Neurobiologist Donald Lo, Ph.D., and cancer researcher Albert Baldwin, Ph.D., believed they would make an effective team for bridging translational science divides in brain cancer research. With support from NCATS’ Clinical and Translational Science Awards (CTSA) Program, they are now working together to develop a novel technique — with promising early results — to test drugs against glioblastoma multiforme. Glioblastoma is the most common form of brain cancer, killing approximately 14,000 people annually in the United States. It is deadly and difficult to treat, infiltrating the brain and nearly impossible to completely eradicate with drugs, radiation therapy and surgery.
Lo, director of the Center for Drug Discovery and associate professor of neurobiology at Duke University, and Baldwin, associate director of basic research at the University of North Carolina Lineberger Comprehensive Cancer Center, are growing tiny human brain tumors in the laboratory that they hope will be a powerful way to model glioblastoma to better understand and predict how individual tumors respond to therapies. The system may enable them to screen drugs to determine the best treatments for patients.
The new approach may be able to circumvent a number of translational roadblocks, speeding the development of compounds into drug candidates and, ultimately, new medicines to treat glioblastoma.
“Closing translational gaps in brain cancer treatment could lead to a range of new personalized approaches,” said Lo.
One roadblock, and a reason glioblastoma is difficult to treat, is the differences among cells within tumors. A therapy that might be effective against one cell type might not work as well against another. A tumor’s makeup also can change over time, particularly after treatment.
“Glioblastoma is made up of multiple cell populations, with dozens of cell lineages forming in the same patient’s tumors,” Baldwin said. “Different cell lineages within tumors can behave differently and can drive drug resistance and recurrence. If a test could anticipate that and predict the drug sensitivity for individual tumors, then we could design combination drug therapies for tumor cell subtypes.”
The standard way to study glioblastoma in the laboratory — implanting human tumors into animals that lack a functional immune system — is less than ideal. Instead, Lo and Baldwin remove clusters of glioblastoma cells from patients and engraft the cells into slices of brain tissue grown in the lab, to develop tumors in an environment that more closely mirrors the human brain. The resulting brain tumors may enable Lo and Baldwin to reproduce tumor cell lineages for study and for the development of new drug therapies.
For now, the researchers are using the model to measure the sensitivity of glioblastoma tumor cell lineages to typical chemotherapy drugs and are trying to characterize the properties of the different tumor cell lineages and their responses. The early results indicate that patients and the different tumor cell lineages respond to drugs in similar ways. Lo and Baldwin also will examine the characteristics of laboratory-grown glioblastoma tumors in response to investigational drugs and combinations.
The CTSA Program hubs at Duke University (Duke Clinical and Translational Science Institute) in Durham, North Carolina and the University of North Carolina (North Carolina Translational and Clinical Sciences Institute) at Chapel Hill supported this work.
Posted September 2017