# Targeting physical stress-driven mechanisms to overcome glioblastoma treatment resistance

> **NIH NIH U01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $592,593

## Abstract

PROJECT ABSTRACT
Patients with glioblastoma multiforme (GBM) have poor prognosis and limited treatment options. Immune
checkpoint therapies, which have shown dramatic benefits in other cancers, have failed to improve outcomes in
GBM patients in all randomized phase III trials. Brain tumors generate mechanical forces as they grow in the
confined space of the cranium, and we have shown that these physical forces affect cell viability and phenotype
(Nature Biotechnology 1997, PNAS 2012, Nature Biomedical Engineering 2016, 2019, Science 2020). Our
preliminary results indicate that compressive forces similar to those in brain tumors are sufficient to upregulate
stress granule protein G3BP2 as well as genes associated with epithelial-mesenchymal transition (EMT),
stemness and the immune checkpoints. Furthermore, we have shown G3BP2 regulates cancer cell stemness
in breast cancer (PNAS 2017). Thus, we hypothesize that mechanical stresses in the GBM environment
contribute to GBM stemness and immunosuppression, and that the pathways involved can be targeted to
enhance tumor killing. In this project, we will dissect the stress-induced pathways involved in mechanical
regulation of stemness and immunosuppression in GBM. We will then block these pathways in orthotopic,
immunocompetent mouse models of GBM to enhance immunotherapy. The overall goal of the study is to identify
new strategies and targets for amplifying anti-tumor immunity based on mechanobiological control mechanisms.

## Key facts

- **NIH application ID:** 10909052
- **Project number:** 5U01CA261842-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Rakesh K. Jain
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $592,593
- **Award type:** 5
- **Project period:** 2021-09-22 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909052

## Citation

> US National Institutes of Health, RePORTER application 10909052, Targeting physical stress-driven mechanisms to overcome glioblastoma treatment resistance (5U01CA261842-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10909052. Licensed CC0.

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