Using microchip-sized labs, scientists are now investigating how brain tumors and other cancers evolve resistance against drugs and radiation therapies. Future research using these tools could help find ways to overcome such resistance.
Cancer has an uncanny ability to quickly adapt to chemotherapy and radiotherapy. “Workshops with the National Cancer Institute told me that despite the hype, we were losing the cancer wars because of the emergence of resistance,” says Princeton University biological physicist Robert Austin.
He and his colleagues experiment with microfluidic technology, which manipulates chemicals and cells just as microelectronics control electricity. These devices, called “labs-on-chips,” essentially shrink beakers, flasks and other laboratory goods to microscopic sizes, helping researchers conduct thousands of experiments simultaneously at a fraction of the time, space, materials, cost and effort of what it might ordinarily have taken with regular equipment.
The researchers had previously investigated how bacteria develop resistance against antibiotics. To learn more about how cancers might similarly evolve resistance against chemotherapy and radiotherapy, they developed chips made of artificial rubber that were each about the size of a postage stamp. Each chip possessed several hundred tiny chambers, each a square-millimeter in area. Every chamber held a few hundred cancer cells. These cells were genetically modified to produce a red fluorescent protein that researchers could track.
Watching evolution of resistance happen
Using their labs-on-chips, the scientists analyzed the effects varying doses of the chemotherapy drug doxorubicin have on brain and breast cancers as well as multiple myeloma, a cancer of the white blood cells that normally produce antibodies.
"Normally, microfluidics is used to study how cancer cells respond to different levels of potential drugs over short time scales to screen for which drugs might be effective against them," says Princeton biological physicist Amy Wu. "We extended the time scales to see how these cells evolve in environments with different gradients of drug concentrations."
The researchers found that colonies of drug-resistant cancer cells developed in two weeks in areas where drug levels were low enough for some cells to remain alive but higher than what is typically used clinically. These resistant cells not only survived, they were then able to migrate toward high-drug regions, “much like what we think happens in cancer patients,” Wu says.
"I was stunned how quickly evolution could proceed," Austin says. "You can’t beat Darwin."
Resisting radiation, too
Austin and his colleagues also explored what effects varying levels of x-rays might have on brain cancer cells. “Radiation is often the only thing you can use in brain cancers that are inoperable,” he says. They similarly found cancer cell growth at radiation levels similar to ones used in radiotherapy.
Wu said one factor underlying resistance is apparently how the level of cancer-killing drug or radiation a patient receives varies over space. “You just always get places in the body with more drug and less drug, depending on how close or far away they are from where the drug was applied,” Wu says. “That gradient is crucial to get drug resistance.”
Scientists are currently working on drugs that can sabotage cancer-resistance mechanisms, such as proteins cancers use to pump out drugs. Wu also notes that the cancer specialists and cell biologists her group is collaborating with suggest one strategy for overcoming the challenge of cancer resistance against therapies: somehow eliminating the gradients of high to low drug levels the disease encounters. “Maybe future work can use ultrasound to enhance drug delivery, so you have equally high levels of drug everywhere, and no more gradients,” she says.
The scientists will detail their findings on March 22 at the American Physical Society meeting in Baltimore.
Top Image: Labware like this is being replaced by microfluidic labs-on-chips. Photo via Shutterstock.