Abstract 4183: Targeting mTOR signaling during gliomagenesis

Abstract

Abstract Diffusely infiltrating gliomas are the most common type of primary brain tumor seen in adults. In a subset of patients, these tumors present as low grade lesions that progress to high grade glioma (HGG). Conventional treatment for gliomas includes surgical resection followed by radiation and temozolomide. Glioma cells invade peripheral brain tissue making complete surgical resection impossible and despite aggressive treatment tumor recurrence is inevitable. Current research has focused on identifying new therapeutic targets, mainly in HGG. However, investigating the therapeutic targets at early stages of gliomagenesis could provide a novel approach for the treatment of low grade gliomas (LGG). Gliomas have been characterized by gene expression profiles and classified into distinct subtypes including proneural, classical and mesenchymal. Proneural gliomas, which account for the majority of LGG, show high expression of PDGFRα and frequently harbor p53 mutations. The resulting alterations in PDGFRα signaling and inactivation of p53 both induce an upregulation in mTOR signaling, which contributes to gliomagenesis via its regulation of cell growth and proliferation. Thus, inhibiting mTOR signaling should have a robust effect on glioma growth. However, inhibiting mTOR signaling in HGG has had limited success. This may be due to the accumulation of genetic alterations that occur during glioma progression resulting in loss of sensitivity to the anti-tumor effects of mTOR inhibitors. We hypothesize that inhibiting mTOR signaling at early stages of gliomagenesis will be more effective. To test this hypothesis we are characterizing the effects of mTOR inhibition at different stages of gliomagenesis in our proneural glioma mouse model. We assessed the effects of inhibiting mTOR with the ATP-competitive mTOR inhibitor (AZD8055) in vitro and in vivo. Our preliminary data show that AZD8055 inhibits mTOR activity and reduces glioma cell viability in vitro. Inhibition of mTOR in our proneural glioma model showed that AZD8055 crosses the blood brain barrier and effectively inhibits mTOR in glioma cells within the tumor, as well as in the surrounding brain tissue. In addition, we have characterized mTOR activity at different time points in glioma formation and show upregulation of mTOR activity during early stages of gliomagenesis. Our findings support the role of mTOR in early stages of gliomagenesis and motivate our ongoing studies to test the effects of AZD8055 for the treatment of LGG. Citation Format: Daniela Torres, Angelina Mela, Canoll D. Peter. Targeting mTOR signaling during gliomagenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4183.