only takes about 15 to 20 days.

"We came up with this idea because the methods for testing new cancer drugs aren't ideal," said Dr. Anant. "We found that by using the tumor in a dish we could develop new drugs and combinations with less animal use and faster results. It could also be a big step forward for personalized medicine by using patient tumor samples to determine which medications will work."

Source: University of Kansas Cancer Center