# Developing a NF-κB/GADD45b targeting strategy for glioblastoma

> **NIH NIH R21** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $176,447

## Abstract

PROJECT SUMMARY
Glioblastoma (GBM) is a devastating disease that kills about 18,000 Americans every year. GBM patients are
treated with temozolamide and ionizing radiation (IR), but the tumor invariably recurs. The molecular
mechanisms driving treatment resistance in GBM are unknown. Molecular targeted therapies including EGFR
and VEGF inhibitors, have failed to extend the dismal (15 month median) survival in GBM. Based on our previous
work, a direct oncogenic role of NF-B signaling and radio-resistance in some subtypes of GBM has been
uncovered. Recently, an independent study validated the efficacy of inhibiting NF-B signaling in GBM.
Therefore, we hypothesize that inhibition of NF-B signaling improves survival in GBM. Nonetheless, there is a
gap in knowledge regarding the efficacy of NF-B inhibitors and the mechanisms by which they inhibit growth of
the various molecular subtypes of GBM. The premise of the application is to test the mechanism of action,
efficacy, and the therapeutic benefit of a novel autocatalytic brain tumor-targeted (ABTT) nanoparticle delivery
of a NF-B pathway inhibitor, DTP3.
In Aim1 we will examine the apoptotic effects of a tripeptide, DTP3, in GBM preclinical models and investigate
its mechanism of action. Because DTP3 functions by inhibiting interaction of the NF-κB-regulated anti-apoptotic
factor GADD45β with MKK7, we will examine the activation of caspase 3 and the phosphorylation of JNK as a
read out of MKK7 activation. In Aim 2 we will test the therapeutic benefits of ABTT-DTP3 as a single agent as
well as a combination with fractionated radiation in molecular subtypes of GBM. Primary end-points will be overall
survival and bioluminescence-image-guided tumor volume measurement. Mechanism of action will be
determined by quantitative assessment of in vivo tumor proliferation, in vivo tumor invasion, histopathological
examination of fixed tissue, and examination of JNK phosphorylation. A critical strength of this proposal is that
we will utilize a nanoparticle mediated delivery of a peptide to specifically target anti-apoptotic functions of NF-
B in brain tumors. This first comprehensive characterization of cancer specific blockade of NF-B using clinical
relevant patient derived models of glioma will provide the foundation for clinical trials using NF-B blockade in
GBM.

## Key facts

- **NIH application ID:** 9901485
- **Project number:** 5R21CA222992-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Krishna PL Bhat
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $176,447
- **Award type:** 5
- **Project period:** 2019-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9901485

## Citation

> US National Institutes of Health, RePORTER application 9901485, Developing a NF-κB/GADD45b targeting strategy for glioblastoma (5R21CA222992-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9901485. Licensed CC0.

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