# Signature-guided treatment of GBM with neddylation inhibitor pevonedistat

> **NIH NIH U19** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2021 · $234,722

## Abstract

PROJECT SUMMARY – PROJECT 3
The ubiquitin/proteasome system maintains intracellular homeostasis via degradation of unwanted proteins.
Neddylation is a specific pathway within the ubiquitin/proteasome system that is overactive in glioblastoma
(GBM), and whose upregulation has been associated with glioma progression and worse survival. Pevonedistat
is a first-in-class small-molecule neddylation inhibitor shown to impact protein degradation and inhibit growth of
GBM cells in culture and orthotopic xenografts. Pevonedistat is in clinical trials and available through NCI’s
Cancer Therapy Evaluation Program (CTEP). Because the molecular heterogeneity within and across GBM
patients obscures therapeutic targets and obfuscates signals of efficacy in clinical trials, we propose the use of
molecular “signatures of vulnerability” to targeted agents in subsets of models, and to use these signatures to
guide patient enrollment in early-stage clinical trials. Our preliminary data revealed molecular determinants of
synergy against PTEN-deleted (PTENdel) and PTEN-mutated (PTENmt) GBM from combining pevonedistat with
a TOP2A inhibitor, etoposide. We hypothesize that a specific “synergy signature” can be used to identify patients
likely to respond to pevonedistat + etoposide and propose a signature-guided clinical trial to achieve synergy in
patients with recurrent GBM (rGBM). We propose the following Aims: Aim 1. Discover and validate the
mechanism underlying the antitumor synergy of pevonedistat + TOP2Ais in GBM. We will use GBM
patient-derived xenograft (PDX) explant cultures and orthotopic tumors to pursue this aim and will validate the
predictive performance of the “synergy signature” in patient tumor samples from the proposed clinical trial in
Aim 3. Aim 2. Validate a “signature of vulnerability” to pevonedistat alone in GBM. We will use GBM PDX
cultures and orthotopic models to refine and test the predictive accuracy of a “signature of vulnerability” to
pevonedistat for future clinical trials. Aim 3. Determine the safety of pevonedistat + etoposide in “synergy
signature” rGBM patients in a phase I clinical trial. We will enroll patients with “synergy signature” GBM to a
phase I study of pevonedistat + etoposide to determine the maximum tolerated dose/recommended phase II
dose of the combination therapy; obtain preliminary response data; define the neuropharmacokinetic (nPK) of
pevonedistat using intracerebral microdialysis; and evaluate the neuropharmacodynamics (nPD) of
pevonedistat using a window of opportunity design in subsets of study participants. This project relies on support
from Core A for nPK analysis, Core B for exome and RNA Seq and bioinformatics, and the Admin Core for
coordination and integration with Projects 1 and 2 for data sharing and comparison of signatures of vulnerability
to OV-αCD47-G1 and tasquinimod. If successful, our project will advance drug development in the setting of a
heretofore recalcitrant tumor by linking molecular subse...

## Key facts

- **NIH application ID:** 10306306
- **Project number:** 1U19CA264512-01
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** MICHAEL E. BERENS
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $234,722
- **Award type:** 1
- **Project period:** 2021-09-13 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10306306

## Citation

> US National Institutes of Health, RePORTER application 10306306, Signature-guided treatment of GBM with neddylation inhibitor pevonedistat (1U19CA264512-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10306306. Licensed CC0.

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