Sex-based Differences in Glioma

PROJECT SUMMARY Glioblastoma (GBM), the most common primary malignant brain tumor, remains uniformly lethal despite aggressive therapies. Epidemiological data demonstrate an increased incidence of cancer in males across many tumors including GBM, genomic analyses have identified sex-specific molecular alterations, and recent reports demonstrate that women with GBM experience longer survival. Due in part to a lack mechanistic understanding behind these outcomes, differences between sexes are not accounted for in the majority of experimental studies, are not considered in the treatment of GBM, and are not accommodated in clinical trial design. To fill this knowledge gap, we propose this Program Project Grant (P01) with the long- term goal of delineating actionable sex-based differences in GBM. This P01 integrates analyses at the molecular and cellular levels to identify and exploit sex-specific molecular mechanisms that underlie the increased incidence of GBM for males and better prognosis for females. This multi-disciplinary project involves established investigators with complementary expertise and a strong collaborative history. Our published observations of differences between males and females in incidence and outcome, genetic risk, and oncogenic pathways have now coalesced to build this P01 and uniquely position us to reveal sex-specific mechanisms that inform GBM patient prognosis and serve as the foundation for sex-specific therapies. We will test the central hypothesis that the confluence of sex differences in tumor cells (intrinsic) and the microenvironment (extrinsic) emerging from oncogenic events (genetic) and normal sexual differentiation (epigenetic) underlies mechanistic differences in gliomagenesis and disease outcome. This hypothesis will be addressed via three synergistic projects and supported by three enabling cores. Project 1, led by Dr. Joshua Rubin, will interrogate distinct male and female epigenetic mechanisms that impact transformation and treatment response. Project 2, led by Dr. James Connor, will interrogate the mechanisms by which sex-specific microenvironmental interactions, including differences in iron metabolism (tumor and host), microglia, and macrophages, alter the dynamics of GBM growth. Project 3, led by Dr. Justin Lathia, will interrogate sex-specific mechanisms of microglia activation and their impact on GBM growth. These projects will be supported by three integrated cores offering: i) administrative, ii) biostatistical/bioinformatics assistance, and iii) state-of-the-art mouse and human GBM models led by Drs. Jill Barnholtz-Sloan, Michael Berens, and Justin Lathia. This P01 is part of our long-term goal to identify sex- specific mechanisms that drive GBM and can be leveraged for future therapies that move beyond using the same treatments for all GBM patients to tailoring treatments to the unique vulnerabilities of male versus female patients with GBM.