Advances in the Study of Glioblastoma
A new role for dopamine
Scientists in the laboratory of Atique Ahmed, PhD, assistant professor of Neurological Surgery, investigated how activation of dopamine receptors plays a role in glioblastoma growth. The team demonstrated that dopamine signaling drives specific changes in glioblastoma cells, shifting them to become both more aggressive and resistant to therapy — even acquiring the ability to produce their own dopamine. The findings were published in The Journal of Neuroscience.
“This represents cancer cells hijacking a normal brain function in order to help themselves,” said research associate and co-first author Jack Shireman. The findings could inform future treatment approaches. For example, existing FDA-approved drugs designed to reduce dopamine signaling could be repurposed for use in glioblastoma. The authors caution, however, that more research is needed before such an approach is ready for patients.
“These cells have a remarkable ability to detect changes in their environment and adapt to them. Our lab strives to better understand this, so we can develop more effective therapies,” said Ahmed.
The study was supported by the National Institute of Neurological Disorders and Stroke grant 1R01NS096376, the American Cancer Society grant RSG-16-034-01-DDC and National Cancer Institute grant R35CA197725 and P50CA221747 SPORE for Translational Approaches to Brain Cancer.
Tumor Mutations Predict Response to Immunotherapy
According to a study published by Northwestern investigators in Nature Medicine, the presence of certain mutations in tumors can influence how patients respond to immunotherapy.
Scientists profiled 66 patients with glioblastoma, tracking their response to PD-1 immune checkpoint inhibitor therapy over time. Genomic analysis revealed that many of the patients who did not respond to therapy had tumors with mutations in a gene called PTEN. These PTEN-rich tumors had gene expression that suggested a high number of regulatory T-cells. However, when the investigators examined the tumors, they didn’t find a high concentration of immunosuppressive T-cells in non-responder patients.
“We were scratching our heads,” said Adam Sonabend Worthalter, MD, assistant professor of Neurological Surgery and co-senior author of the study. “How could some tumors have higher levels of activation for the genes for the T–cells, but not have more of these cells?” They used RNA sequencing to look at the gene expression of individual tumor cells, finding that the tumor cells themselves were expressing the regulatory T-cell genes, potentially mimicking their function — a possible reason why immunotherapy would be less effective. Patient tumors with mutations in the MAP kinase (MAPK) pathway responded better to immunotherapy.
“Whereas careful validation of these findings is necessary, we have little to offer glioblastoma patients. So for the time being, if a patient of mine had these mutations, I would offer immunotherapy,” said Sonabend.
This work has been funded by National Institutes of Health grants R01 CA185486, R01 CA179044, U54 CA193313, U54 209997 and R01 NS103473; NSF/SU2C/V-Foundation Ideas Lab Multidisciplinary Team PHY-1545805, 2018 Stand Up To Cancer Phillip A. Sharp Innovation in Collaboration Awards and Keep Punching Foundation, Northwestern 5DP5OD021356-04, P50CA221747 SPORE for Translational Approaches to Brain Cancer, developmental funds from the Lurie Cancer Center NCI Support Grant no. P30CA060553, the Medical Scientist Training Program T32GM007367, the CUIMC CTSA TL1 Precision Medicine Fellow 1TL1TR001875-01 and Swim Across America.
Alexander Stegh, PhD, associate professor in the Ken & Ruth Davee Department of Neurology in the Division of Neuro-oncology.
New Gene Associated With Glioblastoma
A gene called isocitrate dehydrogenase 3-alpha (IDH3A) promotes glioblastoma tumor growth, according to a study published in Science Advances. A drug that targets this gene could be a new therapy, said Alexander Stegh, PhD, associate professor in the Ken & Ruth Davee Department of Neurology in the Division of Neuro-oncology, and senior author of the study. Jasmine May, a seventh-year student in the Medical Scientist Training Program, was the first author.
Stegh and his collaborators examined IDH3A levels in a large database of genetic data from glioblastoma tumors, and in tumors resected from Northwestern patients. The scientists found IDH3A was expressed at much higher levels in patient tumors than in normal brain tissue. They then tested its function in mice and found that elevated levels of IDH3A promoted tumor progression.
After further study, they found IDH3A allows rapidly dividing tumor cells to increase DNA synthesis, supporting cell division and unabated growth. A therapeutic approach targeting IDH3A could reduce the ability of tumor cells to synthesize DNA, according to Stegh. “Inhibition of DNA synthesis in turn is expected to reduce the growth of highly proliferative cancer cells,” he said.
Jasmine May, a seventh-year student in the Medical Scientist Training Program.
This research was supported by the Center for Cancer Nanotechnology Excellence Initiative of the National Institutes of Health (NIH), under awards U54 CA151880, 199091 and R01CA208783. Other NIH grants include T32 CA09560, T32 GM008152, R01CA193256, P30CA014236, R01LM011297 and R35CA197532. The study was also supported by the brain tumor SPORE grant P50CA221747.