Abstract 354: PI-103 and TCN as proliferative inhibitors of the RTK/PI3K/ATK signaling pathways in astrocytomas

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC 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][1], 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. [1]: /lookup/external-ref?link_type=GENPEPT&access_num=OSU03012&atom=%2Fcanres%2F70%2F8_Supplement%2F354.atom