Summary: Research indicates that BACE1 inhibitors, a drug class developed for Alzheimer’s disease, may be repurposed to treat glioblastoma by reprogramming tumor-associated macrophages to attack tumor cells.
Source: Cleveland Clinic
New research from the Cleveland Clinic reveals that drugs initially developed to target Alzheimer’s disease could offer a promising new approach for glioblastoma, the most common and aggressive primary brain tumor.
The findings were published in Nature Cancer.
BACE1 inhibitors were originally designed to block the enzyme BACE1, which contributes to the production of β-amyloid plaques in Alzheimer’s disease. Although those compounds showed limited success in neurodegenerative clinical trials and were largely set aside, researchers have now identified a different role for BACE1 in the tumor microenvironment of glioblastoma.
BACE1 is not only present in neurons; it is also expressed by tumor-associated macrophages (TAMs), a diverse group of immune cells that populate the non-cancerous component of solid tumors. TAMs are abundant in glioblastoma and can significantly influence tumor behavior and treatment response.
There are two broad functional states of TAMs: tumor-promoting macrophages (pTAMs), which support tumor growth and therapy resistance, and tumor-suppressing macrophages (sTAMs), which can attack cancer cells and help control disease. The research led by Shideng Bao, PhD, considered whether shifting the balance from pTAMs to sTAMs could be an effective therapeutic strategy for glioblastoma.
Through a screening of small-molecule compounds, the investigators identified the BACE1 inhibitor MK-8931 (verubecestat) as a potent agent capable of reprogramming pTAMs into sTAMs. In human-derived preclinical models of glioblastoma, treatment with verubecestat increased macrophage phagocytosis of tumor cells, including glioma stem cells—an aggressive cell population capable of self-renewal and tumor repopulation.
The study reports that converting a larger portion of TAMs into tumor-suppressing cells reduced tumor growth in preclinical models. The antitumor effect was stronger when verubecestat was combined with low-dose radiation, which tends to increase TAM infiltration into tumors and thereby amplifies the drug’s impact on the immune microenvironment.
Mechanistically, the researchers found that BACE1 is more highly expressed in pTAMs than in sTAMs and participates in a signaling network involving interleukin-6 (IL-6), its soluble receptor (sIL-6R), and STAT3 (signal transducer and activator of transcription 3). This IL-6–sIL-6R–STAT3 axis supports the tumor-promoting state of pTAMs. Inhibiting BACE1 with verubecestat appears to interrupt this signaling cascade, enabling macrophages to adopt a tumor-suppressive, phagocytic phenotype.
Because verubecestat and other BACE1 inhibitors were previously developed and tested in human Alzheimer’s trials, they have available safety and pharmacology data that could accelerate translation from laboratory studies to clinical testing in oncology. Drug repurposing in this way can shorten the time and reduce the cost required to evaluate promising therapies in patients.
Kui Zhai, PhD, a postdoctoral fellow in Dr. Bao’s laboratory, is first author on the study, which received support in part from the National Institute of Neurological Disorders and Stroke (a component of the National Institutes of Health). Dr. Bao is the corresponding author and directs the Center for Cancer Stem Cell Research.
About this brain cancer research news
Author: Alicia Reale
Source: Cleveland Clinic
Contact: Alicia Reale – Cleveland Clinic
Image: The image is in the public domain
Original Research: Closed access. “Pharmacological inhibition of BACE1 suppresses glioblastoma growth by stimulating macrophage phagocytosis of tumor cells” by Kui Zhai, Zhi Huang, Qian Huang, Weiwei Tao, Xiaoguang Fang, Aili Zhang, Xiaoxia Li, George R. Stark, Thomas A. Hamilton & Shideng Bao. Nature Cancer
Abstract
Pharmacological inhibition of BACE1 suppresses glioblastoma growth by stimulating macrophage phagocytosis of tumor cells
Glioblastoma (GBM) contains abundant tumor-associated macrophages (TAMs), the majority of which are tumor-promoting (pTAMs), while tumor-suppressive macrophages (sTAMs) are less common. Reprogramming pTAMs into sTAMs represents a compelling therapeutic strategy for this malignancy.
By screening a library of small molecules, the investigators discovered that inhibition of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) with MK-8931 robustly reprograms pTAMs into sTAMs and enhances macrophage-mediated phagocytosis of glioma cells. Additionally, low-dose radiation increases TAM infiltration and synergizes with MK-8931 to suppress malignant growth more effectively.
BACE1 is preferentially expressed by pTAMs in human GBMs and helps sustain pTAM polarization via trans-IL-6–soluble IL-6 receptor (sIL-6R)–STAT3 signaling. Inhibition of BACE1 disrupts this pathway and shifts TAMs toward tumor-suppressive behavior.
Because MK-8931 and other BACE1 inhibitors were developed for Alzheimer’s disease and have been evaluated in human clinical trials, these agents could potentially be repurposed and advanced more rapidly for cancer therapy than entirely new drugs. Collectively, this work highlights a promising macrophage-based approach to treating malignant brain tumors and supports further preclinical and clinical investigation of BACE1 inhibition in glioblastoma.