- Posted Thursday September 17, 2020
NCI funds research into why glioblastoma hits males harder than females
TGen technology is key to brain cancer research consortium led by Cleveland Clinic and Case Western Reserve University
PHOENIX, Ariz. — Sept. 17, 2020 — The Translational Genomics Research Institute (TGen), an affiliate of City of Hope, will employ two relatively new technologies in a study led by Cleveland Clinic Lerner Research Institute and Case Western Reserve University School of Medicine into why men are stricken with glioblastoma brain cancer far more often than women, and why women survive the disease almost twice as long as men.
As part of a five-year $10.4 million grant announced today from the National Cancer Institute (NCI), researchers will delve into the molecular-level biology of glioblastoma — the most common and deadliest adult brain tumor — seeking new therapies against the disease.
“We’ve known for some time that glioblastoma multiforme (GBM) affects men more than women,” said Dr. Michael Berens, a TGen Deputy Director and Head of the institute’s Glioma Research Lab. “It’s been in front of us all along. We just haven’t taken a deep enough dive to appreciate in what ways they are different, and — more significantly from a precision-medicine perspective — how the sex of the patient might inform tailored treatment strategies.”
Dr. Berens will study the tumor microenvironment, and the effect of immune cells on the tumor. A major goal of the study is to find out how to make the normal host cells in the brain more resilient against the tumor; specifically how women respond to the disease, and how to apply those findings to provide better treatment outcomes for men.
First, TGen will employ “single-cell transcriptomics,” which will enable researchers to genetically identify every type of cell that occurs in the tumor, and identify all of the various normal brain cells that surround the tumor.
Then, for the first time in GBM, TGen will use a new technology called “spatial transcriptomics,” which will show the locations of the various cells and how they interact with each other.
“We will be able to see who is there, who is misbehaving, who is next to who and, hopefully, who is influencing who,” Dr. Berens said of the various cellular interactions his team will investigate.
Two specific questions Dr. Berens wants to answer are: Why brain tumor cells connect with neurons, the functioning cells of the brain that determine memory and action; and why brain tumor cells appear to recruit special blood cells from bone marrow known as Myeloid Derived Suppressor Cells (MDSCs), which suppress the body’s immune system.
Previous research, including pioneering work at TGen, has shown that glioblastoma occurs at a rate 60 percent higher in males than in females. And, females have a significant survival advantage over males with a median improved survival of up to 10 months. However, while these sex differences are known, they are poorly understood and are not yet considered when treating glioblastoma.
Glioblastomas are aggressive and rare: fewer than 4 per 100,000 in the U.S. from 2012-16, according to the most recent data available from the Central Brain Tumor Registry of the United States (CBTRUS). The median survival time is 12 to 14 months, and only about 5% of patients survive more than five years.
Leaders of the study
The research team is led by co-principal investigators Justin Lathia, Ph.D., of Cleveland Clinic’s Lerner Research Institute, and Jill Barnholtz-Sloan, Ph.D., of Case Western Reserve University School of Medicine.
“We have the molecular profiling technology and the computing and analytical strength to lead in this effort to better understand the role of sex differences in cancer, particularly for glioblastoma,” said Dr. Barnholtz-Sloan, the Sally S. Morley Designated Professor in Brain Tumor Research and associate director of Data Sciences at the Case Comprehensive Cancer Center, Case Western Reserve School of Medicine.
“This next phase of research relies on vast, varied, and complex datasets — in animals and humans — and promises to be a game-changer in how we understand the role of sex in tumor formation and disease outcomes. This comprehensive approach has applications to all forms of cancer, as well as other diseases,” Dr. Barnholtz-Sloan said.
Dr. Lathia is the vice chair of the Department of Cardiovascular and Metabolic Sciences and co-director of the Brain Tumor Research & Therapeutic Development Center of Excellence at Lerner Research Institute, and co-leader of the Molecular Oncology Program at the Case Comprehensive Cancer Center.
