Reprograming Tumor-associated Macrophages and Targeting Glioma Stem Cells for Glioblastoma Treatment
Glioblastoma (GBM) is the most lethal brain tumor containing tumorigenic glioma stem cells (GSCs) and abundant tumor-associated macrophages (TAMs). Because most TAMs are tumor-promoting macrophages (pTAMs), reprograming pTAMs into tumor-suppressive TAMs (sTAMs) represents an attractive therapeutic strategy. As pTAMs actively interact with GSCs to promote tumor growth and therapeutic resistance, redirecting pTAMs into sTAMs may synergize with targeting GSCs to suppress GBM growth. To identify small molecules that can reprogram pTAMs into sTAMs, we discovered that inhibiting BACE1 by MK-8931 potently redirected pTAMs into sTAMs and promoted macrophage phagocytosis to suppress GBM growth. Moreover, we found that low-dose radiation markedly enhanced TAM infiltration and synergized with MK-8931 treatment. As MK-8931 was shown to be safe for Alzheimer’s disease patients, MK-8931 can be potentially streamlined for GBM therapy. In addition, we found that BMX maintains GSC tumorigenic potential by activating STAT3, and targeting BMX with ibrutinib suppressed GBM growth and impaired radioresistance. As ibrutinib and MK-8931 penetrate the blood-brain barrier very well, repurposing these drugs for GBM treatment should be straightforward. We hypothesize that reprograming pTAMs into sTAMs by MK-9831 synergizes with targeting GSCs by ibrutinib to suppress malignant growth. We will accomplish our objectives through two Aims: (1) Assess the effect of reprograming pTAMs into sTAMs on cytokine profile and GSC maintenance; and (2) Evaluate the therapeutic impact of reprograming pTAMs to sTAMs and targeting GSCs for GBM treatment. The goal is to determine whether synergistically reprograming TAMs and targeting GSCs can serve as a novel therapeutic strategy for GBM.
Our goal is to determine the therapeutic impact of targeting human stem cells and reprograming tumor-associated macrophages can have on improving brain cancer treatment. We want to develop more effective therapeutics to improve the treatment of brain cancer.