# Project 1:  Sex-specific developmental epigenetics in gliomagenesis

> **NIH NIH P01** · CLEVELAND CLINIC LERNER COM-CWRU · 2022 · $405,737

## Abstract

PROJECT SUMMARY 
Glioblastoma (GBM) is the most devastating form of brain cancer. In the next year, approximately 22,000 
Americans will develop GBM and nearly the same number will die from it. While GBM occurs in both males and 
females, we can reliably predict that of the 22,000 new cases, 8,500 will be in females while the remaining 13,500 
cases will be in males. Moreover, while the median survival for female GBM patients next year is expected to be 
approximately 22 months, for males it will be closer to 16 months. The molecular bases for these consistent and 
significant sex differences in incidence and survival are unexplained. In the absence of an explanation, it is 
impossible to fully know what the implications are for modeling GBM in the laboratory and for treating GBM in 
the clinic. Defining the genetic and epigenetic mechanisms that underlie sex differences in GBM 
incidence and survival is the focus of this project. We recently published an analysis of GBM patient imaging, 
transcriptomes, and survival in which we determined that female GBM patients exhibit greater response to the 
current standard treatments and that their survival is highly correlated with expression of components of the 
integrin signaling pathway. In contrast, male GBM patients exhibit less robust response to current treatment and 
their survival appears to be more potently determined by expression levels of the cell cycle regulatory machinery. 
These data not only provide new insights into sex differences in GBM biology, they suggest that sex-specific 
targeting of pathways that support survival in females and males could lead to improved outcomes for all patients. 
Sex differences in health and disease accrue throughout life as a consequence of sexual differentiation. Sexual 
differentiation, which begins at the time of fertilization, involves genetic and epigenetic mechanisms, as well as 
the acute actions of circulating sex hormones. We have developed murine models for studying sex differences 
in GBM. Here, we will use our innovative Cas-9 adaptation of the established four-core genotypes model for 
measuring the distinct contributions of sex chromosome complement and gonadal secretions to sex differences 
in GBM biology. Coupled with in utero electroporation of gRNAs and other genetic constructs, we will be uniquely 
positioned to assess how sex-specific changes in chromatin structure and expression of specific genes mediate 
the sex differences in GBM. We have two aims to address the hypothesis that sex differences in GBM incidence 
and outcome are determined at early stages of in utero sexual differentiation (Aim 1) and involve sex-specific 
patterning in gene expression and activity in integrin and cell cycle regulatory pathways (Aim 2). At all stages of 
this work we will incorporate specific questions about sexual differentiation and iron metabolism (Project 2) and 
microglia function (Project 3). Together these studies will provide critical informat...

## Key facts

- **NIH application ID:** 10463729
- **Project number:** 5P01CA245705-03
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Joshua B Rubin
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $405,737
- **Award type:** 5
- **Project period:** 2020-09-14 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463729

## Citation

> US National Institutes of Health, RePORTER application 10463729, Project 1:  Sex-specific developmental epigenetics in gliomagenesis (5P01CA245705-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10463729. Licensed CC0.

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