“Sex differences are inherent drivers of glioblastoma incidence and survival and we are taking a multidimensional approach to uncover a better understanding of this differentiation,” Dr. Lathia said. “We are incorporating data from tumor cells and their surrounding micro-environment, as well as genetic programs responsible for tumor growth, and underlying epigenetic differences that may be responsible for sex differences. We aim to gain a better understanding of how these variables interrelate to better understand disease mechanism, which in turn defines better diagnostics and more personalized therapies for patients.”
The multi-disciplinary project involves established investigators with complementary expertise and a strong collaborative history. Along with Dr. Lathia and Dr. Barnholtz-Sloan, participating principal investigators include: Dr. Berens of TGen; Joshua Rubin, M.D., Ph.D. of Washington University School of Medicine in St. Louis; and James Connor, Ph.D., of Penn State College of Medicine.
The study’s three related research projects will delve into the basic biology and cellular mechanisms that drive sex differences in glioblastoma formation and progression. These related research projects will inform, synergize and depend on each other. Findings from the labs based on their animal models will then be queried against data from human clinical samples across multiple institutions. The vast amount of data generated from these studies requires robust data management and sophisticated data analysis for a comprehensive view of sex differences across these diverse but related inquiries.
Comprehensive findings will inform future clinical research design, the search for targets for new therapeutics, or the use of existing therapeutics that may be applied differently depending on a patient’s sex.
This NCI grant — Sex-based Differences in Glioma — was awarded under number 1P01CA245705.
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About TGen, an affiliate of City of Hope
Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based nonprofit organization dedicated to conducting groundbreaking research with life-changing results. TGen is affiliated with City of Hope, a world-renowned independent research and treatment center for cancer, diabetes and other life-threatening diseases: CityofHope.org. This precision medicine affiliation enables both institutes to complement each other in research and patient care, with City of Hope providing a significant clinical setting to advance scientific discoveries made by TGen. TGen is focused on helping patients with neurological disorders, cancer, diabetes and infectious diseases through cutting-edge translational research (the process of rapidly moving research toward patient benefit). TGen physicians and scientists work to unravel the genetic components of both common and complex rare diseases in adults and children. Working with collaborators in the scientific and medical communities worldwide, TGen makes a substantial contribution to help our patients through efficiency and effectiveness of the translational process. For more information, visit: tgen.org. Follow TGen on Facebook, LinkedIn and Twitter @TGen.
About Cleveland Clinic
Cleveland Clinic is a nonprofit multispecialty academic medical center that integrates clinical and hospital care with research and education. Located in Cleveland, Ohio, it was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based upon the principles of cooperation, compassion and innovation. Cleveland Clinic has pioneered many medical breakthroughs, including coronary artery bypass surgery and the first face transplant in the United States. U.S. News & World Report consistently names Cleveland Clinic as one of the nation’s best hospitals in its annual “America’s Best Hospitals” survey. Among Cleveland Clinic’s 67,554 employees worldwide are more than 4,520 salaried physicians and researchers, and 17,000 registered nurses and advanced practice providers, representing 140 medical specialties and subspecialties. Cleveland Clinic is a 6,026-bed health system that includes a 165-acre main campus near downtown Cleveland, 18 hospitals, more than 220 outpatient facilities, and locations in southeast Florida; Las Vegas, Nevada; Toronto, Canada; Abu Dhabi, UAE; and London, England. In 2019, there were 9.8 million total outpatient visits, 309,000 hospital admissions and observations, and 255,000 surgical cases throughout Cleveland Clinic’s health system. Patients came for treatment from every state and 185 countries. Visit us at clevelandclinic.org. Follow us at twitter.com/CCforMedia and twitter.com/ClevelandClinic. News and resources available at newsroom.clevelandclinic.org.
About Case Western Reserve University
Case Western Reserve University is one of the country's leading private research institutions. Located in Cleveland, we offer a unique combination of forward-thinking educational opportunities in an inspiring cultural setting. Our leading-edge faculty engage in teaching and research in a collaborative, hands-on environment. Our nationally recognized programs include arts and sciences, dental medicine, engineering, law, management, medicine, nursing and social work. About 5,100 undergraduate and 6,700 graduate students comprise our student body. Visit case.edu to see how Case Western Reserve thinks beyond the possible.
TGen Senior Science Writer
Case Western Reserve