A research team led by UAB is launching a study to find a better model for glioblastoma, a particularly devastating type of brain tumor, to help determine the most appropriate treatment modality. The $3.6 million grant is funded by the National Cancer Institute (NCI). The UAB team will join four other institutions with similar awards -- University of California-San Francisco, Duke University, University of Utah, and Cold Spring Harbor Labs/Jackson Labs, to form the Patient-derived Models Consortium, or PDMC.
For years, the NCI had recommended using a set of cancer cell lines, called the NCI-60, which included glioblastoma cells, for pre-clinical testing. Pre-clinical testing can provide physicians with important information on the makeup of tumors, guiding the development of new treatment approaches. Unfortunately, the clinical success rate following NCI-60 panel testing was not as effective as desired, particularly for glioblastoma.
Use of the NCI-60 has been phased out in favor of patient-derived xenografts, or PDX, in which a patient's own tumor cells are grown in a mouse model. Xenograft models permit cancer cell interactions with other cells and conditions that are not currently fully replicated in a laboratory dish. Creating and testing patient-derived xenografts is a slow process, so the NCI is looking for the most effective ways to use the xenografts to identify new ways to fight cancer.
The UAB-led research team is examining two new technologies, neurospheres and microtumors, and will compare them with PDX.
"Neurospheres are self-assembling groups of cells that can be grown in defined media conditions," said Christopher Willey, MD, PhD, associate professor, Department of Radiation Oncology in the UAB School of Medicine. "Microtumors involve embedding the same type of tumor cells into a matrix material in a three-dimensional structure. Both allow for high-throughput screening of potential drugs, which should produce a cheaper and quicker way to identify compounds that might have therapeutic benefit."
The study will attempt to better understand how the various models -- neurospheres, microtumors or PDX animal models -- are influenced by their growth conditions in terms of their molecular signaling and sensitivity to cancer treatments.
"Our intent is to see how these systems respond to typical therapies, such as chemotherapy or radiation," said Yancey Gillespie, PhD, professor emeritus in the Department of Neurosurgery. "We will be able to directly determine which genes are being expressed and which enzymes are active in the same tumor cells growing in three different environments. This data will allow us to change the models or their environments to mimic the brain tumor environment in the patient and then assess how each model responds to therapy. The idea is to make a more accurate, patient-like model for human brain tumors."
Anita Hielmeland, PhD
"Some treatments we thought would work well in brain tumor patients have not been as effective as hoped. We believe we can identify better therapies if we have a model that most closely represents actual tumors in a human brain," said Anita Hjelmeland, PhD, associate professor in the Department of Cell, Developmental and Integrative Biology.
Jake Chen, PhD
"To characterize these PDX models, we plan to apply an array of new computational tools," said Jake Chen, PhD, chief bioinformatics officer of the UAB Informatics Institute. "Genomic, transcriptomic and kinomic data will be systematically collected from these glioblastoma PDX models. We will develop new bioinformatics and systems biology techniques to integrate all these quantitatively measured signals -- hundreds of thousands of them for each model -- to build 'in silico' models. These models can then be manipulated in computers rapidly and help us predict each tumor's subtype and drug sensitivity behaviors before actual experiments are performed."