Researchers Join $10 Million Project to Better Understand Sex Differences in Brain Cancer Outcomes

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Researchers from Penn State College of Medicine are participating in a $10 million project to better understand why men and women with a common and deadly type of brain cancer have different survival rates. The investigators hope the study results can be used to develop new therapeutic approaches for the most severe type of brain tumor, glioblastoma.

Patients with glioblastoma have a median survival of 12 to 14 months, and only 5% of patients are expected to survive beyond 5 years, heightening the need for improved therapies. Researchers previously determined that this type of brain cancer is more common in men than in women and that women tend to have an improved survival rate of up to 10 months.

James Connor, PhD, Distinguished Professor of Neurosurgery, Neural and Behavioral Sciences and Pediatrics, will lead Penn State’s involvement in the project, which is sponsored by the National Cancer Institute. Justin Lathia, PhD, of Cleveland Clinic’s Lerner Research Institute, and Jill Barnholtz-Sloan, PhD, of Case Western Reserve University School of Medicine are the principal investigators of the multi-institution research team, which will investigate the genetic and metabolic differences in cellular processes associated with different glioblastoma outcomes in men and women.

Exploring the Role of Iron Metabolism

For most of his career, Dr. Connor has studied how iron metabolism in brain cells affects neurologic disease. He began investigating how iron regulation affects glioblastoma outcomes after collaborators on the current project discovered differences between men and women with glioblastoma tumors in the activity of an iron-related transport protein.

“Cells cannot thrive if they lack adequate iron. It is a necessary component of many cellular processes,” said Dr. Connor, a Penn State Cancer Institute researcher. “We have the unique expertise in our lab to further explore how iron metabolism may play a role in the survival differences between male and female glioblastoma patients.”

Darya Nesterova, a medical and graduate student, is a driving force in the College of Medicine’s involvement in the project. She is the lead author of a study demonstrating that differences in the expression of the homeostatic iron regulatory (HFE) gene can affect survival outcomes in male and female patients with glioblastoma.1 The researchers evaluated genetic data and clinical outcomes of more than 450 patients and found that in tumors with low HFE expression, women had a 10-month survival advantage. However, in tumors with high HFE expression, there were poor survival outcomes regardless of the patient’s sex.

Dr. Connor said these results scratch the surface of how iron metabolism in glioblastomas may affect survival. Researchers will further explore how iron affects the complex interactions between genetics and hormonal factors in a tumor or its microenvironment and how that may affect survival outcomes in male and female patients with glioblastoma. 


1. Nesterova DS, Midya V, Zacharia BE, et al: Sexually dimorphic impact of the iron-regulating gene, HFE, on survival in glioblastoma. Neuro-oncol Adv 2: 1-11, 2020.