A growing body of work suggests that astrocytomas and glioblastoma multiforme will require carefully tailored, molecularly targeted therapy for successful treatment. Recent efforts to comprehensively identify mutations and gene expression changes in glioblastoma have shown that mutation of NF1 is a common alteration in human glioblastoma. We have developed and characterized a panel of 14 tumor lines from grades II through IV astrocytomas developed from our Nf1-/+;Trp53-/+cis mouse model and have used this panel to characterize signal transduction pathways and inhibitors that are candidate therapeutic targets for astrocytoma and glioblastoma. We show that these tumors express platelet-derived growth factor receptor-α, epidermal growth factor receptor, and their respective ligands to varying degrees. We find that both the MEK and PI3K signaling pathways downstream of epidermal growth factor receptor and platelet-derived growth factor receptor-α are necessary for full proliferation of astrocytoma cells; however, inhibition of the PI3K pathway is more effective than inhibition of MEK at blocking cell growth. We have examined inhibitors of the PI3K/Akt/mTOR signaling pathway and find that PI-103 and TCN show particular promise for inhibiting growth in Nf1 and Trp53 mutant astrocytoma cells.
INTRODUCTION: Glioblastomas (GBMs), the most aggressive of malignant astrocytomas, are recurrent, infiltrative, and fatal. In GBMs, receptor tyrosine kinases (RTKs) are often mutated and activated, leading to the dysregulation of normal cell signaling pathways. The PI3K/Akt1/mTOR pathway, which is important in normal biological events such as proliferation, survival, invasion, migration and angiogenesis, is often deregulated in malignant cancers, resulting from the simultaneous loss of tumor suppressor PTEN, and the hyperactivation of the Akt pathway. Therefore, pharmacological inhibition of the PI3K/Akt1/mTOR may prove beneficial in arresting the proliferation of astrocytomas and glioblastomas. METHODS: In order to determine if the selected inhibitors PIA-6, OSU03012, Rapamycin, Tricribine (TCN), and PI-103 had an effect on the PI3K/Akt-1/mTOR pathway, we examined their inhibitory effects on mouse astrocytoma cell lines K1861-10 Grade II; KR158 Grade III; K130G#3 Grade IV; human astrocytoma cell lines, U87MG and SF295, both Grades IV; and normal proliferating mouse primary astrocytes using the Alamar blue assay as a measure of metabolic activity and proliferation. Inhibitors with low IC50 values in tumor cells as compared to normal primary astrocytes were favored. RESULTS: From the select panel of inhibitors, only the AKT inhibitor TCN and dual PI3K/mTor inhibitor PI-103 showed low IC50 values in the nM or pM range, suggesting strong inhibition of proliferation in the astrocytoma cell lines tested. Rapamycin, an mTOR inhibitor, showed inconsistent inhibition of cell proliferation on the cell lines tested, although mTor activity was effectively inhibited, suggesting that inhibitory effects of rapamycin at higher concentrations may be acting via different pathways. CONCLUSIONS: Our results support the hypothesis that the PI3K/Akt1/mTOR pathway is a potential druggable target in astrocytomas and glioblastomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 354.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.