2 research outputs found
Novel dopamine receptor 3 antagonists inhibit the growth of primary and temozolomide resistant glioblastoma cells.
Treatment for the lethal primary adult brain tumor glioblastoma (GBM) includes the chemotherapy temozolomide (TMZ), but TMZ resistance is common and correlates with promoter methylation of the DNA repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT). To improve treatment of GBMs, including those resistant to TMZ, we explored the potential of targeting dopamine receptor signaling. We found that dopamine receptor 3 (DRD3) is expressed in GBM and is also a previously unexplored target for therapy. We identified novel antagonists of DRD3 that decreased the growth of GBM xenograft-derived neurosphere cultures with minimal toxicity against human astrocytes and/or induced pluripotent stem cell-derived neurons. Among a set of DRD3 antagonists, we identified two compounds, SRI-21979 and SRI-30052, that were brain penetrant and displayed a favorable therapeutic window analysis of The Cancer Genome Atlas data demonstrated that higher levels of DRD3 (but not DRD2 or DRD4) were associated with worse prognosis in primary, MGMT unmethylated tumors. These data suggested that DRD3 antagonists may remain efficacious in TMZ-resistant GBMs. Indeed, SRI-21979, but not haloperidol, significantly reduced the growth of TMZ-resistant GBM cells. Together our data suggest that DRD3 antagonist-based therapies may provide a novel therapeutic option for the treatment of GBM
Identification of Compounds That Decrease Glioblastoma Growth and Glucose Uptake <i>in Vitro</i>
Tumor heterogeneity has hampered
the development of novel effective
therapeutic options for aggressive cancers, including the deadly primary
adult brain tumor glioblastoma (GBM). Intratumoral heterogeneity is
partially attributed to the tumor initiating cell (TIC) subset that
contains highly tumorigenic, stem-like cells. TICs display metabolic
plasticity but can have a reliance on aerobic glycolysis. Elevated
expression of GLUT1 and GLUT3 is present in many cancer types, with
GLUT3 being preferentially expressed in brain TICs (BTICs) to increase
survival in low nutrient tumor microenvironments, leading to tumor
maintenance. Through structure-based virtual screening (SBVS), we
identified potential novel GLUT inhibitors. The screening of 13 compounds
identified two that preferentially inhibit the growth of GBM cells
with minimal toxicity to non-neoplastic astrocytes and neurons. These
compounds, SRI-37683 and SRI-37684, also inhibit glucose uptake and
decrease the glycolytic capacity and glycolytic reserve capacity of
GBM patient-derived xenograft (PDX) cells in glycolytic stress test
assays. Our results suggest a potential new therapeutic avenue to
target metabolic reprogramming for the treatment of GBM, as well as
other tumor types, and the identified novel inhibitors provide an
excellent starting point for further lead development