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Neuro Update

Researchers join $10 million project to understand sex differences in brain cancer outcomes

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

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

James Connor, distinguished professor of neurosurgery, neural and behavioral sciences and pediatrics, is leading Penn State’s involvement in the project, sponsored by the National Cancer Institute. Justin Lathia of Cleveland Clinic’s Lerner Research Institute and Jill Barnholtz-Sloan of Case Western Reserve University School of Medicine are the principal investigators of the multi-institution research team, which includes researchers from Washington University School of Medicine and the Translational Genomics Research Institute. The group is investigating the genetic and metabolic differences in cellular processes associated with different glioblastoma outcomes in males and females.

For most of his career, Connor has studied how iron metabolism in brain cells affects neurological disease. He began investigating how iron regulation affects glioblastoma outcomes after collaborators on the current project discovered that there were differences in the activity of an iron-related transport protein in male and female glioblastoma tumors.

“Cells cannot thrive if they lack adequate iron. It is a necessary component of many cellular processes,” said 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.”

James Connor, distinguished professor of neurosurgery and anatomy and vice chair for research, Department of Neurosurgery, stands in his lab and looks over the shoulder of graduate assistant Ganesh Shenoy. Both are wearing face masks and white lab coats. Shenoy is holding a yellow device and wearing purple gloves.

James Connor, left, works with graduate assistant Ganesh Shenoy in his lab. Connor is leading Penn State College of Medicine’s $10 million project to understand sex differences in brain cancer outcomes.

Darya Nesterova, a medical and graduate student, is a driving force in the College of Medicine’s involvement in the project. Together with Vishal Midya, Connor, Lathia, Barnholtz-Sloan and other authors, she published a study demonstrating that differences in the expression of the homeostatic iron regulatory (HFE) gene can affect survival outcomes in male and female glioblastoma patients. They evaluated genetic data and clinical outcomes of more than 450 patients and found that in tumors with low HFE expression, females had a 10-month survival advantage. However, in tumors with high HFE expression, there were poor survival outcomes regardless of a patient’s sex.

Connor said that 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 glioblastoma patients.

“The goal of the project is to better understand the biological and cellular functions that drive sex differences in glioblastoma formation and progression,” said Dr. Robert Harbaugh, distinguished professor and chair of the Department of Neurosurgery at Penn State Health Milton S. Hershey Medical Center.

“To achieve this, the Connor lab will rely on clinical data collected by neurosurgeons Dr. Brad Zacharia and Dr. Alireza Mansouri and neuro-oncologists Dr. Michael Glantz and Dr. Dawit Aregawi. This project is a prime example of how our scientists, clinicians and patients are working together to someday find a cure for this deadly cancer.”

Todd Schell of Penn State College of Medicine, Dr. Joshua Rubin of Washington University School of Medicine and Michael Berens of the Translational Genomics Research Institute will also contribute to this research.

This project is supported by funds from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The researchers declare no conflict of interest.

A head-and-shoulders photo of Robert E. Harbaugh, MD, FACS, FAHA

Robert E. Harbaugh, MD, FACS, FAHA

Director, Penn State Neuroscience Institute
Professor, Engineering Science and Mechanics
University Distinguished Professor and Chair, Department of Neurosurgery, Penn State Health Milton S. Hershey Medical Center
Phone: 717-531-3828
Email: rharbaugh@pennstatehealth.psu.edu
Residency: Neurological Surgery, Dartmouth Hitchcock Medical Center, Lebanon, N.H.
Medical School: Penn State College of Medicine, Hershey
Internship: Surgery, General, Dartmouth Hitchcock Medical Center, Lebanon, N.H.
Connect with Robert E. Harbaugh, MD, FACS, FAHA, on Doximity

A head-and-shoulders photo of Brad E. Zacharia, MD, MS

Brad E. Zacharia, MD, MS

Associate Professor of Neurosurgery and Otolaryngology
Co-director, Neuro-Oncology Program
Director, Brain Tumor and Skull Base Surgery, Penn State Health Milton S. Hershey Medical Center
Phone: 717-531-4177
Email: bzacharia@pennstatehealth.psu.edu
Fellowship: Neurosurgical Oncology, Memorial Sloan Kettering Cancer Center, New York
Residency: Neurological Surgery, New York Presbyterian Hospital – Columbia University, New York
Medical School: Columbia University College of Physicians and Surgeons, New York
Connect with Brad E. Zacharia, MD, MS, on Doximity

A head-and-shoulders photo of Seyed A. Mansouri, MD

Seyed A. Mansouri, MD

Assistant Professor, Department of Neurosurgery, Penn State Health Holy Spirit Medical Center
Phone: 717-531-6585
Email: amansouri@pennstatehealth.psu.edu
Fellowship: Neuro-Oncology, UHN-Toronto Western Hospital/University of Toronto, Toronto; Neuro-Oncology, National Institutes of Health, Bethesda, Md.
Residency: Neurosurgery University of Toronto, Toronto
Medical School: University of Toronto Faculty of Medicine, Toronto
Connect with Seyed A. Mansouri, MD, on Doximity

A head-and-shoulders photo of Dawit G. Aregawi, MD

Dawit G. Aregawi, MD

Assistant Professor of Neurosurgery, Penn State Health Milton S. Hershey Medical Center
Phone: 717-531-3828
Email: daregawi@pennstatehealth.psu.edu
Fellowship: Hematology/Oncology, University of Michigan Medical School, Ann Arbor, Mich.; Neuro-Oncology, University of Virginia Medical Center, Charlottesville, Va.; Neuro-Oncology, National Institutes of Health, Bethesda, Md.
Residency: Internal Medicine, Jewish Hospital of Cincinnati, Cincinnati
Medical School: Jimma Institute of Health Sciences, Ethiopia
Connect with Dawit G. Aregawi, MD, on Doximity

The Penn State logo, a Nittany Lion inside a blue shield.

Michael Glantz, MD, PhD

Neuro-oncologist, Penn State Health Milton S. Hershey Medical Center
Professor, neurosurgery, Penn State College of Medicine
Phone: 717-531-3828
Email: mglantz@pennstatehealth.psu.edu
Fellowship: Neuro-Oncology, Duke University Hospital, Durham, N.C.
Residency: Neurology, SUNY Health Science Center – Stony Brook, Stony Brook, N.Y.
Medical School: Brown University School of Medicine, Providence, R.I.
Internship, Internal Medicine: SUNY Health Science Center – Stony Brook, Stony Brook, N.Y.
Connect with Michael Glantz, MD, PhD, on Doximity

A head-and-shoulders photo of James Connor, MS, PhD

James Connor, MS, PhD

Distinguished Professor and Vice Chair for Research, Department of Neurosurgery
Professor, Department of Neural and Behavioral Sciences
Professor, Department of Pediatrics
Phone: 717-531-4541
Email: jrc3@psu.edu
Connect with Department of Neurology on Doximity

Penn State Neuroscience Institute fosters collaboration among the neuroscience-related departments and divisions within Penn State Health Milton S. Hershey Medical Center and Penn State College of Medicine.

Our mission is to:

Assure excellence in basic and clinical research studies that increase our understanding of the normal and diseased brain.

Promote the translation of research findings into new treatments for neurological disease.

Improve the care of patients with neurological and neurobehavioral diseases.

Provide a rich intellectual environment that enhances the educational experience in all neuroscience disciplines.

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