# Radiation-induced senescence in the brain microenvironment: Implications for glioblastoma recurrence and therapy

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2022 · $349,406

## Abstract

Abstract
Glioblastomas (GBM) are aggressive and radioresistant brain cancers for which better therapeutic approaches
are desperately needed. GBM patients are treated with 50-60 Gy of ionizing radiation (IR), and concurrent and
adjuvant chemotherapy with temozolomide (TMZ). Radiation still remains the most effective therapeutic
modality for GBM, yet these tumors inevitably recur, and the recurrent tumors are highly resistant to standard
therapy. Any improvement in therapy would require a better understanding of the basis of GBM recurrence and
therapy resistance of the recurrent tumor. Published research from our lab with transgenic mouse models has
established that IR is potently gliomagenic, and that gliomas arising after radiation exposure are marked by
genomic alterations such as MET amplification which promote a cancer stem cell phenotype and
radioresistance. This raises the possibility that genetic alterations in GBM cells wrought by radiation therapy
could render the recurrent tumor refractory to further therapeutic intervention. Exciting new results from our lab
show that radiation also promotes the development of a senescence-associated secretory phenotype (SASP)
in the brain microenvironment which promotes tumor development via secretion of growth factors like HGF
(ligand for MET). This suggests that radiation-induced senescence of normal brain cells in the vicinity of the
tumor could alter the microenvironment to promote tumor recurrence and radioresistance. Translationally
significant results from our lab show that novel “senolytic” drugs can selectively eliminate senescent astrocytes
in the brain and mitigate the pro-tumorigenic effects of SASP. We hypothesize that radiotherapy-induced
genetic alterations in GBM cells (e.g., MET amplification) cooperate with senescence-associated
changes in the brain microenvironment (e.g., HGF secretion) to promote tumor recurrence and
radioresistance. We propose to analyze if “senolytics” can selectively kill senescent brain cells arising
due to radiotherapy, thereby radiosensitizing GBM and delaying tumor recurrence. There is an urgent
need for experimental strategies to understand such “acquired” therapy-resistance mechanisms in GBM and
develop translational approaches. We have developed novel patient-derived xenograft (PDX) and syngeneic
models of GBM recurrence for this purpose. Using these models, and human GBM specimens, we will
investigate (1) how MET amplification caused by radiotherapy might, via reprogramming transcription factors
like SOX2 and OLIG2, generate cancer stem cells with augmented DNA repair capabilities, (2) how secretion
of tumor promoting factors, like the MET ligand HGF, by senescent astrocytes might promote growth and
radioresistance of GBM cells with MET amplification, and (3) how cooperation between the GBM and its
senescent microenvironment can be negated with “senolytic” drugs in order to improve the outcome of GBM
therapy. This project can lead to the development of ef...

## Key facts

- **NIH application ID:** 10394384
- **Project number:** 5R01CA246807-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Sandeep Burma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $349,406
- **Award type:** 5
- **Project period:** 2021-04-16 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10394384

## Citation

> US National Institutes of Health, RePORTER application 10394384, Radiation-induced senescence in the brain microenvironment: Implications for glioblastoma recurrence and therapy (5R01CA246807-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10394384. Licensed CC0.

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