https://doi.org/10.1016/j.apsb.2023.09.009
Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and is poorly controlled. Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression, and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment.
Therefore, this study developed a novel and selective inhibitor of CSF1R and VEGFR, SYHA1813, possessing potent antitumor activity against GBM. SYHA1813 inhibited VEGFR and CSF1R kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo. SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models, including temozolomide (TMZ) insensitive tumors.
Notably, SYHA1813 could penetrate the blood–brain barrier (BBB) and prolong the survival time of mice bearing intracranial GBM xenografts. Moreover, SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody. As a clinical proof of concept, SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial.
Keywords: Small molecule inhibitor, Glioblastoma, VEGFR, CSF1R, Angiogenesis, Macrophage, Tumor microenvironment, Immune-checkpoint inhibitor
Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S2211383523003635-ga1_lrg.jpg
SYHA1813 exerts anti-tumor effects by simultaneously inhibiting angiogenesis and affecting tumor-associated macrophages and shows the therapeutic potential of glioma by efficiently crossing the blood–brain barrier.
