Abstract 145: PIK3CB inhibitors selectively block the survival of glioblastoma cells

Abstract

Abstract Objective: To explore the divergent role of PI3K isoforms in glioblastoma Background: Glioblastoma multiforme is the most malignant brain tumor in adults. Despite aggressive treatments, the median survival and five-year overall survival of glioblastoma patients remains low (14.6 months and 4.7%, respectively). Nearly 90% of patients experience recurrence within two years, leaving patients with few treatment options. Recently, PI3K pan inhibitors have been used to treat recurrent glioblastoma and achieved modest effect in the clinic. PI3K has four catalytic isoforms (PIK3CA, B, D, and G); hence, it is possible that these isoforms may have different roles in glioblastoma and need to be selectively targeted. This idea is further supported by our recent results, in which we have shown that elevated expression of PIK3CB, but not other PI3K isoforms, significantly correlated with higher rate, risk, and poor prognosis of recurrent glioblastomas. Hence, we hypothesize that PIK3CB-selective inhibitors are more effective for glioblastoma. Design/Methods: We used a panel of glioblastoma cells with different levels of PIK3CB, treated them with PI3K-isoform-selective inhibitors, and compared them to pan PI3K inhibitors. We measured cell viability using the MTS cell viability assay. Normal human astrocytes were used as controls to determine toxicity. Results: We found that PIK3CB inhibitors TGX-221 and GSK2636771 significantly blocked the proliferation of PIK3CB-high U87MG and SF295 cells, while it had no effect on the viability of PIK3CB-low A172 and LN229 cells. In contrast, other PI3K inhibitors and pan inhibitors either non-selectively blocked or had no effect on these cells. Importantly, these compounds, but not PIK3CB inhibitors, blocked the growth of astrocytes. Conclusions: Selective blockade of PIK3CB, but not other PI3K isoforms, is an effective therapy for glioblastoma with a low toxicity to normal tissues. Citation Format: Lamvy Le, Zhi Sheng. PIK3CB inhibitors selectively block the survival of glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 145. doi:10.1158/1538-7445.AM2017-145