Abstract 1171: Identifying small molecules that specifically inhibit glioma stem cells

Glioblastomas (GBM) are the most common primary malignant brain tumor in adults and are recognized as one of the deadliest forms of cancer. Despite aggressive therapy consisting of maximal surgical resection followed by concomitant radiation and temozolomide (TMZ) chemotherapy, GBM remains to have a median survival time of ~ 15 months. Glioblastoma stem cells (GSCs) are suggested to play a critical role in the GBM phenotype; GSC have tumor initiation ability, propagation ability, and have been shown to be a driver in promoting GBM resistance to current therapeutic interventions. Due to these poor clinical outcomes and resistance to current treatments, more potent and preferably more specific pharmacological therapies are needed in order to target cellular-molecular pathways to eradicate GSCs and effectively treat GBM. In an effort to identify agents that specifically inhibit GSC growth, we recently conducted a drug screen of over 3,000 small molecules. HSR020913 patient derived neurospheres were treated for 72 hours with library agents at a concentration of 10 µM and cell growth was observed for a period of 5 days. We identified twelve highly potent compounds in the primary screen that inhibited the growth of HSR020913 neurospheres by over 50%. Subsequently, the potency of these compounds was tested on five additional GBM patient derived neurosphere lines (HSR040622, HSR040822, CCF3691, CCF3832, and CCF08-387) at even lower concentrations. We next sought to determine the specificity of these compounds in killing GSCs but not normal cells. To this aim we tested these compounds against immortalized human neural stem cells (v-Myc hNSCs) and normal human astrocytes (NHA). Of the twelve potent compounds identified in the primary screen, three compounds (AGSC9, AGSC11, AGSC12) showed to have negligible to minimal effect, only at higher doses, on normal neural stem cells. The respective half maximal inhibitory concentration (IC50) was determined for all the neurosphere lines utilized. Subsequent studies determined the inhibitory effect of these compounds on clonogenic capacity and enzymatic activity. Future studies are warranted to identify molecular pathways targeted by these compounds and determine their effect on tumor progression and survival in vivo. Citation Format: Anthony R. Sloan, Raffaella Spina, Dillon M. Voss, Sophie Laye, Eli E. Bar. Identifying small molecules that specifically inhibit glioma stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1171.