Potent in vivo efficacy of oral gallium maltolate in treatment-resistant glioblastoma. Front Oncol 2023;13:1278157
Date
01/30/2024Pubmed ID
38288102Pubmed Central ID
PMC10822938DOI
10.3389/fonc.2023.1278157Scopus ID
2-s2.0-85183616626 (requires institutional sign-in at Scopus site)Abstract
BACKGROUND: Treatment-resistant glioblastoma (trGBM) is an aggressive brain tumor with a dismal prognosis, underscoring the need for better treatment options. Emerging data indicate that trGBM iron metabolism is an attractive therapeutic target. The novel iron mimetic, gallium maltolate (GaM), inhibits mitochondrial function via iron-dependent and -independent pathways.
METHODS: In vitro irradiated adult GBM U-87 MG cells were tested for cell viability and allowed to reach confluence prior to stereotactic implantation into the right striatum of male and female athymic rats. Advanced MRI at 9.4T was carried out weekly starting two weeks after implantation. Daily oral GaM (50mg/kg) or vehicle were provided on tumor confirmation. Longitudinal MRI parameters were processed for enhancing tumor ROIs in OsiriX 8.5.1 (lite) with Imaging Biometrics Software (Imaging Biometrics LLC). Statistical analyses included Cox proportional hazards regression models, Kaplan-Meier survival plots, linear mixed model comparisons, and t-statistic for slopes comparison as indicator of tumor growth rate.
RESULTS: In this study we demonstrate non-invasively, using longitudinal MRI surveillance, the potent antineoplastic effects of GaM in a novel rat xenograft model of trGBM, as evidenced by extended suppression of tumor growth (23.56 mm3/week untreated, 5.76 mm3/week treated, P < 0.001), a blunting of tumor perfusion, and a significant survival benefit (median overall survival: 30 days untreated, 56 days treated; P < 0.001). The therapeutic effect was confirmed histologically by the presence of abundant cytotoxic cellular swelling, a significant reduction in proliferation markers (P < 0.01), and vessel normalization characterized by prominent vessel pruning, loss of branching, and uniformity of vessel lumina. Xenograft tumors in the treatment group were further characterized by an absence of an invasive edge and a significant reduction in both, MIB-1% and mitotic index (P < 0.01 each). Transferrin receptor and ferroportin expression in GaM-treated tumors illustrated cellular iron deprivation. Additionally, treatment with GaM decreased the expression of pro-angiogenic markers (von Willebrand Factor and VEGF) and increased the expression of anti-angiogenic markers, such as Angiopoietin-2.
CONCLUSION: Monotherapy with the iron-mimetic GaM profoundly inhibits trGBM growth and significantly extends disease-specific survival in vivo.
Author List
Al-Gizawiy MM, Wujek RT, Alhajala HS, Cobb JM, Prah MA, Doan NB, Connelly JM, Chitambar CR, Schmainda KMAuthors
Jennifer M. Connelly MD Professor in the Neurology department at Medical College of WisconsinKathleen M. Schmainda PhD Professor in the Biophysics department at Medical College of Wisconsin
