Abstract PR002: Investigating the effect of dopamine signaling on glioblastoma development

Abstract Glioblastoma (GBM) is the deadliest form of primary brain malignancy in the adult population. Despite ongoing attempts to improve treatments for this devastating disease, the outcome of patients remains dismal, necessitating the need to reform our understanding of the tumor biology. The location of glioblastoma – the central nervous system (CNS) is known for its complex network of neurons and rapid cellular communications dispersed throughout the brain, it is thus suspected that glioblastoma might have a regional-specific incorporation of neurons, which can be harnessed to manage tumor growth. This idea led to the emergence of cancer neuroscience, where high-impact publications have shown that the activity of glutamatergic, cholinergic, serotonergic, and GABAergic neurons regulates brain tumor growth. In parallel, the Dirks lab previously interrogated 680 neurochemical compounds on patient-derived glioblastoma stem cells and found that blockade of dopamine receptor 4 (DRD4) leads to massive glioblastoma stem cell apoptosis in vitro and impaired glioblastoma growth in vivo, postulating a regulatory role of dopamine in glioblastoma progression. Thus, the current study intends to unravel the mechanism underlying the pro-survival effect of dopamine signaling on glioblastoma. And by executing targeted manipulation of dopaminergic neurons on murine models of glioblastoma through stereotaxic surgery, along with tumor monitoring using magnetic resonance imaging (MRI), we have recently found that neurotoxin-induced dopamine ablation completely inhibits glioblastoma formation in the primary dopamine-projecting area – the striatum. Strikingly, this inhibitory effect can be reversed by administration of Levedopa (L-DOPA), the immediate precursor of dopamine. Additionally, we engrafted tumor cells dissociated from mouse striatal tumors into dopamine-depleted striata of wild-type C57BL/6 mice, and by tracking cell growth with bioluminescence imaging (BLI), we here show that these cells exhibit a strong growth dependency on dopamine in vivo. Together, these findings underlie the therapeutic potential of targeting dopamine signaling in glioblastoma control and highlight the possibility of harnessing the brain’s innate neurochemical function to manage brain tumor growth. Citation Format: Yaxu-Sofia Wang, Matthaeus Ware, Lilian Lee, Heather Whetstone, Chunying Yu, Garrett Bullivant, Michelle Kushida, Sonam Dolma, Peter Dirks. Investigating the effect of dopamine signaling on glioblastoma development [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr PR002.