# Sex-specific differences in the tumor microenvironment alter glioblastoma growth

> **NIH NIH P01** · CLEVELAND CLINIC LERNER COM-CWRU · 2024 · $200,445

## Abstract

ABSTRACT 
Sex differences are present in many pathological conditions, including a number of non-reproductive cancers. 
These differences have been observed from an epidemiolocal perspective, and mechanistic studies have 
revealed broad-ranging differences between sexes at the genetic, epigenetic, and cellular levels. In glioblastoma, 
the most common primary malignant brain tumor, males present with disease nearly twice as often as females 
and experience a poorer prognosis given the same standard-of-care treatments. As part of a current Program 
Project Grant (P01 CA245705), we are focused on the cell-intrinsic and cell-extrinsic influences of sex 
differences, as well as their interplay, in glioblastoma. These efforts have focused on multiple mechanisms, 
including sex differences in the immune response, and found differences in the resident (microglial) and 
infiltrating (namely myeloid-derived suppressor cell) immune populations. While these initial observations were 
made using transplantable mouse glioblastoma models generated from genetically engineered or carcinogen- 
induced mouse models and validated in human samples, these models are not strongly representative of the 
human disease, as they lack key drivers, including mutation in the epidermal growth factor receptor (EGFR, 
namely EGFRvIII). Using in vivo electroporation approaches supported by the NCI IMAT program, more 
representative GBM models have been generated using Mosaic Analysis with Dual Recombinase (MADR) and 
Genome Editing of Synthetic Target Arrays for Lineage Tracing (GESTALT) technologies that leverage 
concomitant expression of key oncogenes such as EGFRvIII and deletion of key tumor suppressors such as 
NF1 and p53. The overall objective of this revision application is to enhance our program through the use of 
these more representative glioblastoma models to determine sex-specific immune response effects. In Aim 1, 
we will determine how the glioblastoma immune microenvironment is arranged as a function of the biological sex 
of the tumor. In parallel with these benchmarking studies, Aim 2 will take an unbiased, hypothesis-generating 
approach to determine how the neural cell composition of the tumor microenvironment is generated as a function 
of the biological sex of the developing glioblastoma. The MADR-GESTALT will be applied to wild-type mice, as 
well as Project 3-specific mouse models (junctional adhesion molecule-A) and the four-core genotype model that 
separates chromosomal and gonadal sex. The short-term goal of this application is to enhance Project 3 of our 
Program Project Grant and provide this new model for all projects through Core C, which houses experimental 
models. The long-term goal of this project is to leverage these more representative glioblastoma models for 
future functional and mechanistic studies on sex differences in glioblastoma.

## Key facts

- **NIH application ID:** 10916681
- **Project number:** 3P01CA245705-05S1
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Daniel J Silver
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $200,445
- **Award type:** 3
- **Project period:** 2020-09-14 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10916681

## Citation

> US National Institutes of Health, RePORTER application 10916681, Sex-specific differences in the tumor microenvironment alter glioblastoma growth (3P01CA245705-05S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10916681. Licensed CC0.

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