# Translational Investigation of XPO1 Inhibition in High-Grade Glioma and Diffuse Intrinsic Pontine Glioma

> **NIH NIH K08** · UNIVERSITY OF COLORADO DENVER · 2020 · $191,160

## Abstract

Abstract
Pediatric high-grade glioma (HGG), including diffuse intrinsic pontine glioma (DIPG), represent the
most common cause of cancer death in children. Aside from radiation therapy (RT), few effective
treatment options exist. This is especially true for DIPG, in which hundreds of chemotherapy clinical
trials have failed to improve outcomes. One potential issue is that systemically-delivered medications
cannot penetrate DIPG. Both HGG and DIPG overexpress Exportin 1 (XPO1), which controls the
nuclear export of tumor suppressor proteins. Selinexor is a selective XPO1 inhibitor that has shown a
strong antitumor effect in patient-derived DIPG cell lines and patient-derived HGG cell lines and murine
xenograft (PDX) models. It has a good safety profile in adults and is currently the subject of a phase 1
trial in children, with a focus on recurrent non-DIPG HGG. In vitro results show that the mechanism of
action of XPO1 inhibition in HGG appears to depend on NGFR induction, resulting in NF-κB
suppression. Selinexor appears to synergize with proteasome inhibitors against HGG/DIPG. It also
represents a candidate drug to study the pharmacokinetics (PK) of systemic chemotherapy in DIPG for
the first time. The hypothesis of this project is that XPO1 inhibition will synergize with proteasome
inhibition and radiation therapy (RT) to suppress NF-κB, leading to apoptosis, but selinexor cannot
adequately penetrate DIPG to achieve therapeutic effect through systemic delivery. In this project,
HGG/DIPG laboratory models will be used in combination with samples from ongoing clinical trials to
achieve maximum impact. First, selinexor's interaction with NGFR and NF-κB will be elucidated using
PDX models validated in pediatric HGG clinical trial tissue. Next, the therapeutic relationship of XPO1
inhibition with proteasome inhibitors and RT will be measured using cell culture and PDX models, with
a focus on the effect on NF-κB. Finally, the pharmacodynamic (PD) effects and PK of selinexor will be
compared between DIPG and HGG clinical trial tumor specimens, and DIPG/HGG PDX tumors. This
translational laboratory work during clinical investigation will help optimize the use of XPO1 inhibition as
a strategy to improve treatment for pediatric HGG and DIPG patients. The educational aims of this
project tie directly to the research aims. They include improved understanding of basic science in
molecular biology techniques, hypothesis investigation, and data analysis. All of these will be key to the
pathway investigation and complex comparison of cancer model and human tumor data central to this
project. Completion of this project will produce strong career development, leading to an independent
career using translational research to improve patient outcomes in pediatric HGG and DIPG.

## Key facts

- **NIH application ID:** 10003419
- **Project number:** 5K08NS102532-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Adam Lyon Green
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $191,160
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003419

## Citation

> US National Institutes of Health, RePORTER application 10003419, Translational Investigation of XPO1 Inhibition in High-Grade Glioma and Diffuse Intrinsic Pontine Glioma (5K08NS102532-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10003419. Licensed CC0.

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