Abstract Background: GBM is the most common primary brain malignancy with dismal prognosis. Current standard of care is chemoradiation&surgery. The main issue with GBM is the resistance & recurrence. GBM can have high Ferritin levels associated with disease progression & immunosuppression in the GBM TME. Ferritin light chain (FTL), a key protein in iron metabolism, is mutated in GBM leading to high ferritin levels (both light& heavy chain) & is associated with poor survival of (GBM) patients in part due to inhibition of ferroptosis. Panobinostat is a histone deacetylase inhibitor with antineoplastic & antiangiogenic effects in glioma. Imipridone ONC206 is under Phase I clinical development in treatment of adult & pediatric patients with newly diagnosed and/or recurrent primary brain tumors (NCT04732065 and NCT04541082).We investigated the novel combination of irradiation, Panobinostat and ONC206 with regard to GBM cell line sensitivity&ferritin levels. Materials & methods: We investigated cell viability and drug synergies of ONC206 plus Panobinostat with or without radiation in 4 human GBM cell lines at 72 hours. Changes in Ferritin level treatment in U87 & U251 cells were measured using cytokine profiling at 24 h time point. Information regarding recurrent cases of adult GBM from TCGA &GlioVis were used for survival data. Results: We previously have shown the synergy between Panobinostat, Irradiation and ONC206 (2023 AACR meeting). Treatment of U87 cells with Panobinostat and ONC206 at their IC50s +/- 4 Gy radiation at 24h time point led to reduction in secreted ferritin levels (Panobinostat alone: 26.3% decrease; ONC206 alone: 14.7% decrease; RT 4Gy alone 14.7% decrease; triple therapy: 32.2% decrease). In panobinostat treated U251 cells there was a 10% increase in ferritin at 24 h. ONC206 resulted in a reduction by 34.71%, 4 Gy RT caused a slight increase of 4% in ferritin amount while the triple showed 49.96% reduction in ferritin levels. mRNA expression of FTL gene (Ferritin Light Chain) is significantly higher in GBM tumors compared to normal brain tissue. From TCGA 17 cases of recurrent gliomas with FTL mutation were available with median survival of less than a year. In data from GlioVis of recurrent GBM cases 263 patients had high FTL with median survival of 12.6 months compared to 262 patients with low FTL with median survival of 14.9 months. Conclusions: GBM with high ferritin correlates with poor patient survival. FTL is associated with cell proliferation &angiogenesis of GBM cells & is protective from ferroptosis in glioma cells. ferritin may be a therapeutic target in recurrent & therapy resistant cases of GBM and ferroptosis modulating drugs &can be a novel treatment option. ONC206 & Panobinostat with irradiation is a novel combination & can be considered for temozolomide or radiation-resistant & recurrent cases. More studies are needed to investigate the mechanism & impact of ferritin in disease progression, therapy resistance& ferroptosis targeting therapeutics. We are currently exploring these directions including in vivo studies. Citation Format: Vida Tajiknia, Wafik El Deiry, Lanlan Zhou, William Macdonald, Praveen Srinivasan. Ferritin, associated with worse overall survival in recurrent GBM, is reduced by combination of HDACi, ONC206 and radiation [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A050.
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