Abstract 5362: Targeting PIK3CB in glioblastoma

Abstract

Abstract Background: Glioblastoma (GBM) is the most common and one of the most lethal malignant brain tumors in existence. The poor prognosis of this disease is due in part to tumor recurrence and temozolomide (TMZ) resistance, for which PI3K/AKT pathway overactivation has been implicated. Our work is to demonstrate that p110β inhibition could represent a therapeutic target in sensitizing recurrent tumors to TMZ therapy, and demonstrate the utility of personalized GBM treatments. Objective: We aim to develop a more effective treatment for TMZ resistant GBM patients. We hypothesize that a p110β inhibitor will sensitize resistant GBM cell lines to TMZ therapy. We intend to support this hypothesis by demonstrating that the p110β inhibitor TGX-221 in combination with TMZ will provide a significantly greater level of cytotoxicity on TMZ resistant GBM cell lines than TGX-221 or TMZ monotherapy alone. We also intend to provide further evidence for this therapy by utilizing it to overcome TMZ resistance in glioblastoma stem cells (GSC’s). Methods: We compared the cytotoxicity of TMZ, TGX-221, and a TMZ/TGX-221 combination therapy on p110β-high/TMZ resistant and p110β-low/TMZ sensitive GBM cell lines. Cell viability was determined using the MTS assay. We then tested these reagents on normal human astrocytes to determine any potential dose-limiting off-target effects. Lastly, we tested these reagents using human-derived GSC’s. Results: A statistically significant difference (p < 0.01) in cell viability was found using the TMZ/TGX-221 combination therapy as compared to either TMZ or TGX-221 alone in our TMZ resistant SF295 cells, and a significant different was found between the combination therapy and TMZ monotherapy in our TMZ resistant U87MG cells. No significant difference was found between treatments in our TMZ sensitive A172 cells or normal human astrocytes. Conclusions: The results of our GBM cell line experiments provide support that combination TMZ/TGX-211 is superior in cytotoxicity to either monotherapy alone in TMZ resistant cell lines. This indicates that TGX-211, through p110β inhibition, is able to sensitize resistant cell lines to TMZ therapy. More experiments are ongoing to determine if this effect will also be demonstrated in human-derived GSC’s. Citation Format: Marc R. Fromherz, Kevin J. Pridham, Zhi Sheng. Targeting PIK3CB in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5362.