Researchers working at Lerner Research Institute, Cleveland Clinic reported in the November 8, 2021, issue of Nature Cancer that an inhibitor of the beta-amyloid producing enzyme, BACE1, could reprogram tumor-promoting M2 macrophages to exert M1 tumor-suppressing activities in animal models of glioblastoma multiforme (GBM).
Glioblastomas and brain metastases are highly lethal and contain abundant macrophages, where anti-PD-1 or PD-L1 immunotherapy has failed partially due an inability to cross the blood-brain barrier and the insufficient infiltration of T cells into glioblastomas.
Macrophages constitute 5-20% of the cells in every tissue of the body, and tumor-associated macrophages have emerged as especially prominent players in brain tumors, such as glioblastoma. In some glioblastomas, tumor-associated macrophages account for more than 35% of total cells in the tumors.
Despite progress in understanding the important role of tumor-associated macrophages, including the recent appreciation of macrophage phenotypes associated with either tumor-promoting (M2) or less commonly a tumor-suppressing (M1) phenotype, glioblastoma remains a particularly challenging cancer with limited treatment options.
Because most tumor-associated macrophages in glioblastoma are tumor-promoting and have lost their ability to phagocytose tumor cells, the investigators explored whether they could identify molecules that reprogram macrophages to become capable of engulfing cancer cells by the process of phagocytosis.
The project started out with an unbiased small molecule screen using induced pluripotent stem cell (iPSC)-derived macrophages labeled with transgenic GFP (green fluorescent protein) co-cultured with glioma cells labeled with a red fluorescent protein called tdTomato. The screen was designed to identify molecules that could reprogram the macrophages to activate macrophage phagocytosis of glioma cells.
The small molecule MK-8931 (verubecestat), an inhibitor of beta-secretase 1 (BACE1), was identified as possessing potent activities stimulating macrophages to phagocytose cancer cells.
Principal investigator Shideng Bao, PhD, Director at the Center for Cancer Stem Cell Research, Lerner Research Institute, Cleveland Clinic, told BioWorld Science, "Several BACE1 inhibitors including MK-8931 have been developed for Alzheimer's disease. These inhibitors have been shown to be safe for humans in clinical trials, and they penetrate the blood-brain barrier well. These inhibitors could be potentially streamlined for cancer therapy, especially for treatment of lethal cancers including glioblastoma and brain metastases." MK-8931 was the first BACE1 inhibitor that proceeded to phase III trials.
The researchers demonstrated that inhibition of BACE1 with MK-8931 promoted macrophage phagocytosis of tumor cells and suppressed growth of malignant tumors including glioblastoma. Moreover, radiation enhanced macrophage infiltration into glioblastoma and synergized with MK-8931 treatment.
To date, the transmembrane protease BACE1 (also known as beta-site amyloid precursor protein cleaving enzyme 1), had been most prominently appreciated in the context of Alzheimer's disease since it catalyzes the reaction producing precursor part of the hallmark diagnostic feature of Alzheimer's, beta-amyloid associated plaques. However, this new discovery suggested that BACE1 may play a role in controlling the specification of macrophage to subtypes controlling tumor growth and progression.
Accordingly, the investigators performed BACE1 loss-of-function studies using short hairpin RNA to eliminate BACE1 protein expression and determined that BACE1 was required for maintaining the tumor-supportive macrophages via the trans IL-6-STAT3 signaling.
Inhibition of BACE1 with MK-8931 promoted the reprograming of tumor promoting macrophages to tumor-suppressive macrophages, which suppressed malignant growth and extended the survival of animal models of glioblastoma xenografts derived from human glioblastoma cells.
Next investigators plan to perform more preclinical studies in other models of malignant tumors and also plan to initiate a clinical trial using MK-8931 alone or in combination with radiation for glioblastoma treatment at Cleveland Clinic.
Bao's team has been focused for over a decade on the long-term goal to develop effective novel therapeutics to significantly improve the treatment for highly lethal tumors such as glioblastoma and brain metastases.Bao emphasized that, "Although these BACE1 inhibitors were not effective for treating AD in clinical trials, repurposing these drugs for cancer treatment should be straightforward. Our study offers a promising therapeutic approach to enhance the macrophage-based therapy for malignant tumors."