An important element of drug discovery is the scientific models used to study drugs. Increasingly, the laboratory models scientists use to determine if, how and why a drug works don’t work well in cancer. To address that weakness, Kimmel Cancer Center investigators are pushing the boundaries and developing inventive new ways to study drugs.
Tiny structures about the size of a fly’s eye provide a new futuristic opportunity to study pediatric brain cancers. These complex, organized spheres of human neural and nerve cells are dubbed organoids or minibrains. They cannot think or learn like a human brain, but their structure is similar enough to the anatomy of a developing brain that molecular radiation scientist Sonia Franco believes they can be used to replicate how pediatric brain cancers naturally grow and spread and to study more closely how these cancers respond to radiation and drug treatment. It takes about three months to grow the minibrain structures in the lab.
They grow to about 4 millimeters and provide a window of four to six months for research before the cells begin to die off. Hundreds of them can be created simultaneously The research is in its infancy, making its way into the laboratory about four years ago. They were stumbled upon almost accidentally as Austrian researchers were growing neural stem cells, the cells that give rise to all other brain cells. The cells were placed in a rotating flask so they would form into small spheres. Checking on the cells one day, a researcher noticed a tiny black speck on her organisms and thought the cells had become contaminated.
A closer look under the microscope revealed that the tiny black spot was a primitive eye. “They had self-organized and differentiated into 3-D, brainlike structures,” says Franco. The cells took cues from their environment—a nutrient-enriched gel in a constantly rotating flask that allowed the nutrients and oxygen to get deeper into the tissue, Franco explains. It closely mimics the natural environment of how brains develop in an embryo so that cells developed into a very early version of a human brain. Minibrains are best known as the model used to help scientists figure out how the Zika virus causes undersized brains in the infants of infected pregnant women. Franco is the first to grow cancers in the minibrains. Implanting tiny remnants of human brain tumors into the minibrains will provide new insights about how tumors grow and what drugs work best against them. Ultimately, she would like to use the research model to create a precision medicine stand-in for patients.
Minibrains can be created from the cells of any person. For example, researchers have the ability to coax simple skin cells to regress to their earliest form— flexible stem cells that, with the right environment, can be developed into any type of cell. Franco envisions creating a minibrain stand-in for a patient receiving treatment and implanting it with cells from the patient’s brain cancer. Testing drugs in the personalized model could help guide doctors toward the most effective therapies for each patient.
Franco expects the new minibrain model to be less expensive and work better than the animal models typically used in the laboratory. “The minibrains will show the natural physiological way cancer cells migrate and spread into the brain,” says Franco. “Animal models do not have this ability, so findings don’t translate well into the clinic.” Franco is collaborating with Kimmel Cancer Center at Sibley radiation oncologist and brain tumor expert Matthew Ladra to perfect her model. Ladra received funding from Children’s National Pediatric Cancer Center to explore the effects of radiation therapy on pediatric tumors and the surrounding normal brain. The joint effort is the result of a unique collaboration between pediatric oncologists and surgeons from Children’s National and radiation oncologists at the Kimmel Cancer Center to create the first dedicated pediatric radiation oncology program in the national capital region.
Ladra is sharing tumor samples with Franco she can implant in her minibrains. “We have the potential to make minibrains for different pediatric brain cancer types, including medulloblastoma and glioblastoma, and measure responses to drugs,” says Franco. “If we are treating a minibrain with the same therapy the patient is receiving and it’s not working, it would alert us that we might need to change the patient’s treatment plan.” Franco is also collaborating with radiation physicist John Wong, who invented the Small Animal Radiation Research Platform. It is a miniature version of human equipment and the only realistic laboratory representation of the therapy radiation oncologists provide in the clinic.
Right now, it is used on animal models, but Franco and Wong believe its size provides the potential to conduct radiation research with the minibrain model. The minibrain model could provide new clues about radiation resistance. Surgery followed by radiation therapy is a mainstay in children being treated for brain cancer, but brain cancers almost always come back. Franco wants to use the minibrains to study drugs that prevent cancer cells from repairing their DNA after radiation therapy. These repairs allow cancer cells to survive. “If we give drugs before radiation treatment that prevent these repairs, radiation therapy would kill more cancer cells,” says Franco.
There is also research evidence that pediatric brain cancer patients may benefit from drugs known as HDAC inhibitors. The minibrain model could provide valuable information about how these drugs work alone and in combination with other brain cancer therapies. “This method could really accelerate drug discovery,” says Franco. “Right now, it is difficult to get drug companies to develop and provide drugs for pediatric cancer. Using such a humanlike model could provide convincing results about the effectiveness and toxicity to brain cells needed to get drug companies on board.”