# Mechanism and therapeutic potential of macrophage regulation in glioblastoma

> **NIH NIH K99** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $108,081

## Abstract

Project Summary/Abstract
Glioblastoma (GBM) is the most lethal form of brain cancer in adults, with a median survival of one year following
diagnosis. Unfortunately, both conventional and targeted therapies have failed to improve GBM patient survival
over the last 40 years. Immune cells in the tumor microenvironment (TME) are genetically stable, and have
emerged as promising therapeutic targets. Tumor-associated macrophages/microglia (TAMs) are the most
abundant immune cells infiltrating the GBM TME (which can account for up to 50% of total live cells), where they
exhibit an important role in promoting tumor progression and inducing immunotherapy resistance. However, the
promise of TAM-targeted therapy or immunotherapy in general has not yet been realized in GBM, due in part to
a limited understanding of the molecular mechanisms underlying TAM behavior and function in GBM.
My postdoctoral work in the DePinho lab revealed novel mechanisms governing the recruitment of macrophages
and microglia into the GBM TME. Notably, I determined that targeting macrophage/microglia infiltration via
inhibition of lysyl oxidase (LOX) or circadian regulator CLOCK represents a promising therapeutic approach for
GBM (Chen et al., Cancer Cell 2019; Chen at al., Cancer Discovery, under revision). Upon recruitment,
macrophages/microglia exhibit a spectrum of phenotypes, including the immunostimulatory M1 phenotype and
immunosuppressive M2 phenotype. It is well known that TAMs in GBM are usually polarized toward an M2
phenotype, and reprogramming TAMs from M2 to M1 phenotype could be a promising therapeutic strategy for
GBM. My preliminary studies show that TANK binding kinase 1 (TBK1) is uniformly expressed by TAMs in GBM
and that this druggable kinase can control macrophage polarization switch between M1 and M2 phenotypes.
Both genetic and pharmacological inhibition of macrophage TBK1 impaired M2 polarization and inhibited GBM
progression in multiple GBM mouse models (Chen et al., manuscript in preparation). In the K99 phase, this
proposal will further investigate how macrophage TBK1 is regulated/activated in GBM and how TBK1 controls
macrophage M2 polarization. Since TAMs are immune suppressive cells, in the R00 phase this proposal will
investigate whether inhibition of TAM infiltration (LOX or CLOCK inhibition) and/or M2 polarization (inhibition of
TBK1 and its related signaling pathways) can alter anti-tumor responsiveness to immune checkpoint blockade
(ICB), i.e., I will test potential combination therapeutic strategies targeting TAMs and immune checkpoints in
GBM. Finally, the proposed studies will identify the key factors from TBK1-regulated TAMs which might contribute
GBM progression. I propose to employ an integrated strategy combining gain- and loss-of-function approaches,
in vitro and in vivo systems, as well as proteomic and transcriptomic analysis to identify and characterize these
factors. Together, this project will uncover novel mechanisms of GBM progres...

## Key facts

- **NIH application ID:** 9976205
- **Project number:** 1K99CA240896-01A1
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Peiwen Chen
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $108,081
- **Award type:** 1
- **Project period:** 2020-04-08 → 2020-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976205

## Citation

> US National Institutes of Health, RePORTER application 9976205, Mechanism and therapeutic potential of macrophage regulation in glioblastoma (1K99CA240896-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9976205. Licensed CC0.

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