# Project 2: Restore Myeloid Phagocytosis in Glioblastoma by Targeting the QKI/PPARb/RXRa Complex

> **NIH NIH P50** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $339,950

## Abstract

SUMMARY: PROJECT 2
 Immunotherapies, including immune checkpoint blockades, have not benefited patients with glioblastoma
(GBM), largely due to abundant immune-suppressive GBM-associated microglia/macrophages (GAMs), which
can comprise up to ~30% of the tumor mass. A major gap in our current knowledge is how to reverse
therapeutically the immunosuppressive features of GAMs. Although heterogeneous, GAMs almost ubiquitously
exhibit pro-tumorigenic states with defective phagocytosis. We reasoned that restoration of phagocytosis in
GAMs would promote anti-tumor activity by enhancing their ability to digest and process glioma cells and present
tumor specific antigens to activate the adaptive immune system. By analyzing human and mouse GBM samples
by single cell RNA sequencing, we found that suppression of Quaking (QKI) is a universal feature in human and
mouse GAMs and contributes to the impairment of the phagocytic activity of GAMs. QKI forms a complex with
peroxisome proliferator-activated receptor β (PPARβ) and retinoid X receptor α (RXRα), called QPR, which
regulates unsaturated fatty acids (UFAs) synthesis, influencing membrane fluidity and driving phagocytosis.
Conditional knockout of Qki or PPARβ in GAMs greatly impairs the phagocytosis of GAMs and enhances
gliomagenesis by decreasing immune cell infiltration. Conversely, activating QPR through small molecule
agonists of PPARβ (KD3010) or RXRα (bexarotene) greatly enhances the phagocytic ability of GAMs and
suppresses GBM growth in syngeneic glioma mouse models, demonstrating the therapeutic potential of these
agents. Based on the above evidence, we hypothesize that activating QPR with small molecular agonists will
restore GAM phagocytosis, normalize the defective immune microenvironment of GBM and consequently halt
GBM progression. To test this hypothesis, we will: Decipher the molecular mechanisms underlying the effect of
QPR activators on phagocytic activity in GAMs in vitro (Aim 1); Investigate the molecular and cellular effects of
KD3010/bexarotene on GAMs in pre-clinical in vivo animal models (Aim 2); And perform a window-of-opportunity
clinical trial to evaluate the therapeutic potential of bexarotene in patients with recurrent GBM (Aim 3). In all,
these studies will define QPR agonists as a new class of immunotherapeutics that can provide new hope for
curing GBM by overcoming the immunosuppressive tumor microenvironment that drives this dreaded disease.
.

## Key facts

- **NIH application ID:** 10847568
- **Project number:** 2P50CA127001-16
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Jian Hu
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $339,950
- **Award type:** 2
- **Project period:** 2008-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10847568

## Citation

> US National Institutes of Health, RePORTER application 10847568, Project 2: Restore Myeloid Phagocytosis in Glioblastoma by Targeting the QKI/PPARb/RXRa Complex (2P50CA127001-16). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10847568. Licensed CC0.

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