The Biology of Brain Tumors

FINDING WAYS TO UNDERSTAND BETTER THE BIOLOGY of brain tumors is key to helping scientists develop more targeted treatments and possibly, one day, a cure for brain cancer.  Zach Reitman, MD, Ph.D., and his colleagues are conducting work that may provide significant biological insights into various types of brain tumors. This work could improve care for adults and children and help doctors match patients with the right therapies.

In one project, Reitman and his team are looking for ways to enhance the efficacy of radiation therapy in a deadly type of pediatric brain tumor called diffuse midline gliomas. Radiation therapy is the only therapy known to help, but even after treatment, cancer inevitably progresses, and the patients die within one year of diagnosis.

Using mouse models, Reitman and his team hope to learn which genetic subtypes of tumors will best respond to radiation therapy in combination with other drugs that make cancer cells more vulnerable to radiation therapy. Such drugs include a new one that targets ATM (ataxia telangiectasia mutated) kinase.

“It’s an exciting opportunity because the drug is already being tested in another type of brain tumor,” says Reitman, a medical instructor in the Department of Radiation Oncology. “If we can add to that with our mouse modeling work, we might be able to build a scientific rationale to open clinical trials of this drug in children with this devastating disease and perhaps make an important advance.”

In another project, the Reitman lab hopes to identify drugs that could effectively treat the vast majority of glioblastomas. Reitman, along with others at the Preston Robert Tisch Brain Tumor Center, including Hai Yan, MD, Ph.D., made the critical discovery that about 80 percent of adult glioblastomas contain a mutation that affects a gene called the telomerase reverse transcriptase or TERT. So far, no one has been able to target this mutation in a way that benefits patients with glioblastoma. Reitman hopes to change that. He and his team have developed cell lines that will allow them to conduct genetic and chemical screens to find vulnerabilities associated with the TERT mutations. The idea is to find a way to repurpose existing drugs to target the mutations.

“The screens that we’re doing will look at whether knocking out any of 18,000 genes in the genome might lead to a specific vulnerability in TERT mutant brain tumors, which has never been done in this way before,” he says.

A third project aims to understand the makeup of brain tumors at a single cell level, potentially leading to improved ways to diagnose, monitor, and treat brain tumor patients. Before his recruitment to Duke, Reitman and his colleagues used single-cell RNA sequencing to examine the single-cell transcriptional landscape of a pediatric brain tumor called pilocytic astrocytoma. They also used single-cell RNA sequencing to study drugs treating brain tumors. They found significant findings about these drugs by targeting the MAP kinase pathway.

“A big mystery has been that the responses to these MAPK-directed drug therapies were very different from patient to patient,” Reitman says. “Our study provided a potential explanation: that only a subset of the tumor cells is highly expressing the MAP kinase pathway.”

In August 2019, the Tisch Brain Tumor Center recruited Reitman to Duke to use single cell genomics techniques to study brain tumors. “Our long-term goal is that this would allow us to develop tests in the clinic that would allow us to select the right drugs for the right patients.”